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Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20–35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0–24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0–24 following a VAN LD of 20 mg/kg. Methods: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0–24. Therapeutic AUC0–24 was defined as 400–600 mg/l*h. Results: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0–24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0–24, patients with subtherapeutic AUC0–24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0–24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0–24. Conclusions: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations. [ABSTRACT FROM AUTHOR]

Glioblastoma remains a devastating disease with a bleak prognosis despite continued research and numerous clinical trials. Convection-enhanced delivery offers researchers and clinicians a platform to bypass the blood–brain barrier and administer drugs directly to the brain parenchyma. While not without significant technological challenges, convection-enhanced delivery theoretically allows for a wide range of therapeutic agents to be delivered to the tumoral space while preventing systemic toxicities. This article provides a comprehensive review of the antitumor agents studied in clinical trials of convection-enhanced delivery to treat adult high-grade gliomas. Agents are grouped by classes, and preclinical evidence for these agents is summarized, as is a brief description of their mechanism of action. The strengths and weaknesses of each clinical trial are also outlined. By doing so, the difficulty of untangling the efficacy of a drug from the technological challenges of convection-enhanced delivery is highlighted. Finally, this article provides a focused review of some therapeutics that might stand to benefit from future clinical trials for glioblastoma using convection-enhanced delivery. [ABSTRACT FROM AUTHOR]

Purpose: The goal was to assess, for lipophilic drugs, the impact of logP on human volume of distribution at steady-state (VDss) predictions, including intermediate fut and Kp values, from six methods: Oie-Tozer, Rodgers-Rowland (tissue-specific Kp and only muscle Kp), GastroPlus, Korzekwa-Nagar, and TCM-New. Method: A sensitivity analysis with focus on logP was conducted by keeping pKa and fup constant for each of four drugs, while varying logP. VDss was also calculated for the specific literature logP values. Error prediction analysis was conducted by analyzing prediction errors by source of logP values, drug, and overall values. Results: The Rodgers-Rowland methods were highly sensitive to logP values, followed by GastroPlus and Korzekwa-Nagar. The Oie-Tozer and TCM-New methods were only modestly sensitive to logP. Hence, the relative performance of these methods depended upon the source of logP value. As logP values increased, TCM-New and Oie-Tozer were the most accurate methods. TCM-New was the only method that was accurate regardless of logP value source. Oie-Tozer provided accurate predictions for griseofulvin, posaconazole, and isavuconazole; GastroPlus for itraconazole and isavuconazole; Korzekwa-Nagar for posaconazole; and TCM-New for griseofulvin, posaconazole, and isavuconazole. Both Rodgers-Rowland methods provided inaccurate predictions due to the overprediction of VDss. Conclusions: TCM-New was the most accurate prediction of human VDss across four drugs and three logP sources, followed by Oie-Tozer. TCM-New showed to be the best method for VDss prediction of highly lipophilic drugs, suggesting BPR as a favorable surrogate for drug partitioning in the tissues, and which avoids the use of fup. [ABSTRACT FROM AUTHOR]

This commentary further reflects on the paper of De Sutter et al. on predicting volume of distribution in neonates, and the performance of physiologically based pharmacokinetic models We hereby stressed the add on value to collaborate on real world data to further close this knowledge gap. We illustrated this by weight distribution characteristics in breastfed (physiology) and in asphyxiated (pathophysiology), with additional reflection on their kidney and liver function. [ABSTRACT FROM AUTHOR]

Purpose: To develop a population pharmacokinetic (PPK) model for methotrexate (MTX) dosage for all ages, assess the association between concentration and clearance, and determine covariates affecting MTX disposition. Methods: We compared MTX PK profiles among neonates, children, and adults by performing a systematic literature search for published population MTX models and conducted a Monte Carlo-based meta-analysis. Subsequently, we evaluated study quality and covariates significantly affecting dosage regimens and compared LDMTX and HDMTX PK profiles. Results: Of the total 40 studies included, 34 were HDMTX, and six were LDMTX studies. For HDMTX, three studies involving neonates reported estimated apparent clearances (median, range) of 0.53 (0.27–0.77) L/kg/h; for 14 studies involving children, 0.23 (0.07–0.23) L/kg/h; and for 13 involving adults, 0.11 (0.03–0.22) L/kg/h. Neonates had a higher volume of distribution than children and adults. For LDMTX studies, apparent clearance was 0.085 (0.05–1.68) L/kg/h, and volume of distribution was 0.25 (0.018–0.47) L/kg, lower than those of HDMTX studies, with large between-subject variability. Bodyweight significantly influenced apparent clearance and volume of distribution, whereas renal function mainly influenced clearance. Mutations in certain genes reduced MTX clearance by 8–35.3%, whereas those in others increased it by 15–48%. Body surface area (BSA) significantly influenced apparent clearance with a median reduction of 51% when BSA increased in pediatric patients. Conclusions: Methotrexate dosage regimens were primarily based on body surface area and renal function. Further studies are needed to evaluate MTX pharmacokinetics and pharmacodynamics in both children (especially infants) and adults. [ABSTRACT FROM AUTHOR]

Toxic ingestions are a significant cause of pediatric morbidity and mortality, with some requiring extracorporeal removal for therapy. Given the emergent and life-threatening nature of such scenarios, it is paramount that clinicians caring for intoxicated children be familiar with the subject. This review summarizes the following: (a) the properties of a substance which lend it amenable to removal; (b) the current extracorporeal treatment modalities available for such removal (of which hemodialysis is typically the ideal choice); (c) an introduction and framework to use a quick reference guide from the Extrip organization, which has a website available to guide clinicians' rapid decisions; and (d) new membranes/approaches that may optimize clearance of certain intoxications. [ABSTRACT FROM AUTHOR]

Background: In acute-on-chronic liver failure (ACLF), adequate antibiotic dosing is challenging due to changes of drug distribution and elimination. We studied the pharmacokinetics of linezolid in critically ill patients with ACLF during continuous renal replacement therapy compared to patients without concomitant liver failure (NLF). Methods: In this prospective cohort study, patients received linezolid 600 mg bid. Linezolid serum samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modelling was performed followed by Monte-Carlo simulations of 150 mg bid, 300 mg bid, 450 mg bid, 600 mg bid, and 900 mg bid to assess trough concentration target attainment of 2–7 mg/L. Results: Eighteen patients were included in this study with nine suffering from ACLF. Linezolid body clearance was lower in the ACLF group with mean (standard deviation) 1.54 (0.52) L/h versus 6.26 (2.43) L/h for NLF, P < 0.001. A trough concentration of 2–7 mg/L was reached with the standard dose of 600 mg bid in the NLF group in 47%, with 42% being underexposed and 11% overexposed versus 20% in the ACLF group with 77% overexposed and 3% underexposed. The highest probability of target exposure was attained with 600 mg bid in the NLF group and 150 mg bid in the ACLF group with 53%. Conclusion: Linezolid body clearance in ACLF was markedly lower than in NLF. Given the overall high variability, therapeutic drug monitoring (TDM) with dose adjustments seems required to optimize target attainment. Until TDM results are available, a dose reduction may be considered in ACLF patients to prevent overexposure. [ABSTRACT FROM AUTHOR]

The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82–0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data. [ABSTRACT FROM AUTHOR]

Methods for extrapolating measured in vitro intrinsic clearance to a whole‐body biotransformation rate constant (kB) have been developed to support modeled bioaccumulation assessments for fish. The inclusion of extrapolated kB values into existing bioaccumulation models improves the prediction of chemical bioconcentration factors (BCFs), but there remains a tendency for these methods to overestimate BCFs relative to measured values. Therefore, a need exists to evaluate the extrapolation procedure to assess potential sources of error in predicted kB values. We examined how three different approaches (empirically based, composition based, and polyparameter linear free energy relationships [ppLFERs]) used to predict chemical partitioning in vitro (liver S9 system; KS9W), in blood (KBW), and in whole fish tissues (KFW) impact the prediction of a chemical's hepatic clearance binding term (fU) and apparent volume of distribution (VD), both of which factor into the calculation of kB and the BCF. Each approach yielded different KS9W, KBW, and KFW values, but resulted in fU values that were of similar magnitude and remained relatively constant at log octanol–water partition ratios (KOW) greater than 4. This is because KBW and KS9W values predicted by any given approach exhibit a similar dependence on log KOW (i.e., regression slope), which results in a cancelation of "errors" when fU is calculated. In contrast, differences in KBW values predicted by the three approaches translate to differences in VD, and by extension kB and the BCF, which become most apparent at log KOW greater than 6. There is a need to collect KBW and VD data for hydrophobic chemicals in fish that can be used to evaluate and improve existing partitioning prediction approaches in extrapolation models for fish. Environ Toxicol Chem 2023;42:33–45. © 2022 SETAC [ABSTRACT FROM AUTHOR]

Objective(s): Diabetes mellitus (DM) affects the pharmacokinetics of drugs. Ranolazine is an antianginal drug that is prescribed in DM patients with angina. We decided to evaluate the effect of DM on the pharmacokinetics of ranolazine and its major metabolite CVT-2738 in rats. Materials and Methods: Male rats were divided into two groups: DM (induced by 55 mg/kg Streptozotocin (STZ)) and non-DM. All animals were treated with 80 mg/kg of ranolazine for 7 continuous days. The blood samples were collected immediately at 0 (prior to dosing), 1, 2, 3, 4, 8, and 12 hr after administration of the 7th dose of ranolazine. Serum ranolazine and CVT-2738 concentrations were determined using the high-performance liquid chromatography (HPLC) method. Pharmacokinetic parameters were calculated using a non-compartmental model and compared between the two groups. Results: The peak serum concentration (Cmax) and area under the curve (AUC) of ranolazine significantly decreased in DM compared with non-DM rats. DM rats showed significantly higher volumes of distribution (Vd) and clearance (CL) of ranolazine than non-DM rats. DM did not affect Ke, Tmax, and T1/2 of ranolazine. The concentration of metabolite was lower than the HPLC limit of detection (LOD). Conclusion: It was found that streptozotocin-induced DM increased Vd and CL of ranolazine, thereby decreasing the AUC of the drug. Therefore, dosage adjustment may be necessary for DM patients, which requires further clinical studies. [ABSTRACT FROM AUTHOR]

Valsartan is an antihypertensive drug that was developed using common marmosets (Callithrix jacchus) in pivotal toxicity studies as a non-rodent species. The aim of the present study was to investigate the utility of marmosets in the candidate selection of this drug from a pharmacokinetic and metabolic viewpoint. Valsartan, as well as three other angiotensin II type-I receptor blockers, assumed as competitive candidates, were administered to common marmosets. Human pharmacokinetic parameters predicted by single-species allometric scaling and Wajima superposition suggested that valsartan may exhibit promising pharmacokinetic properties in humans. In vitro metabolic studies of valsartan using isolated rat, dog, marmoset, cynomolgus monkey, and human hepatocytes revealed that the marmoset was the most relevant animal species to humans presenting with the most abundant human metabolite, 4-hydroxyvalsartan. Oral administration of an elevated dose of valsartan to a common marmoset demonstrated that the level of 4-hydroxyvalsartan in the plasma was comparable to that in clinical practice and suggested that safety of the human metabolite might have been confirmed in the toxicity studies using common marmosets. These results suggest that common marmosets, the small, non-human primates, had been a suitable species for the development of valsartan. [ABSTRACT FROM AUTHOR]

Volume of distribution at steady state (Vss) is an important pharmacokinetic endpoint. In this study we apply machine learning and conformal prediction for human Vss prediction, and make a head-to-head comparison with rat-to-man scaling, allometric scaling and the Rodgers-Lukova method on combined in silico and in vitro data, using a test set of 105 compounds with experimentally observed Vss. The mean prediction error and % with <2-fold prediction error for our method were 2.4-fold and 64%, respectively. 69% of test compounds had an observed Vss within the prediction interval at a 70% confidence level. In comparison, 2.2-, 2.9- and 3.1-fold mean errors and 69, 64 and 61% of predictions with <2-fold error was reached with rat-to-man and allometric scaling and Rodgers-Lukova method, respectively. We conclude that our method has theoretically proven validity that was empirically confirmed, and showing predictive accuracy on par with animal models and superior to an alternative widely used in silico-based method. The option for the user to select the level of confidence in predictions offers better guidance on how to optimise Vss in drug discovery applications. [ABSTRACT FROM AUTHOR]

The pharmacokinetic characteristics of toltrazuril (TZR) and its metabolites toltrazuril sulphoxide (TZR.SO) and toltrazuril sulphone (TZR.SO2) were assessed in non-pregnant and pregnant goats. Ten healthy Baladi female goats were allocated into two groups (n = 5 per group): non-pregnant goats (group 1) and pregnant goats at 2-3 months of gestation (group 2). Toltrazuril was administered once orally to all goats at 20 mg/kg. Plasma samples were collected at 0 (before TZR administration), 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 h and 5, 7, 9, 12, 16, 20, 24, 27, 30, and 35 days post therapy to measure the concentrations of TZR and its metabolites. In pregnant goats, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and the area under the plasma concentration-time curve from time zero to the last sample (AUC0-last) of TZR were significantly higher (P < 0.05) compared to the non-pregnant ones, whereas the volume of distribution (Vz_F_obs) and clearance (Cl_F_obs) were significantly lower (P < 0.05) in pregnant goats. No significant differences were observed in the elimination half-life (T1/2λz), and mean residence time (MRT) between the two groups. In non-pregnant goats, TZR.SO and TZR.SO2 could be detected in plasma until 12 and 30 days, respectively; whereas in pregnant goats, they were quantified up to 16 and 35 days, respectively. Conclusively, TZR was well absorbed and rapidly metabolized to TZR.SO and TZR.SO2, after oral dosing in goats. Pregnancy caused significant alterations in some of the pharmacokinetic indicators of TZR and its metabolites in goats. [ABSTRACT FROM AUTHOR]

The pharmacokinetic characteristics of toltrazuril (TZR) and its metabolites toltrazuril sulphoxide (TZR.SO) and toltrazuril sulphone (TZR.SO2) were assessed in non-pregnant and pregnant goats. Ten healthy Baladi female goats were allocated into two groups (n = 5 per group): non-pregnant goats (group 1) and pregnant goats at 2–3 months of gestation (group 2). Toltrazuril was administered once orally to all goats at 20 mg/kg. Plasma samples were collected at 0 (before TZR administration), 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 h and 5, 7, 9, 12, 16, 20, 24, 27, 30, and 35 days post therapy to measure the concentrations of TZR and its metabolites. In pregnant goats, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and the area under the plasma concentration-time curve from time zero to the last sample (AUC0-last) of TZR were significantly higher (P < 0.05) compared to the non-pregnant ones, whereas the volume of distribution (Vz_F_obs) and clearance (Cl_F_obs) were significantly lower (P < 0.05) in pregnant goats. No significant differences were observed in the elimination half-life (T1/2λz), and mean residence time (MRT) between the two groups. In non-pregnant goats, TZR.SO and TZR.SO2 could be detected in plasma until 12 and 30 days, respectively; whereas in pregnant goats, they were quantified up to 16 and 35 days, respectively. Conclusively, TZR was well absorbed and rapidly metabolized to TZR.SO and TZR.SO2, after oral dosing in goats. Pregnancy caused significant alterations in some of the pharmacokinetic indicators of TZR and its metabolites in goats. The pharmacokinetic characteristics of toltrazuril (TZR) and its metabolites toltrazuril sulphoxide (TZR.SO) and toltrazuril sulphone (TZR.SO2) were assessed in non-pregnant and pregnant goats. Ten healthy Baladi female goats were allocated into two groups (n = 5 per group): non-pregnant goats (group 1) and pregnant goats at 2–3 months of gestation (group 2). Toltrazuril was administered once orally to all goats at 20 mg/kg. Plasma samples were collected at 0 (before TZR administration), 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72 h and 5, 7, 9, 12, 16, 20, 24, 27, 30, and 35 days post therapy to measure the concentrations of TZR and its metabolites. In pregnant goats, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and the area under the plasma concentration-time curve from time zero to the last sample (AUC0-last) of TZR were significantly higher (P < 0.05) compared to the non-pregnant ones, whereas the volume of distribution (Vz_F_obs) and clearance (Cl_F_obs) were significantly lower (P < 0.05) in pregnant goats. No significant differences were observed in the elimination half-life (T1/2λz), and mean residence time (MRT) between the two groups. In non-pregnant goats, TZR.SO and TZR.SO2 could be detected in plasma until 12 and 30 days, respectively; whereas in pregnant goats, they were quantified up to 16 and 35 days, respectively. Conclusively, TZR was well absorbed and rapidly metabolized to TZR.SO and TZR.SO2, after oral dosing in goats. Pregnancy caused significant alterations in some of the pharmacokinetic indicators of TZR and its metabolites in goats. [ABSTRACT FROM AUTHOR]

Aims: For a given passively‐distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, Vd) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in Vd associated with obesity across a series of drugs. Methods: Cohorts of normal‐weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil). Lipid solubility was measured by the log‐transformed values of the high‐pressure liquid chromatographic (HPLC) retention index (Log10(HPLC)), and the octanol–water partition coefficient (LogP). Results: Among normal‐weight controls, Vd normalized for protein binding was highly correlated with Log10(HPLC) (R2 =.65) and with LogP (R2 =.78). Vd of all drugs was increased in the obese cohort, but the relative increase (compared to controls) for individual drugs was disproportionately greater as lipid solubility increased. Since clearance was unrelated to lipophilicity, the increased Vd produced a parallel disproportionate increase in elimination half‐life in the obese cohort that was associated with Log10(HPLC) (R2 =.62). Conclusion: Lipophilicity is a principal correlate of in vivo Vd, as well as the increased Vd of drugs in obese patients. The consequent prolongation of half‐life in obesity has clinical safety implications in terms of delayed drug accumulation and washout during and after chronic dosage. The magnitude and importance of this effect for a given drug depends on the degree of obesity, as well as the lipid‐solubility of the specific drug. [ABSTRACT FROM AUTHOR]

Background: Little is known about effects of factors such as kidney disease, affecting ampicillin pharmacokinetics in dogs. Objectives: Determine the pharmacokinetics of ampicillin after a single intravenous dose in healthy and azotemic dogs. Animals Nine dogs presenting with acute kidney injury and 10 healthy dogs. Methods: This was a prospective study. An ampicillin dose of 22.2 mg/kg (mean dose) was administered once intravenously. Blood samples were obtained at timed intervals (just before administration, 1, 2, 4, 12, and 24 hours), analyzed using high‐pressure liquid chromatography followed by pharmacokinetic analysis of the plasma drug concentrations. Results: Peak ampicillin concentration (mcg/mL; 97.07 (36.1) vs 21.3 (50.26)), P<.001 (geometric mean (coefficient of variation, CV%)), half‐life (hours; 5.86 (56.55) vs 0.97 (115.3)), P<.001) and AUC (h × mcg/mL; 731.04 (83.75) vs 33.57 (53.68)), P<.001) were greater in azotemic dogs than in healthy dogs. Azotemic dogs also had significantly lower clearance (30.06 (84.19) vs 655.03 (53.67); mL/kg h, P <.001) and volume of distribution (253.95 (30.14) vs 916.93 (135.24); mL/kg, P <.001) compared to healthy dogs. Conclusion and Clinical Importance: Increased drug concentrations and slower clearance of ampicillin in azotemic dogs could have clinical importance in contributing to antibiotic associated morbidity requiring indicating the need to adjust ampicillin dosing in dogs with decreased kidney function. [ABSTRACT FROM AUTHOR]

This tutorial introduces background and methods to predict the human volume of distribution (Vd) of drugs using in vitro and animal pharmacokinetic (PK) parameters. The physiologically based PK (PBPK) method is based on the familiar equation: Vd = Vp + ΣT(VT × ktp). In this equation, Vp (plasma volume) and VT (tissue volume) are known physiological values, and ktp (tissue plasma partition coefficient) is experimentally measured. Here, the ktp may be predicted by PBPK models because it is known to be correlated with the physicochemical property of drugs and tissue composition (fraction of lipid and water). Thus, PBPK models' evolution to predict human Vd has been the efforts to find a better function giving a more accurate ktp. When animal PK parameters estimated using i.v. PK data in = 3 species are available, allometric methods can also be used to predict human Vd. Unlike the PBPK method, many different models may be compared to find the best-fitting one in the allometry, a kind of empirical approach. Also, compartmental Vd parameters (e.g., Vc, Vp, and Q) can be predicted in the allometry. Although PBPK and allometric methods have long been used to predict Vd, there is no consensus on method choice. When the discrepancy between PBPK-predicted Vd and allometry-predicted Vd is huge, physiological plausibility of all input and output data (e.g., r²-value of the allometric curve) may be reviewed for careful decision making. [ABSTRACT FROM AUTHOR]

Background: Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Adequate dosing of antimicrobial therapy is of central importance to improve outcome. Liver failure may alter antibiotic drug concentrations via changes of drug distribution and elimination. We studied the pharmacokinetics of meropenem in critically ill patients with ACLF during continuous veno-venous hemodialysis (CVVHD) and compared it to critically ill patients without concomitant liver failure (NLF). Methods: In this prospective cohort study, patients received meropenem 1 g tid short-term infusion (SI). Meropenem serum samples were analyzed by high-performance liquid chromatography. A population pharmacokinetic analysis was performed followed by Monte Carlo simulations of (A) meropenem 1 g tid SI, (B) 2 g loading plus 1 g prolonged infusion tid (C) 2 g tid SI, and (D) 2 g loading and continuous infusion of 3 g/day on days 1 and 7. Probability of target attainment (PTA) was assessed for 4× the epidemiological cut-off values for Enterobacterales (4 × 0.25 mg/L) and Pseudomonas spp. (4 × 2 mg/L). Results: Nineteen patients were included in this study. Of these, 8 patients suffered from ACLF. A two-compartment model with linear clearance from the central compartment described meropenem pharmacokinetics. The peripheral volume of distribution (V2) was significantly higher in ACLF compared to NLF (38.6L versus 19.7L, p =.05). PTA for Enterobacterales was achieved in 100% for all dosing regimens. PTA for Pseudomonas spp. in ACLF on day 1/7 was: A: 18%/80%, B: 94%/88%, C: 85%/98% D: 100%/100% and NLF: A: 48%/65%, B: 91%/83%, C: 91%/93%, D: 100%/100%. Conclusion: ALCF patients receiving CVVHD had a higher V2 and may require a higher loading dose of meropenem. For Pseudomonas, high doses or continuous infusion are required to reach PTA in ACLF patients. [ABSTRACT FROM AUTHOR]

Background: Currently, the achievement of the target area under the curve (AUC)/minimum inhibitory concentration ratio during the first 24 - 48 h of treatment is associated with reduced 30-day mortality and greater microbiological eradication in patients with methicillin-resistant Staphylococcus aureus bacteremia. This study aimed to determine the AUC and pharmacokinetic parameters on the first day of vancomycin administration based on the Bayesian theorem to optimize the dosing regimen in critically ill patients. Materials and Methods: This retrospective study included participants meeting the following criteria: 1) ≥18 years old; 2) receipt of at least one dose of vancomycin; 3) measurement of 2 vancomycin serum concentrations during the first 24 h of treatment; and 4) an intensive care unit admission, mechanical ventilator use, or an Acute Physiology and Chronic Health Evaluation II score >15 points. The AUC on day 1 of treatment and the estimated vancomycin pharmacokinetic parameters were measured using PrecisePK software based on the Bayesian theorem. Results We obtained 132 vancomycin concentrations from 66 patients. The vancomycin pharmacokinetic parameters were as follows: AUC0-24, 571.09 (± standard deviation [SD] 188.62) mg/L·h; clearance (CL), 2.97 (± SD 1.81) L/h; volume of distribution (Vd), 50.60 (± SD 13.91) L; elimination rate constant, 0.062 (± SD 0.039) h−1; and half-life, 18.19 (± SD 15.96) h. Focusing on the vancomycin loading dose, AUC0-24 400 - 600 was achieved in 41.7, 46.1, 44.4, and 26.3% of patients with loading doses of <20, 20 – 24.9, 25 – 30, and >30 mg/kg, respectively. Whereas AUC0-24 ≥521 was achieved in 50, 50, 77.8, and 84.2% of patients with loading doses of <20, 20 – 24.9, 25 – 30, and >30 mg/kg, respectively. The CL of vancomycin was correlated with creatinine CL, whereas the Vd of vancomycin was significantly correlated with age and body weight.Conclusion This study revealed that the higher Vd and CL values on the first day of vancomycin therapy were found in critically ill patients. Additionally, a higher vancomycin loading dose (25 – 30 mg/kg) might be required to achieve target of AUC0-24 during early phase of administration for critically ill patients. [ABSTRACT FROM AUTHOR]

In some positron emission tomography (PET) studies, a reversibly binding radioligand is administered as a constant infusion to establish true equilibrium for quantification. This approach reduces scanning time and simplifies data analysis, but assumes similar behavior of the radioligand in plasma across the study population to establish true equilibrium in all subjects. Bias in outcome measurements can result if this assumption is not met. This work developed and validated a correction that reduces bias in total distribution volume (V T) estimates when true equilibrium is not present. This correction, termed tissue clearance correction (TCC), took the form V T = V T (A) / (1 + β γ V T (A) ) , where β is the radioligand clearance rate in tissue, γ is a radiotracer-specific constant, and V T(A) is the apparent V T. Simulations characterized the robustness of TCC across imperfect values of γ and β and demonstrated reduction to false positive rates. This approach was validated with human infusion data for three radiotracers: [18F]FPEB, (−)-[18F]flubatine, and [11C]UCB-J. TCC reduced bias in V T estimates for all radiotracers and significantly reduced intersubject variance in V T for [18F]FPEB data in some brain regions. Thus, TCC improves quantification of data acquired from PET infusion studies. [ABSTRACT FROM AUTHOR]

A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open-label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed-effect modeling. The plasma maximal concentrations (Cmax ) showed striking nonlinear disposition of sultiame, with a 10-fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two-compartment model with first-order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results. [ABSTRACT FROM AUTHOR]

Objective: To report the case of an infant who required high-dose vancomycin therapy after an unsuccessful gastroschisis repair surgery. Case Summary: An infant born at 35 weeks and 5 days of gestation underwent a gastroschisis repair on day of life 47. The repair was unsuccessful causing fluid backup and accumulation into the stomach. A replogle was placed to allow for suctioning of this fluid. During this admission, the patient received 3 courses of vancomycin. During the first course, the patient had minimal output via the replogle tube. On the infant's second and third courses of vancomycin, the infant necessitated vancomycin dosing above that of the neonatal protocol, and subsequent levels were still found to be below goal. Vancomycin was increased to a maximum of 15 mg/kg every 4 hours (90 mg/kg/d) in order to achieve serum trough levels greater than 10 mg/L. Residuals were drawn from the replogle ranging from 0.76 to 4.33 mL/kg/h during the second and third course of vancomycin. Discussion: A premature male infant required up to 90 mg/kg/d of vancomycin to achieve trough levels above 10 mg/L after an unsuccessful gastroschisis repair surgery and gastric suctioning. Conclusion: Clinicians should be aware of the possibility for decreased vancomycin levels and the potential need for increased monitoring in postsurgical infants receiving gastric suctioning. [ABSTRACT FROM AUTHOR]

Objective: To assess the pharmacokinetics of combined oral contraceptive (COC) components and prevalence of ovulation in HIV-positive women using ritonavir-containing antiretroviral regimens compared to those using regimens previously found not to interact with COCs or not using any antiretrovirals.Study Design: We conducted a prospective cohort pharmacokinetic pilot study comparing the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) in HIV-positive women taking ritonavir-containing antiretroviral regimens to those in women using non-ritonavir-containing regimens or no antiretrovirals. Participants received COCs containing LNG/EE 150/30 mcg for 21 days. Beginning day 21, we collected serial blood samples over 72 h. The primary outcome was area under the curve (AUC) of LNG, with secondary outcomes including other LNG pharmacokinetic measures, EE pharmacokinetics and ovulation as measured by serum progesterone.Results: Pharmacokinetic parameters of LNG showed a trend toward increased exposure in women on ritonavir. LNG AUClast increased by 32.6% (312±60.9 vs. 243±82.6 ng/mL*h, p=.033, n=5) in women taking ritonavir compared to the control group (n=10). The Cmax (9.68±1.81 vs. 7.62±2.29 ng/mL) and Cmin (4.97±1.15 vs. 3.70±1.29 ng/mL) were also higher in the ritonavir arm. After excluding the inconsistent users (n=2), CL of LNG was reduced in the ritonavir arm (p=.032). EE pharmacokinetic profiles were not different between groups. The progesterone concentrations were similar in women of both groups, and none were consistent with ovulation during the treatment cycle.Conclusion: Women on ritonavir showed an approximately 30% increase in LNG exposure but no difference in EE exposure.Implications: The current data suggest that ritonavir does not have a clinically significant impact on oral contraceptive pharmacokinetics. [ABSTRACT FROM AUTHOR]

In this study, total body clearance (CLt), volume of distribution at steady state (Vss) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. On the basis of assumption that unbound intrinsic clearance (CLUint) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp) in chimeric mice estimated from a difference between the observed and predicted Vss. These physiological approaches showed high prediction accuracy for CLt and Vss values in humans. We compared the predictability of CLt and Vss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method. Simulation of human plasma concentration-time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CLUint and SFKp obtained from chimeric mice. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds. [ABSTRACT FROM AUTHOR]

Purpose: Prospective prediction of pharmacokinetic properties for individuals of different ethnic groups could provide useful information for the design of multiregional clinical trials. The accuracy of interethnic scaling of fraction unbound (fu) of a drug could determine in large part the predictive capability of volume of distribution as well as renal clearance. As such, exploring the interethnic extrapolation of fu from healthy Caucasian to Chinese subjects and associated effect on the scaling of volume of distribution is highly warranted.Methods: This study assessed the interethnic scaling of fu from healthy Caucasians to Chinese by using physiologically based principles and verified the approach after examining with experimentally determined fu values of a variety of reference compounds with differing binding characteristics. Moreover, the fundamental assumption of interethnic extrapolation of volume of distribution (Vd), namely the equivalency of unbound Vd (Vd,u) across different ethnic groups, was tested on the basis of observed Vd data derived from comprehensive literature analysis and scaled fu values through qualified extrapolation method.Results: The interethnic extrapolation approach of fu provided a high accuracy with 94.7% scaled Chinese fu values (n = 19) being within a 1.25%-fold error range. Specifically, 100% of scaled Chinese fu values for the albumin-bound compounds and 90% for those bound to alpha 1-acid glycoprotein fell within the 1.25%-fold error range. All the percentage prediction errors of scaled Chinese fu values were ≤ 30%, with a majority of those ≤ 20%. Additionally, correlation between the prediction errors and the observed fu levels was not observed. Regarding interethnic scaling of Vd, the bodyweight-normalized Vd,u instead of Vd was similar across ethnic groups.Conclusion: The current study verified for the first time the ability to scale Chinese fu from Caucasian values after examining with experimentally determined fu values of a variety of reference compounds. Similarities in bodyweight-normalized Vd,u between non-obese Caucasians and Chinese have also been shown for the first time. This investigation could greatly enhance the confidence in the interethnic extrapolation of fu and Vd from healthy non-obese Caucasian to Chinese subjects. [ABSTRACT FROM AUTHOR]

Objective: The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women.Study Design: We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA).Results: Increasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly.Conclusions: The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations.Implications: This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives. [ABSTRACT FROM AUTHOR]

The terminal half-life (T 1/2) of a biphasic declining plasma concentration-time profile of a drug after intravenous administration is proportional to a ratio between its systemic clearance (CL) and volume of distribution at pseudo-distribution equilibrium (Vd β). Due to lack of understanding of Vd β , simply known as a proportionality constant between the amount of drug in the body and its plasma concentration during the terminal phase, the effects of various physiologically based pharmacokinetic parameters of drug on T 1/2 could not have been evaluated. The objective of the current study is to offer a new theoretical ground, using the Taylor series expansion, for a better understanding of relationships among T 1/2 , CL, distributional clearance (CL d) and volumes of distribution in the tissue compartment (V T) and at steady state (Vd ss) of drug in a 2-compartment model after intravenous administration. Similar CL and Vd ss yet different T 1/2 of drugs found in pharmacokinetic studies might be due to differences in CL d and V T of those drugs. In conclusion, the new equation (T 1/2 ≈ 0.693 (Vd ss /CL + V T /CL d) explicitly shows how the physiologically based pharmacokinetic parameters of drug could affect its T 1/2 after intravenous administration. [ABSTRACT FROM AUTHOR]

The Widmark equation is commonly used when blood alcohol calculations are required in forensic and legal medicine, such as in road-traffic cases and alcohol-related deaths. An important biological variable in this connection is the volume of distribution (Vd) of ethanol, which is commonly referred to as the rho-factor. Although a person's Vd can be determined empirically through controlled drinking experiments, this approach is not very practical in reality. For this reason, a number of anthropometric equations have been developed that utilize sex, age, height and weight to estimate the person's total body water (TBW) and hence Vd of ethanol. To date, there are not any studies that compare Vd derived from anthropometric data with robust values measured empirically. From the literature we compiled information about the Vd of ethanol from drinking studies with 173 Caucasian males and 63 Caucasian females from Western Europe. These empirically derived values of Vd were then compared with estimates derived from various anthropometric equations. In males the Watson, Watson and Batt regression equation involving age, height and weight gave the most accurate results (bias was 0.00L/kg) and 95% range ±0.13L/kg. The equation derived by Forrest, which took into consideration a person's body mass index (BMI), gave the best estimates of Vd for females; mean bias -0.01L/kg and range ±0.15L/kg. [ABSTRACT FROM AUTHOR]

Aims: Serelaxin is a recombinant human relaxin‐2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. Methods: Serum concentration–time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed‐effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. Results: A three‐compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady‐state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady‐state volume of distribution (Vss) was higher in patients with AHF (544 ml kg–1) or chronic heart failure (434 ml kg–1), compared with typical nonheart failure subjects (347 ml kg–1). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. Conclusions: Patients with HF showed higher Vss but similar clearance (and therefore steady‐state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady‐state concentration was moderate and therefore unlikely to be clinically relevant. [ABSTRACT FROM AUTHOR]

Chemical ionization plays an important role in many aspects of pharmacokinetic (PK) processes such as protein binding, tissue partitioning, and apparent volume of distribution at steady state (Vd ss ). Here, estimates of ionization equilibrium constants (i.e., p K a ) were analyzed for 8132 pharmaceuticals and 24,281 other compounds to which humans might be exposed in the environment. Results revealed broad differences in the ionization of pharmaceutical chemicals and chemicals with either near-field (in the home) or far-field sources. The utility of these high-throughput ionization predictions was evaluated via a case-study of predicted PK Vd ss for 22 compounds monitored in the blood and serum of the U.S. population by the U.S. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES). The chemical distribution ratio between water and tissue was estimated using predicted ionization states characterized by p K a . Probability distributions corresponding to ionizable atom types (IATs) were then used to analyze the sensitivity of predicted Vd ss on predicted pK a using Monte Carlo methods. 8 of the 22 compounds were predicted to be ionizable. For 5 of the 8 the predictions based upon ionization are significantly different from what would be predicted for a neutral compound. For all but one (foramsulfuron), the probability distribution of predicted Vd ss generated by IAT sensitivity analysis spans both the neutral prediction and the prediction using ionization. As new data sets of chemical-specific information on metabolism and excretion for hundreds of chemicals are being made available (e.g., Wetmore et al., 2015), high-throughput methods for calculating Vd ss and tissue-specific PK distribution coefficients will allow the rapid construction of PK models to provide context for both biomonitoring data and high-throughput toxicity screening studies such as Tox21 and ToxCast. [ABSTRACT FROM AUTHOR]

We studied the agreement between plasma clearance of mannitol and the reference method, plasma clearance of 51Cr- EDTA in outpatients with normal to moderately impaired renal function. Forty-one patients with a serum creatinine <200 μmol l−1 entered the study. 51Cr- EDTA clearance was measured with the standard bolus injection technique and glomerular filtration rate ( GFR) was calculated by the single-sample method described by Jacobsson. Mannitol, 0·25 g kg−1 body weight (150 mg ml−1), was infused for 4-14 min and blood samples taken at 1-, 2-, 3- and 4-h ( n = 24) or 2-, 3-, 3·5- and 4-h after infusion ( n = 17). Mannitol in serum was measured by an enzymatic method. Plasma clearance for mannitol and its apparent volume of distribution (Vd) were calculated according to Brøchner-Mortensen. Mean plasma clearance (± SD) for 51Cr- EDTA was 59·7 ± 18·8 ml min−1. The mean plasma clearance for mannitol ranged between 57·0 ± 20·1 and 61·1 ± 16·7 ml min−1 and Vd was 21·3 ± 6·2% per kg b.w. The between-method bias ranged between −0·23 and 2·73 ml min−1, the percentage error between 26·7 and 39·5% and the limits of agreement between −14·3/17·2 and −25·3/19·9 ml min−1. The best agreement was seen when three- or four-sample measurements of plasma mannitol were obtained and when sampling started 60 min after injection. Furthermore, accuracy of plasma clearance determinations was 88-96% (P30) and 41-63% (P10) and was highest when three- or four-sample measurements of plasma mannitol were obtained, including the first hour after the bolus dose. We conclude that there is a good agreement between plasma clearances of mannitol and 51Cr- EDTA for the assessment of GFR. [ABSTRACT FROM AUTHOR]

A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35  has excellent CBP potency (CBP IC 50  = 1 nM, MYC EC 50  = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile. [ABSTRACT FROM AUTHOR]

Nanotechnology, in conjunction with convection-enhanced delivery (CED), has gained traction as a promising method to treat many debilitating neurological diseases, including gliomas. One of the key parameters to evaluate the effectiveness of delivery is the volume of distribution (V d ) of nanoparticles within the brain parenchyma. Measurements of V d are commonly made using fluorescent reporter systems. However, reported analyses lack accurate and robust methods for determining V d . Current methods face the problems of varying background intensities between images, high intensity aggregates that can shift intensity distributions, and faint residual backgrounds that can occur as artifacts of fluorescent imaging. These problems can cause inaccurate results to be reported when a percentage of the maximum intensity is set as the threshold value. Here we show an implementation of Otsu’s method more reliably selects accurate threshold values than the fixed-threshold method. We also introduce a goodness of fit value η that quantifies the appropriateness of using Otsu’s method to calculate V d . Adoption of Otsu’s method and reporting of η may help standardize fluorescent image analysis of nanoparticles administered by convection-enhanced delivery. [ABSTRACT FROM AUTHOR]

Background: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to compare the prediction accuracy of different body weight descriptors for volume of distribution and to propose an optimal loading dose (LD) for continuous infusion regimens in adults. Methods: Pharmacokinetic variables were computed using one-compartmental analysis. Simulated LDs of vancomycin were evaluated for each patient. Results: Volume of distribution, clearance, and half-life median values (interquartile range) for vancomycin in the study population (n = 30) were 0.45 (0.39–0.61) L.kg−1, 0.026 (0.015–0.040) L.h−1.kg−1, and 10.3 (7.7–21.3) h, respectively. The observed volume of distribution was better predicted by total body weight (TBW) than by the ideal body weight or the adjusted body weight. Conclusions: An LD of 10.7 mg per kg TBW was optimal in our study population. Using this LD, 17.9% of simulated vancomycin serum levels were just below the therapeutic range, only 10.7% concentrations exceeded the target range and no concentration was toxic. The use of a LD would lead to reduced median time to reach target concentrations from 17 to 1 h. [ABSTRACT FROM AUTHOR]

Purpose: Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution. Methods: Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively. Results: The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers. Conclusions: These results suggest that V can be predicted for most drugs from plasma protein binding and microsomal partitioning. [ABSTRACT FROM AUTHOR]

Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients' home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy. [ABSTRACT FROM AUTHOR]

Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to body weight-related differences in metabolism rates. Confusing in some of the literature is that a few studies have reported erroneously calculated pharmacokinetic parameters after multiple dosing of oral contraceptives. A demonstration of appropriate pharmacokinetic methodology is provided. [ABSTRACT FROM AUTHOR]

HPLC methods that use chromatographic retention times for gaining information about the properties of compounds for the purpose of designing drug molecules are reviewed. Properties, such as lipophilicity, protein binding, phospholipid binding, and acid/base character can be incorporated in the design of molecules with the right biological distribution and pharmacokinetic profile to become an effective drug. Standardization of various methodologies is suggested in order to obtain data suitable for inter-laboratory comparison. The published HPLC methods for lipophilicity, acid/base character, protein and phospholipid binding are critically reviewed and compared with each other using the solvation equation approach. One of the most important discussion points is how these data can be used in models and how they can influence the drug discovery process. Therefore, the published models for volume of distribution, unbound volume of distribution and drug efficiency are also discussed. The general relationships between the chemical structure and biomimetic HPLC properties are described in view of ranking and selecting putative drug molecules. [ABSTRACT FROM AUTHOR]

AIM: To study which weight estimate calculation used in paediatric resuscitation results in optimal drug dosing; Advanced Paediatric and Life Support (APLS) or the UK Resuscitation Council age-based formula. Method Commonly used drugs used in paediatric resuscitation were selected and a literature search conducted for each drug's pharmacokinetic properties, concentrating on the volume of distribution (Vd). Hydrophobic drugs have a higher Vd than hydrophilic drugs as they distribute preferentially to fat mass (FM). The larger the Vd, the higher the initial dose required to achieve therapeutic plasma concentrations. Actual body weight (ABW) estimates are a good indicator of Vd for hydrophobic drugs as they correlate well with FM. Ideal body weight (IBW) estimates may be a better indicator of Vd for hydrophilic drugs, as they correlate better with lean body mass. This highlights potential variation between ABW and IBW, which may result in toxic or sub-therapeutic dosing. Results The new APLS formulae give higher estimates of expected weight for a wider age range. This may be a more accurate reflection of ABW due to increasing prevalence of obesity in children. The UK Resuscitation Council's formula appears to result in a lower estimate of weight, which may relate more closely to IBW. Conclusion The main drugs used in paediatric resuscitation are hydrophilic, thus the APLS formulae may result in too much being given. Therefore the UK Resuscitation Council's single formula may be preferred. In addition, a single formula may minimize error in the context of a child of unknown weight requiring administration of emergency resuscitation drugs. [ABSTRACT FROM AUTHOR]

Obtaining pharmacokinetic data from the intravenous route for drugs intended for oral administration has traditionally been expensive and time consuming because of the toxicology requirements and challenges in intravenous formulations. Such studies are necessary, however, particularly when regulator agencies request absolute bioavailability data. A method has emerged whereby the drug administered intravenously is isotopically labeled and dosed at a maximum of 100 mg concomitantly with an oral administration given at a therapeutically relevant level. The intravenous administration has been termed a microtracer and obviates intravenous toxicology requirements as well as simplifying formulations. The study design also essentially removes issues of nonlinear pharmacokinetics that may occur when oral and intravenous doses are administered separately. This review examines the methodology and the literature to date, including those studies intended for regulatory submission. The method has been extended to the study of prodrug-to-active drug kinetics and to obtaining clearance, volume of distribution, and absolute bioavailability at steady-state conditions. [ABSTRACT FROM AUTHOR]

The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution ( V ss, ivt ) and clearances (CL ivt ) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure. V ss, ivt and CL ivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular weight compounds was obtained with two descriptors: Log D 7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively ( Q 2 Y = 0.62). For 80% of the compounds the V ss, ivt was 1.18–2.28 ml; too narrow range for QSPR model building. Integration of the estimated V ss, ivt and predicted CL ivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration. The present work presents for the first time a database of CL ivt and V ss, ivt values and the dependence of the CL ivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems. [ABSTRACT FROM AUTHOR]

Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700 L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment. [ABSTRACT FROM AUTHOR]

Background: Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Results: Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Conclusions: Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. [ABSTRACT FROM AUTHOR]

In subjects without fluid retention, the total plasma clearance of a renal filtration indicator (inulin, 99m Tc- DTPA, 51 Cr- EDTA) is close to the urinary plasma clearance. Conversely, in patients with fluid retention (oedema, pleural effusions, ascites), there is a substantial discrepancy between the total plasma clearance and the urinary plasma clearance. This is owing to delayed indicator distribution to smaller or larger parts of the interstitial space, which in patients with ascites may simulate a peritoneal dialysator. In patients with fluid retention, urinary plasma clearance should be assessed to obtain a correct measurement of the glomerular filtration rate ( GFR). In theory, total plasma clearance with late samples (24-h, 48-h) may be applied in patients with fluid retention, but validation hereof has not been performed. Until such studies are completed, it is recommended that patients with fluid retention have their GFR measured by a urinary plasma clearance technique with controlled quantitative urinary sampling within a few hours after indicator injection. [ABSTRACT FROM AUTHOR]

Purpose: To develop a QSAR model, based on calculated molecular descriptors and an Artificial Neural Networks Ensemble (ANNE), for the estimation of rat tissue-to-blood partition coefficients (K), as well as the assessment of the applicability domain of the model and its utility in predicting the drug distribution in humans. Methods: A total of 1460 individual K values (75% train and 25% validation), obtained in 13 different rat tissues were collected in the literature. A correlation between simple molecular descriptors for lipophilicity, ionization, size and hydrogen bonding capacity and K data was attempted by using an ANNE. Results: Similar statistics were observed between the train and validation group of data with correlations, between the observed values and the predicted average ANNE values, of 0.909 and 0.896, respectively. A degradation of the correlations was observed for predicted values with high uncertainty, as judged by the standard deviations of the ANNE outputs. This was further observed when using the ANNE K values in a Physiologically based pharmacokinetic (PBPK) model for predicting the Human Volume of distribution of another 532 drugs. Conclusions: This model (available as a MS Excel® workbook in the Supporting material of this article) may be a valuable tool for prediction and simulation in early drug development, allowing the in silico estimation of rat K values for PBPK purposes and also indicating its applicability domain. [ABSTRACT FROM AUTHOR]

The volume of distribution of ethanol was already established in 1930s by Widmark. However, since then the average body composition has changed considerably. The effect of the body mass index (BMI) on the volume of distribution of ethanol was evaluated in this study. Fifty healthy volunteers (23 men and 27 women), with BMI-values between 16.0 and 36.0 kg/m², were asked to drink a dose of 0.4g ethanol per kilogram body weight after an overnight fast. The ethanol content was measured by a fully validated headspace-GC-FID method. The volume of distribution of ethanol varied between 0.40 and 0.68 L/kg for women, and between 0.43 and 0.73 L/kg for men. For both sexes, the volume of distribution decreased with increasing BMI. Regression analysis resulted in the following equations: volume of distribution = 0.8202 - 0.0090 x BMI for men (r = 0.66), and 0.7772 - 0.0099 x BMI for women (r=0.78). Population probability prediction interval limits were also calculated. In view of the current study, fixed values for the volume of distribution of 0.7 L/kg and 0.6 L/kg for men and women, respectively, of t en applied in legal blood alcohol calculations, are mainly suited to judge underweight or normal weight people, but not obese persons. [ABSTRACT FROM AUTHOR]

-Highlights: [•] Vertical allometry is a real occurrence with a handful of drugs. [•] There is no clear method to identify vertical allometry. [•] Protein binding appears to be an important component of vertical allometry. [ABSTRACT FROM AUTHOR]

Abstract: A compilation of rat tissue-to-blood partition coefficient data obtained both in vitro and in vivo in thirteen different tissues for a total of 309 different drugs is presented. An evaluation of the relationship between several fundamental physicochemical molecular descriptors and these distribution parameters was made. In addition, the ability to predict the Human Volume of distribution by regression analysis and by a Physiologically-based approach was also tested. Results have shown different trends between the drug classes and tissues, consistent with earlier described relationships between physicochemical properties and pharmacokinetic behavior. It was also possible to conclude for the acceptable ability to predict the volume of distribution in Humans by both regression and mechanistic approaches, which suggests that this type of data represents a convenient tool to describe the drug distribution on a new drug development context. These observations and analyses, along with the large database of rat tissue distribution data, should enable future efforts aimed toward developing a full in silico quantitative structure–pharmacokinetic relationships and improving our understanding of the correlations between fundamental chemical characteristics and drug distribution. [Copyright &y& Elsevier]