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Aims: This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp., Methods: Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance., Results: Ninety-eight per cent of predicted AUC, 95% of predicted C max , and 100% of predicted CL values were within two-fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, C max , and CL values were all within two-fold of the observed values., Conclusion: The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This paper quantitatively investigated the contribution of molecular properties to the volume of distribution in human (V(d human) ) when extrapolated from preclinical animal data, and identified which molecular descriptors and animal species were essential or better for acquiring the optimal accuracy of extrapolation. First, several two-dimensional molecular descriptors which can potentially contribute to V(d) were selected to establish the model to predict V(d) in humans. Then, several linear predictive models were constructed by partial least squares (PLS) using three or one animal data in combination with or without the molecular descriptors. Stepwise regression was performed to determine the important molecular descriptors. For comparison, the allometric method was also performed to estimate the V(d human) from preclinical species (rat, dog and monkey) data. The predictive accuracy of PLS models was better than that obtained by the allometric method. Moreover, the predictive accuracy of these models was improved when the molecular descriptors were introduced. Interestingly, the common contributors selected were molecular weight (MW) and the negatively charged fraction value (f(i-) ) for any stepwise regression model concerning molecular descriptors. Additionally, the dog was a more suitable species for predicting V(d human) during drug-lead pharmacokinetic optimization. More importantly, the introduction of molecular properties could improve the predictive accuracy for the prediction of V(d human) from the preclinical species, among which MW and f(i-) were the significant parameters and the latter was considered in the extrapolation process for the first time., (Copyright © 2010 John Wiley & Sons, Ltd.)

For the accurate prediction of in vivo hepatic clearance or drug-drug interaction potential through in vitro microsomal metabolic data, it is essential to evaluate the fraction unbound in hepatic microsomal incubation media. Here, a structure-based in silico predictive model of the nonspecific binding (fu(mic), fraction unbound in hepatic microsomes) for 86 drugs was successfully developed based on seven selected molecular descriptors. The R(2) of the predicted and observed log((1 - fu(mic))/fu(mic)) for the training set (n = 64) and test set (n = 22) were 0.82 and 0.85, respectively. The average fold error (AFE, calculated by fu(mic) rather than log((1 - fu(mic))/fu(mic))) of the in silico model was 1.33 (n = 86). The predictive capability of fu(mic) for neutral drugs compared well to that for basic compounds (R(2) = 0.82, AFE = 1.18 and fold error values were all below 2, except for felodipine and progesterone) in our model. This model appears to perform better for neutral compounds when compared to models previously published in the literature. Therefore, this in silico model may be used as an additional tool to estimate fu(mic) and for predicting in vivo hepatic clearance and inhibition potential from in vitro hepatic microsomal studies.

The first-principle, quantitative structure-hepatic clearance relationship for 50 drugs was constructed based on selected molecular descriptors calculated by TSAR software. The R(2) of the predicted and observed hepatic clearance for the training set (n=36) and test set (n=13) were 0.85 and 0.73, respectively. The average fold error (AFE) of the in silico model was 1.28 (n=50). The prediction accuracy of in silico model was superior to in vitro hepatocytes' model in literature (n=50, AFE=2.55). It is attractive to predict human hepatic clearance based on molecular descriptors merely. The structure-based model can be used as an efficient tool in the rapid identification of hepatic clearance of new drug candidates in drug discovery.

Recent studies have shown that many promising new drug candidates were abandoned due to poor pharmacokinetic properties (PKs). Therefore, it is important to predict the PKs of compounds during the early stages of drug development. The volume of distribution (VD) is one of the most important PK parameters. When considered along with systemic clearance, the VD determines the biological half-life, which is used for designing suitable dosage regimens and rational formulations. At present, the methods used to predict VD include (i) the extrapolation of animal data, (ii) physiologically based pharmacokinetic (PBPK) modeling and (iii) in silico approaches that employ quantitative structure-pharmacokinetic relationships (QSPR). In this article, the latest progress in the field of VD prediction is summarized in terms of the above three areas, respectively, and these approaches are expected to be valuable for screening new drugs during the early stages of drug discovery and development.

Anaprazole, a newly developed oral proton pump inhibitor, was evaluated for safety, tolerability, and pharmacokinetics in healthy Chinese subjects. This study involved administering either anaprazole sodium enteric‐coated tablet or placebo, followed by monitoring the incidence and severity of any adverse events (AEs). The pharmacokinetic parameters of anaprazole, its isomer, and main metabolisms were determined. The results showed that both single‐dose (2.5‐120 mg) and multiple‐dose (20 mg once daily, 40 mg once daily, or 20 mg twice daily) oral administration of anaprazole sodium enteric‐coated tablet were safe and well tolerated. Following single‐dose administration, the median time to reach maximum plasma concentration of anaprazole was between 3.50 and 5.25 hours, with mean elimination half‐life of 1.22‐3.79 hours. The absorption and elimination of anaprazole in the human body appeared to basically follow linear kinetics. After repeated dosing, steady‐state concentrations of anaprazole, its isomer, and primary metabolites were achieved, with a median time to reach maximum plasma concentration of 3‐3.75 hours and a mean elimination half‐life of 1.61‐2.27 hours for anaprazole. There was no significant drug accumulation after multiple‐dose oral administration. In conclusion, anaprazole sodium enteric‐coated tablets were found to be safe and well tolerated in healthy Chinese individuals. Anaprazole is absorbed and metabolized consistently in the human body without any accumulation. [ABSTRACT FROM AUTHOR]

Background and Objective: Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. Methods: The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. Result: Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. Conclusion: Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females. [ABSTRACT FROM AUTHOR]

Aim: To employ a model‐informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong‐acting dipeptidyl peptidase‐4 (DPP‐4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. Methods: Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model‐based meta‐analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP‐4 inhibitors. We hypothesized a consistent relationship between PK and DPP‐4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP‐4 inhibition and HbA1c. Finally, the predicted PK/DPP‐4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. Results: The PK/DPP‐4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long‐term efficacy in T2D patients, based on healthy subjects. Conclusions: Successful waiver approval for the phase 2b dose‐finding study was achieved through model‐informed recommendations, facilitating the clinical development of HSK7653 and other DPP‐4 inhibitors. [ABSTRACT FROM AUTHOR]

PB‐201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB‐201 will be broad. Because the liver is the primary organ for PB‐201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB‐201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB‐201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB‐201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically‐based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB‐201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age‐induced changes in physiological factors may significantly increase the exposure under fasted state by 36%–158% and 48%–82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB‐201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB‐201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results. [ABSTRACT FROM AUTHOR]

Background and Objective: PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals. Methods: Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed. Results: Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration–time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials. Conclusions: PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals. [ABSTRACT FROM AUTHOR]

HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi‐enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model‐informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates. However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%–39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%–31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure–response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486. [ABSTRACT FROM AUTHOR]

JNJ‐73763989, composed of the 2 short‐interfering RNA triggers JNJ‐73763976 and JNJ‐73763924, targets all hepatitis B virus messenger RNAs, thereby reducing all viral proteins. In this phase 1, single‐site, open‐label, parallel‐group, randomized study, participants were given 1 subcutaneous injection of JNJ‐73763989 (100 or 200 mg) to investigate the pharmacokinetics, safety, and tolerability of JNJ‐73763989 in healthy Chinese adult participants. Plasma and urine pharmacokinetic parameters were determined for each trigger up to 48 hours after dosing. Eighteen participants, 9 per dose group, were enrolled. The median age and weight were 33.0 years and 73.65 kg; 83.3% were male. Exposure of both triggers increased dose proportionally. Median time to maximum concentration ranged from 6.0 to 10.0 hours, and mean elimination half‐life ranged from 4.5 to 4.8 hours across both triggers and doses. Mean urinary excretion for JNJ‐73763976 and JNJ‐73763924 ranged from 17.7% to 19.4% and 13.1% to 13.2% for the 100‐ and 200‐mg dose groups, respectively. All treatment‐emergent adverse events (AEs) were mild and resolved by study end, and no AEs or serious AEs resulted in premature study discontinuation or death. Overall, the pharmacokinetics of JNJ‐73763989 in healthy Chinese participants were consistent with previous studies, and JNJ‐73763989 was generally safe and well tolerated after a single dose. [ABSTRACT FROM AUTHOR]

This phase 1, open‐label, single‐center study evaluated the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of single‐dose emicizumab in healthy Chinese males. Overall, 16 subjects received a single subcutaneous dose of 1‐mg/kg emicizumab. Blood samples were obtained before dosing on day 1 and at regular intervals over 16 weeks after dosing for PK evaluation. A single 1‐mg/kg subcutaneous dose of emicizumab was safe and well tolerated in healthy Chinese male subjects in the study. Mean (± standard deviation) area under the concentration‐time curve from time 0 to infinity and maximum concentration were 287 ± 74.2 μg⋅d/mL and 7.11 ± 1.77 μg/mL, respectively, with a terminal half‐life of 26.7 (±4.3) days. Emicizumab administration did not show significant impact on pharmacodynamic markers tested, which mostly remained stable throughout the study. One subject tested positive for antidrug antibody, with no impact on his PK or safety profile. Compared with results from healthy Japanese and Caucasian subjects receiving the same dose in previous clinical trials, the current results further indicated the absence of difference of emicizumab PK profile across Chinese, Japanese, and Caucasian subjects, validating the use of similar therapeutic doses in Asian and non‐Asian populations. [ABSTRACT FROM AUTHOR]

To preliminarily develop physiologically based population models for Chinese renal impairment patients and to evaluate the prediction performance of new population models by renally cleared antibacterial drugs. First, demographic data and physiological parameters of Chinese renal impairment patients were collected, and then the coefficients of the relative demographic and physiological equation were recalibrated to construct the new population models. Second, drug‐independent parameters of ceftazidime, cefodizime, vancomycin, and cefuroxime were collected and verified by Chinese healthy volunteers, Caucasian healthy volunteers, and Caucasian renal impairment population models built in Simcyp. Finally, the newly developed population models were applied to predict the plasma concentration of four antibacterial drugs in Chinese renal impairment patients. The new physiologically based pharmacokinetic (PBPK) population models can predict the main pharmacokinetic parameters, including area under the plasma concentration–time curve extrapolated to infinity (AUCinf), renal clearance (CLr), and peak concentration (Cmax), of ceftazidime, cefodizime, vancomycin, and cefuroxime following intravenous administrations with less than twofold error in mild, moderate, and severe Chinese renal impairment patients. The accuracy and precision of the predictions were improved compared with the Chinese healthy volunteers and Caucasian renal impairment population models. The PBPK population models were preliminarily developed and the first‐step validation results of four antibacterial drugs following intravenous administration showed acceptable accuracy and precision. The population models still need more systematic validation by using more drugs and scenarios in future studies to support their applications on dosage recommendation for Chinese renal impairment patients. [ABSTRACT FROM AUTHOR]

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure–response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2–5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2–3: 500 mg BID, Days 4–5: 250 mg BID, CQ phosphate), and other vulnerable populations (e. g., renal and hepatic impairment and elderly patients, Days 1–5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19. A PBPK model of chloroquine was developed to understand the drug exposure at the site of action as well as in the tissues of interest where toxicity is of concern, and to predict optimized dosage regimens for patients with COVID-19. Image 1 [ABSTRACT FROM AUTHOR]

Background and Objectives: New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. Methods: The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. Results: Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0–∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0–∞ and Cmax of 2.06 (90% confidence interval 1.86–2.30) and 1.95 (90% confidence interval 1.65–2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. Conclusions: Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries. [ABSTRACT FROM AUTHOR]

Objectives: Pharmacokinetics of vitamins is still a challenge. In this study, folic acid (FA) was used as a model drug and aimed at investigating a reliable method for its detailed pharmacokinetic evaluations. Methods: An high‐performance liquid chromatography–tandem mass spectrometry method was developed and performed to determinate the FA and 5‐methyltetrahydrofolic acid (5‐methylTHF) simultaneously, which was applied to characterize the circadian rhythms as well as the pharmacokinetics of different preparations. Key findings: The plasma concentration of 5‐methylTHF in fasted state was twofold higher than that in fed state. The circadian rhythms were studied before the pharmacokinetics and revealed that free FA was almost undetected in blank plasma, while 5‐methylTHF had a slight decrement at 12:00. Hence, the pharmacokinetics of FA was conducted and showed that the administration of FA solution resulted in enhancing bioavailability of 5‐methylTHF comparing with FA raw material suspension, whereas the free FA level in plasma was similar. The mechanism could be that FA was rapidly metabolized to 5‐methylTHF in intestinal epithelial cell after absorption, which revealed that intestinal metabolism would affect its bioavailability. Conclusion: A suitable method was established considering the baseline level, circadian rhythms and intestinal metabolism to investigate the pharmacokinetics of FA for guiding the further research of vitamins. [ABSTRACT FROM AUTHOR]

Aim The aim of the study was to assess ticagrelor's effects on inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRU, measure of platelet P2Y12 receptor blockade), pharmacokinetic (PK) parameters and safety in Chinese patients with stable coronary artery disease (CAD). Methods This was an open label, single centre, randomized study. Thirty-six patients on low dose aspirin (75-100 mg day-1) received ticagrelor 45, 60 or 90 mg (single dose, days 1 and 7; twice daily, days 3-6). IPA (final extent), PRU and ticagrelor and AR-C124910XX plasma concentrations were determined. Results On day 1, peak IPA >80% occurred 2-6 h post-dose (all doses). PRU was markedly reduced at 1 h vs. baseline (all doses). With ticagrelor 45 and 90 mg twice daily, maximum IPA (mean, SD) was 91% (13%), and 99% (3%), and maximum PRU reduction from baseline (mean, SD) was 82% (17%) and 92% (9%), respectively. Approximate dose-proportional increases (mean [%CV]; 45 vs. 90 mg twice daily) in ticagrelor Cmax (616 [37] vs. 1273 [43] ng ml-1) and AUC (3882 [42] vs. 8206 [51] ng ml-1 h) and AR-C124910XX parameters were seen. Pharmacodynamic and PK differences between 45 and 60 mg were small. No safety issues were identified. Conclusions In Chinese patients with CAD, ticagrelor (45, 60 and 90 mg) markedly reduced platelet aggregation. The IPA and PRU magnitude increased generally with increasing doses. However, the mean pharmacodynamic differences between 45 and 60 mg doses were small. Following single and multiple doses, the mean Cmax and AUC values of ticagrelor and AR-C124910XX increased approximately dose proportionally between 45 and 90 mg doses. [ABSTRACT FROM AUTHOR]

The aim of this study was to improve the oral absorption of loratadine, a pH-sensitive drug, by self-microemulsifying drug delivery systems (SMEDDSs). The optimal SMEDDS was analysed and evaluated after emulsification in distilled water with diameter of 26.57 ± 0.71 nm and zeta potential of −30.5 ± 4.5 mV. Dissolution experiments in vitro were carried out in different released media of pH values and the SMEDDS formulations were able to release loratadine completely in different media while market tablets just performed similarly in the media of pH 1.2. Furthermore, the oral bioavailability and the pharmacokinetic behaviour of loratadine formulations in vivo were studied after a single dose of 1 mg/kg loratadine in beagle dogs. The SMEDDS formulations displayed higher Cmax and AUC, approximately 9 and 5 times increase than those of market tablets ( p < 0.01) respectively. These results demonstrated that SMEDDS formulations had significantly increased the oral absorption of loratadine in beagle dogs. [ABSTRACT FROM AUTHOR]

Andrographolide has a low aqueous solubility and oral bioavailability, which limits its clinical application. Reform the dosage forms of andrographolide to improve its aqueous solubility and oral bioavailability. The formulation, characterisation, stability, anti-inflammatory effect, pharmacokinetics and oral toxicity of andrographolide-loaded microemulsion, were studied. An formulation of O/W microemulsion consisting of an oil phase of isopropyl myristate, a surfactant phase of Tween 80, a co-surfactant of alcohol, and water was found to be ideal, with mean droplet size of 15.9 nm, a high capacity of solubilisation for andrographolide (8.02 mg mL−1). Such an andrographolide-loaded microemulsion is stable by monitoring the time, temperature and gravity-dependent change, and has a much better anti-inflammatory effect and a higher biological availability than andrographolide tablets. Besides, it also shows a very low acute oral toxicity. The andrographolide-loaded microemulsion is a promising dosage form of andrographolide. [ABSTRACT FROM AUTHOR]

Abstract: Tomographic imaging techniques are attractive tools for the visualization of the internal structural characteristics of pharmaceutical solid dosage forms. In this paper, the internal structure of the tablet core for a monolith osmotic drug delivery system, felodipine sustained-release tablet, was visualized via synchrotron radiation X-ray computed microtomography during the drug release process. The surface areas and three dimensional parameters of the tablet core were calculated based on the three dimensional reconstruction of the images. At different stages of the drug release process, the surface morphology, the hydration, the swelling, and the structure changing of the tablet, were visualized from the two dimensional monochrome X-ray images. The three dimensional volumes of the remaining tablet core correlated well with the percentages of felodipine (R =0.9988). Also, the three dimensional surface area almost unchanged during the drug release process, which clearly demonstrated the intrinsic drug release mechanism of the osmotic drug delivery system. In conclusion, the synchrotron radiation X-ray computed microtomography, with rapid acquisition, high intensity and micro-scale spatial resolution, was found to be a useful tool for the quantitative elucidation of the intrinsic drug release kinetics and the three dimensional parameters such as surface areas of the remained core obtained by the synchrotron radiation. Thus, X-ray computed microtomography can be considered as a new and complimentary analytical tool to standard compendial pharmaceutical tests for quality control of osmotic drug delivery systems. [Copyright &y& Elsevier]

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children. [ABSTRACT FROM AUTHOR]

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases. [ABSTRACT FROM AUTHOR]

To evaluate the biodistribution of hydroxychloroquine (HCQ) in cynomolgus macaques and receive dynamic quantitative relationship between plasma, blood, and lung tissue concentration using the population pharmacokinetic modeling method, seventeen cynomolgus macaques were divided into six groups according to different HCQ dosing regimens over 5 days. The monkeys were euthanized, and blood, plasma, urine, feces and ten tissues were collected. All the samples were prepared by protein precipitation and analyzed by HPLC-MS/MS detection. The population pharmacokinetics of HCQ in the plasma, red blood cells, and lung tissue was conducted and simulated via ADAPT program. Results demonstrated that the maximum concentration (C max) of HCQ was 292.33 ng/mL in blood and 36.90 ng/mL in plasma after single dose of 3 mg/kg. The value of area under curve (AUC0–∞) was determined as 5,978.94 and 363.31 h* ng/mL for the blood and plasma, respectively. The descending order of the tissue-to-plasma concentration ratio was liver > spleen > kidney > lung > heart > subcutaneous fat > brain. The tissue-to-plasma concentration ratio and the tissue-to-blood concentration ratio for lung were found to be time-dependent with 267.38 and 5.55 at 120 h postdose, respectively. A five-compartment model with first-order oral absorption and elimination best described the plasma, blood, and lung tissue pharmacokinetics. The estimated elimination rate constant (ke) for a typical monkey was 0.236 h−1. The volume of distribution in central (Vc/F) and other two peripheral compartments (Vb/F and Vl/F) were 114, 2.68, and 5.55 L, respectively. Model-based simulation with PK parameters from cynomolgus macaques showed that the ratio of the blood or plasma to lung tissue was a dynamic change course, which suggested that the rate of HCQ concentration decrease in the blood or plasma was faster than that in the lung tissue. HCQ was found to be accumulated in tissues, especially in the liver, kidney, lung, and spleen. Also, the tissue-to-plasma concentration ratio increased over time. The population pharmacokinetic model developed could allow for the assessment of pharmacokinetics–pharmacodynamics relationships, especially relevant tissue concentration-response for HCQ. Determining appropriate treatment regimens in animals allows translation of these to clinical studies. [ABSTRACT FROM AUTHOR]

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0–72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, RTTCC was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O2). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically. [ABSTRACT FROM AUTHOR]

A simple, rapid and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for simultaneous determination of six components including apigenin, quercetin, apigenin-7- O -β- d -glucoside, quercetin-3- O -β- d -glucoside, 3′-methoxyluteolin-7- O -β- d -glucoside, and tricin-7- O -β- d -glucopyranoside in rat plasma using formononetin as the internal standard (IS). The plasma samples were pretreated by a one-step liquid–liquid extraction with dichloromethane. The chromatographic separation was carried out on a ZORBAX SB-Aq column with a gradient mobile phase consisting of acetonitrile and 2 mM aqueous ammonium acetate. All analytes and IS were quantitated through electrospray ionization in negative ion multiple reaction monitoring mode. The mass transitions were as follows: m / z 269.1 → 117.2 for apigenin, m / z 301.2 → 151.2 for quercetin, m / z 431.3 → 311.2 for apigenin-7- O -β- d -glucoside, m / z 463.2 → 300.2 for quercetin-3- O -β- d -glucoside, m / z 461.3 → 283.1 for 3′-methoxyluteolin-7- O -β- d -glucoside, m / z 491.3 → 313.1 for tricin-7- O -β- d -glucopyranoside, and m / z 267.2 → 252.2 for IS, respectively. All calibration curves exhibited good linearity with correlation coefficient ( r ) > 0.995. The intra-day and inter-day precisions (RSD) at three QC levels were both less than 14.0% and the accuracies ranged from 89.8% to 113.8%. The extraction recoveries of six compounds ranged from 82.3% to 92.5%. The validated method was successfully applied to pharmacokinetic study of the six components in male rat plasma after oral administration of Paulownia tomentosa flower extract. [ABSTRACT FROM AUTHOR]

• Exposure of anticoagulants in Chinese older adults is 21–88% greater than in Chinese adults. • Aging has no drastic impact on drug interaction extent of inhibitors on anticoagulants. • Absolute increase in drug exposure during drug interaction in older adults is of concern. • Moderate inhibitors potentially increase bleeding risk of older adults on anticoagulants. • Reduced dose adaptation results in similar exposure with standard dose monotherapy. Drug-drug interaction (DDI) is one of the major concerns for the clinical use of NOACs in the older adults considering that coexistence of multiple diseases and comorbidity were common. Current guidelines on the DDI management were established based on clinical studies conducted in healthy adults and mainly focus on the Caucasians, whereas systemic and ethnic differences may lead to distinct management in the Chinese older adults. To investigate the impact of aging on the DDI magnitude between P-gp and/or CYP3A4 inhibitors with dabigatran etexilate and rivaroxaban in older adults, providing additional information for the use in clinical practice. Compared with the simulated adult, the AUC of the simulated older adults increased by 42–88% (DABE) and 21–60% (rivaroxaban), respectively, during NOACs monotherapy. Simulation on DDIs predicted that verapamil and clarithromycin further increase the exposure of dabigatran by 29–72% and 40–47%, whereas clarithromycin, fluconazole, and ketoconazole increase the exposure of rivaroxaban by 21–30%, 16–24%, and 194–247% in the older adults. Overall, our simulation result demonstrated that aging and DDIs both increased the exposure of NOACs. However, aging does not have a drastic impact on the extent of DDIs. The DDI ratios of young and old older adults were similar to the adults and were also similar between Caucasians and Chinese. We further simulated the interactions under steady-state based on the EHRA guideline (2021). Our simulation results revealed that recommended reduced dosing regimen of dabigatran etexilate during comedication with verapamil and clarithromycin (110 and 75 mg BID for Chinese young and old older adults) will result in exposure (trough concentration) that was either slightly higher or similar to the trough concentration of patients with any bleeding events. Routine monitoring of bleeding risk is encouraged. Further studies on the use of rivaroxaban in Chinese older adults are warranted. Aging and DDI increases exposure of drug in Chinese older adults. However, aging does not have a drastic impact on the extent of DDIs. Clinical management of DDIs in Chinese older adults in the absence of complex polypharmacy can a priori be similar to the EHRA guideline but routine monitoring of bleeding risk is encouraged when dabigatran etexilate given with verapamil and clarithromycin. [Display omitted] [ABSTRACT FROM AUTHOR]

• Antibacterial resistance has led to a need for multiple treatment options • Ceftolozane/tazobactam (C/T) was well tolerated in healthy Chinese participants • C/T pharmacokinetics (PK) for Chinese participants was comparable to that in other ethnicities • PK in Chinese participants supports C/T dosing schedule used by other ethnicities Ceftolozane/tazobactam (C/T) is approved in several countries to treat complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. There is a paucity of pharmacokinetics and safety data for C/T in Chinese participants. This study evaluated the pharmacokinetics, safety, and tolerability of C/T in 12 healthy Chinese participants after three single administrations of increasing doses (0.75 g, 1.5 g, and 3 g) and multiple administrations of 1.5 g C/T every 8 h for 3 days. After single doses, maximum concentrations of ceftolozane and tazobactam were reached by the end of the 1-h infusion and declined in a biphasic manner thereafter, with mean half-lives of 1.9–2.2 h and 0.74–0.95 h, respectively. Volume of distribution (V d) and renal clearance (CL) were consistent across the three single-dose levels for ceftolozane (V d , 15.8–19.5 L; CL, 5.68–6.09 L/h) and tazobactam (V d , 23.3–28.6 L; CL, 20.8–23.5 L/h). Area under the concentration–time curve (AUC) extrapolated to infinity (ceftolozane, 88.1–328 h∙μg/mL; tazobactam, 10.7–48.0 h∙μg/mL) increased in a dose-dependent manner. After multiple doses over 3 days, AUC from time 0 to 8 h, and concentration at the end of infusion were similar to single-dose measurements (geometric mean ratios, 0.87–1.01 for both drugs). C/T was well tolerated, with no serious adverse events or discontinuations reported; all adverse events were mild. The pharmacokinetics and safety/tolerability of C/T in healthy Chinese participants was comparable to that in previous studies in other populations, supporting the use of C/T for the treatment of Chinese patients. [ABSTRACT FROM AUTHOR]

Abstract: A rapid, sensitive and specific method for the determination of cepharanthine in human plasma using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS) was described. Cepharanthine and the internal standard (I.S.), telmisartan, were extracted from human plasma by methanol to precipitate the protein. A centrifuged upper layer was then evaporated and reconstituted with 100μL methanol. Chromatographic separation was performed on an AGILENT XDB-C8 column (150mm×2.1mm, 5.0μm, Agilent, USA) using a gradient mobile phase with 1mmol/L ammonium acetate in water with 0.05% formic acid and methanol. Detection and quantitation was performed by MS/MS using electrospray ionization (ESI) and multiple reaction monitoring (MRM) in the positive ion mode. The most intense [M+H]+ MRM transition of cepharanthine at m/z 607.3→365.3 was used for quantitation and the transition at m/z 515.5→276.4 was used to monitor telmisartan. The calibration curve was linear within the concentration range of 0.5–200.0ng/mL (r =0.9994). The limit of quantification (LOQ) was 0.5ng/mL. The extraction recovery was above 81.1%. The accuracy was higher than 92.3%. The intra- and inter-day precisions were less than 9.66%. The method was accurate, sensitive and simple and was successfully applied to a pharmacokinetic study after single intravenous administration of 50mg cepharanthine in 12 healthy Chinese volunteers. [ABSTRACT FROM AUTHOR]