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Background: Esaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK + )., Methods: The relationships between model-derived individual esaxerenone exposure and efficacy (blood pressure [BP]) and safety (increased sK + ) were evaluated using multivariate linear regression and Cox regression analyses, respectively, using data from 1453 hypertensive patients with or without diabetic kidney disease in five clinical studies., Results: Exposure-efficacy analyses demonstrated that higher exposure was linearly associated with greater BP reduction over the investigated dose range. Exposure-safety analyses showed that higher exposure was associated with a higher risk of increased sK + under a fixed-dosing regimen; higher baseline sK + and lower baseline estimated glomerular filtration rate (eGFR) were influential covariates. Model-based simulations suggested that fewer occurrences of increased sK + are expected under the up-titration regimen (from 1.25 to 5 mg) relative to the fixed-dosing regimen (5 mg) in patients with different combinations of these covariates., Conclusions: The exposure-response analyses supported the esaxerenone recommended doses and the safety benefits of using the up-titration regimen., (© 2023 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.)

This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials, primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates, ORRs) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, and 79 with other cancers). In gastric cancer, the T-DXd 6.4 mg/kg steady-state exposure metrics were lower compared with 6.4 mg/kg in breast cancer, but were similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, the T-DXd steady-state minimum concentration was associated with a confirmed ORR in univariate logistic regression analysis (P = .023). The model-predicted confirmed ORRs in gastric cancer were 36.0% (90%CI 29.3% to 43.7%) with 5.4 mg/kg and 40.0% (90%CI 33.1% to 47.6%) with 6.4 mg/kg. Among 808 patients in the exposure-safety analyses, the model-predicted estimates for the rates of any-grade interstitial lung disease (ILD) over a period of 180 days were 10.2% (90%CI 8.7% to 12.8%) with 6.4 mg/kg in gastric cancer and 9.7% (90%CI 8.2% to 11.8%) with 5.4 mg/kg in breast cancer. In gastric cancer, the efficacy of T-DXd was higher at 6.4 mg/kg than at 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: Esaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters., Methods: A total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers, 1097 hypertensive patients and 360 patients with diabetic nephropathy were pooled. A three-compartment model with sequential zero- and first-order absorption was used to describe the time-courses of plasma esaxerenone following single and multiple doses once daily for up to 12 weeks. Covariate effects were estimated using the full covariate modeling approach. Clinical relevance of covariates was ascertained using tornado plots., Results: Esaxerenone was estimated to have high bioavailability (85.3%), low clearance (3.28 L/h) and relatively large distribution volume at steady state (94.8 L). Body weight (-26 to +36%) and coadministration of itraconazole (+64%) or rifampicin (-68%) were associated with a greater influence on esaxerenone exposure., Conclusions: The most influential covariates on esaxerenone exposure were coadministrations of itraconazole and rifampicin, followed by body weight. The clinical relevance of effects of renal impairment, mild to moderate hepatic impairment, and age is limited., Competing Interests: Declaration of competing interest Kazutaka Yoshihara: Employee of Daiichi Sankyo Co., Ltd. Masato Fukae: Employee of Daiichi Sankyo Co., Ltd. Helen Kastrissios: Former employee of Certara Inc., which received consulting fees from Daiichi Sankyo Co., Ltd., and current employee of QuanTx Consulting. Russell Wada: Former employee of Certara Inc., which received consulting fees from Daiichi Sankyo Co., Ltd., and current chief executive officer of QuanTx Consulting. Takako Shimizu: Former employee of Daiichi Sankyo Co., Ltd, and current employee of OrphanPacific, Inc. Hitoshi Ishizuka: Employee of Daiichi Sankyo Co., Ltd., (Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims: To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients., Methods: A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA-I exposure. Exposure-response modeling was conducted to describe the relationship between apoA-I exposure and total or ATP binding cassette transporter A1-(ABCA1)-dependent CEC and to identify clinical predictors of CEC., Results: A two-compartment model described apoA-I PK. ApoA-I clearance was slightly lower in subjects with AMI, whereas baseline apoA-I was marginally higher in female and Japanese subjects. Covariate effects on apoA-I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA-I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA-I exposure increment was comparable in AMI and non-AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels., Conclusions: The model-based exposure-response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk., (© 2020 CSL Behring. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including pharmacokinetics/pharmacodynamics and simulation reports., (© 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers)., (© 2014, The American College of Clinical Pharmacology.)

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.

The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria. The dataset included 6 phase I and IIa studies in patients with type 2 diabetes mellitus. The pharmacokinetic profile of CS-917 and its metabolites was described by a series of linked 1- and 2-compartmental models. Simulations showed that moderate renal impairment has a clinically significant impact on exposure to R-125338. A separate population pharmacokinetic analysis of R-125338 alone revealed similar results. In conclusion, a population pharmacokinetic model fit to the active moiety alone yielded similar predictions and substantially reduced the analysis time compared to the more complex model developed for CS-917 and its metabolites. Increased exposure to R-125338 in the presence of moderate renal impairment may be an important consideration for dose selection.

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.

Purpose: Patient adherence is critical in evaluating the effectiveness of an oral therapy. We sought to measure adherence among women randomly assigned to capecitabine in a preplanned substudy of a multicenter clinical trial., Patients and Methods: Cancer and Leukemia Group B study CALGB 49907 was a randomly assigned trial comparing standard chemotherapy versus oral chemotherapy with capecitabine in patients age 65 years or older with early-stage breast cancer. We used microelectronic monitoring system (MEMS) caps on participants' capecitabine bottles to record pill bottle openings. Capecitabine was given in two divided daily doses for 14 consecutive days of a 21-day cycle for six cycles. Adherence was calculated as the number of doses taken divided by doses expected, taking into account toxicity-related dosing changes. A participant was defined as adherent if 80% or more of expected doses were recorded by MEMS., Results: Overall, 161 patients were enrolled. Median age was 71 years (range, 65 to 89 years); 124 patients (83%) persisted with capecitabine to completion of planned protocol therapy. Adherence was 78% across all cycles, and adherence did not vary by cycle (P = .32). Twenty-five percent of participants took fewer than 80% of expected doses and were nonadherent. In a logistic regression model, participants with node-negative disease (P = .01) and mastectomy (P = .01) were more likely to be nonadherent. Adherence was not related to age, tumor stage, or hormone receptor status. Adherence was not significantly associated with relapse-free survival or grade 3 or 4 toxicity., Conclusion: Most older women with early-stage breast cancer were adherent to short-term oral chemotherapy in a randomized clinical trial. Age was not associated with adherence.

Aim: To develop a pain relief model for a cyclooxygenase (COX)-2 inhibitor, CS-706, that permits prediction of doses for acute pain relief in Japanese and Western populations., Methods: A categorical response model was developed to describe the probability of pain relief (PR) over time for a Phase 2a study. Models were also developed to describe patient's use of rescue medication and onset of pain relief., Results: The placebo response was described by a first-order increase in PR that achieved a stable response after 4 h. The effect of CS-706 on PR was described using an E(max) model; the plasma concentration of CS-706 producing 50% of the maximum response was estimated to be 87 ng ml(-1), the median peak plasma concentration achieved after a 50-mg oral dose. The probability of rescue medication (REMD) decreased over time and was a function of the last observed PR score. This probability was < 16% for patients with a PR score > or =2. The probability of experiencing meaningful PR was 98% in patients who did not require REMD and 47% in those who required REMD. For patients who did not require REMD, the median onset time of meaningful pain relief (TMPR) decreased with increasing doses. In patients who required REMD, there was a saturable decline in TMPR, with the greatest improvement occurring from placebo to 50-mg doses., Conclusions: The set of models developed permitted compilation of multiple dose-response curves for dose selection of CS-706 in Westerners and facilitated scaling of doses to a Japanese population.

The objectives of these analyses were to (1) develop a population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor (CS-706) using data from primarily Caucasian subjects, (2) predict responses in subpopulations of interest (including Japanese subjects), and (3) correlate pharmacodynamic parameters to safety outcomes. The model was developed using data from 130 healthy adults following single or multiple doses of CS-706. Serial plasma concentrations of CS-706 and ex vivo whole-blood cyclooxygenase-1 (COX-1) and COX-2 activity were determined up to 72 hours postdose. An E(max) model described relationships between CS-706 plasma concentrations and COX-1 and COX-2 inhibition. CS-706 potency (EC(50)) was 397 ng/mL for COX-1 and 20 ng/mL for COX-2. None of the tested covariates influenced the pharmacodynamics of CS-706. Japanese subjects are expected to show a slightly reduced response to CS-706, consistent with lower exposure following the same dose given to Caucasian subjects. Predictive pharmacokinetic/pharmacodynamic modeling for COX-1 and COX-2 inhibition indicates a 20-fold potency ratio that is expected to be similar in Japanese and Caucasians. There was good correlation between COX-1 inhibition and the incidence of 7-day gastroduodenal mucosal injury. A dose of less than 25 mg bid could be adequate to inhibit COX-2 activity with a low risk of gastrointestinal mucosal injury.

A predictive population pharmacokinetic model was developed for a novel cyclooxygenase-2 (COX-2) inhibitor CS-706, using data from 130 subjects in 3 phase 1 trials after single or multiple doses of CS-706 (2- to 800-mg doses daily, up to 14 days) and validated using sparse data from a separate study. A 2-compartment model described the data. Typical apparent clearance (CL/F) was 47.2 L/h and was reduced by 43% at doses greater than 200 mg. Apparent clearance was decreased by 38% in female subjects and by 64% and 15%, respectively, in poor/intermediate CYP 2D6 and poor CYP 2C9 metabolizers. Typical apparent volume of the central compartment was 166 L and increased with body weight. Bioavailability increased by 42% after nighttime doses and decreased saturably with increasing dose (50% reduction at 221 mg). Predicted exposures in Japanese subjects were reduced relative to whites because of a lower frequency of poor metabolizers. The model may aid in optimizing the design of future studies and predicting exposures in other subpopulations.

Objective: To evaluate medication adherence, pharmacokinetics and exposure versus response relationships in patients with myelodysplastic syndromes (MDS)., Methods: Ninety adult patients with MDS received oral topotecan (1.2 mg/m2) either once a day for 10 days or twice a day for 5 days every 21 days for up to six cycles. Dosing histories were collected using electronic monitoring devices fitted to medication vials. Topotecan plasma concentrations were measured, and exposure was determined by a sparse sampling approach and Bayesian estimation methods. Relationships between exposure and clinical response and toxicity were evaluated using logistic regression., Results: Overall adherence was excellent with 90% of patients taking the prescribed number of doses in cycle 1. Adherence did not differ between the two regimens. Topotecan pharmacokinetics were described using a one compartment open model with first order absorption and elimination. Pharmacokinetic parameter estimates did not differ between the once a day and twice a day dosing groups. While topotecan exposure was greater in the twice a day arm compared to the once a day arm due to drug accumulation, exposure did not correlate with clinical response. However, the probability of needing a platelet transfusion in the twice a day arm was significantly increased (by 35%) as a result of greater steady-state plasma topotecan concentrations., Conclusions: Adherence is high in patients with MDS receiving oral topotecan, whether the drug is prescribed once or twice daily. The optimal schedule cannot be determined from this study, as there was no evident relationship between any pharmacokinetic parameter and clinical response.

The pharmacological effects of morphine are mediated via the central nervous system (CNS) but its clearance from the CNS in neonates has not been investigated. We have proposed that neonatal development of the blood-brain barrier affected CNS clearance mechanisms and CNS exposure to morphine. Male piglets (n = 5) aged one, three and six weeks were given morphine sulfate (0.5 mg kg(-1), i.v.). Serial blood and cerebrospinal fluid (CSF) samples were withdrawn over 360 min after morphine administration. Morphine concentration was measured by radioimmunoassay. A three-compartment model was fitted to individual data. Estimated parameters were reported as median and range. The peak morphine concentrations in plasma were not significantly different in the one-, three- or six-week-old piglets. Plasma clearance at one week (4.5, 3.8-8.6 mL min(-1) kg(-1)) was significantly lower than at three weeks (30.0, 19.1- 39.0 mL min(-1) kg(-1)) and six weeks (37.0, 29.7-82.8 mL min(-1) kg(-1)). The peak morphine concentration in CSF at one week (59.84, 31-67 ng mL(-1)) was higher than at three weeks (18.8, 17.7-25 ng mL(-1)) and six weeks (24.51, 16.5-84 ng mL(-1)), while CSF clearance was lower at one week (1.0, 0.18-9 mL min(-1) kg(-1)) compared with three weeks (6.2, 2.3-9.3 mL min(-1) kg(-1)) and six weeks (3.95, 1.3-85.7 mL min(-1) kg(-1)). Apparent plasma:CSF transfer ratio at one week was greater than at three and six weeks. The reduced plasma and CSF morphine clearance in early infancy resulted in elevated systemic and central morphine exposure in neonatal pigs.

Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

Background: To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction., Patients and Methods: Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients., Results: Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study., Conclusions: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Objective: The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN-38 and SN-38 glucuronide (SN-38G)., Methods: Plasma concentrations were obtained during and up to 48 hours after a 90-minute continuous intravenous infusion of irinotecan (100-340 mg/m(2)) in 78 patients. Data splitting was used to create model-building and model-validation data sets. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolites that are dependent on the disposition of the parent compound. Relationships between patient attributes and estimates of clearance (CL) and volume of the central compartment for irinotecan, as well as CL and volume of the central compartment adjusted for the fraction metabolized for SN-38 and SN-38G, were explored by use of generalized additive models and graphic analysis. Selected covariates were introduced into the final population model by stepwise additions or deletions with the likelihood ratio test., Results: SN-38 and SN-38G were shown to be formation rate-limited and were characterized by first-order rate constants of formation and elimination. Two subpopulations of SN-38 disposition were identified, presumably because of differences in the fraction of metabolite formed from the parent compound. Estimated irinotecan CL (25.2 L/h) was similar to that determined in other studies. Age and performance status were found to be important predictors of irinotecan CL, whereas variability in systemic exposure to the active metabolite, SN-38, was predicted by sex and hepatic function., Conclusion: The validated population pharmacokinetic model describing the disposition of irinotecan and 2 of its metabolites should facilitate the design of future studies to elucidate the relative contributions of the parent compound and SN-38 to the pharmacologic and toxic effects of irinotecan therapy.

Aims: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction., Methods: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods., Results: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods., Conclusions: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.

The aim of the study was to evaluate the effect of cirrhosis on the disposition of the haemoglobin-based oxygen carrier, diaspirin cross-linked haemoglobin (DCLHb). Cirrhosis was induced in male Sprague-Dawley rats (200-250 g) by inhalational exposure to carbon tetrachloride (CCl4), over a period of 6 weeks. Pharmacokinetic evaluation was performed after a single intravenous bolus administration of DCLHb (400 mg kg(-1)). Serum biochemistry, including aspartate transaminase, alkaline phosphatase, bile acids, serum albumin, and serum creatinine, were measured in CCl4-treated (n = 6) and age-matched control (n = 6) rats. After 6 weeks, the jugular vein and carotid artery were cannulated for bolus DCLHb administration (400 mg kg(-1)) and blood sampling, respectively, in both groups of rats. Cirrhosis produced significant (P < 0.05) elevations in alkaline phosphatase (497.4 +/- 84.8 U L(-1) vs 241.2 +/- 5.1 U L(-1)), aspartate transaminase (920.5 +/- 190.9 U L(-1) vs 238.2 +/- 118.1 U L(-1)) and bile acids (333.8 +/- 77.3 mg dL(-1) vs 43.8 +/- 4.2 mg dL(-1)) compared with the control group. No significant renal dysfunction was observed as a result of CCl4 exposure. Plasma DCLHb concentrations declined approximately log-linearly. Systemic clearance of DCLHb was estimated to be 2.2 +/- 0.7 mL h(-1) in the treatment group and was slightly, but not significantly, less in the control group (3.6 +/- 1.7 mL h(-1)). There was also a trend toward a longer elimination half-life in the treatment group (4.7 +/- 2.2 h) compared with the control group (3.8 +/- 0.8 h), although this difference was not statistically significant. Cirrhosis does not significantly alter the disposition of DCLHb perhaps due to increased extra-hepatic metabolism by the reticulo-endothelial system.

Purpose: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity., Patients and Methods: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel., Results: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions., Conclusion: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).

Objective: To characterize drug-taking behavior using continuous electronic monitoring in an AIDS clinical trial., Setting: This was a substudy of AIDS Clinical Trials Group (ACTG) protocol 175, a phase II/III study of dideoxynucleoside monotherapy versus combination therapy in asymptomatic HIV-positive subjects. Participants were required to comply with regimens containing zidovudine, zalcitabine and didanosine, or matching placebos; the total daily pill count was 16., Design: For participants at two ACTG 175 sites, electronic devices were used to monitor drug-taking behavior of all study medications over a period of approximately 90 days., Measurements: Four indices of drug-taking behavior were calculated and their distributions and relationship to the prescribed regimen were examined., Results: Data from 41 subjects were analyzed. Of the prescribed doses of zidovudine, zalcitabine and didanosine, 88, 84 and 82%, respectively, were taken. Of these, 55, 66 and 79%, respectively, were taken at the prescribed dosing frequency. The median percentage of days on which participants failed to take any of the doses was 2-5%. There was a trend towards lower adherence in the combination therapy arms compared with those assigned to receive monotherapy. In this analysis, older patients demonstrated better adherence, although patient characteristics, in general, were poorly predictive of adherence., Conclusion: Drug-taking behavior for all three active study medications differed from that prescribed. One result of this erratic adherence was that study participants sustained little antiretroviral effect during more than 25% of the monitoring period.

Objectives: To assess adherence to study medications in an AIDS clinical trial, to evaluate whether study participants adhered to only one component of a multidrug regimen ('differential adherence'), and to determine whether there was evidence of non-uniform adherence to study medications among treatment groups., Setting: This was a substudy of AIDS Clinical Trials Group protocol 175, a large, double-blind, randomized study of monotherapy versus combination dideoxynucleoside therapy. Participants were required to adhere to a complex regimen of zidovudine, zalcitabine and didanosine, or their matching placebos., Design: Between October 1992 and January 1994, study sites were selected at random, and a 1-week period was designated during which study participants attending routine clinic visits provided a blood sample and dosing history. Participants were not informed of the purpose of the substudy., Measurements: Adherence was assessed using plasma drug concentrations and defined by the presence of detectable drug in a plasma sample obtained within a specified analysis window., Results: Of 722 plasma samples analyzed, approximately 75% contained detectable concentrations of the assigned drugs and 5-14.5% contained no detectable drugs. Approximately 7 and 13% of samples from participants assigned to monotherapy arms contained non-prescribed dideoxynucleosides, and 14 and 19% assigned to combination therapies contained only one drug., Conclusions: Various non-adherence behaviors were observed, including patterns of underdosing and taking non-prescribed drugs. Non-adherence was moderate but uniform amongst the treatment groups and may have contributed to a marginal reduction in the power of the primary intent-to-treat analysis to detect differences in efficacy amongst the assigned treatments.

Patient compliance (adherence) with prescribed medication is often erratic, while clinical outcomes are causally linked to actual, rather than nominal medication dosage. We propose here a hierarchical Markov model for patient compliance. At the first stage, conditional upon individual random effects and a set of individual-specific nominal daily dose times, we assume that (i) the subject-specific probability of taking zero, one, or more than one dose associated with a given nominal dose time depends on the value of certain covariates, and on the number of doses associated with the immediate previous time, but is independent of any other previous or future dosing events (the Markov hypothesis); and (ii) the set of 'errors' between actual dose times associated with each nominal time is multivariate normally distributed, conditional on covariates and the number of such actual dose times, as in (i). At the second stage, a multivariate normal distribution is assumed for the individual random effects. We fit this model by maximum likelihood to data collected over three months using an electronic system for recording actual dose times in HIV-positive patients assigned to a regimen of zidovudine thrice daily. Beyond its value for describing and quantifying compliance behaviour, as illustrated here, the model may prove useful for explanatory analyses of clinical trials.

We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

Well-designed clinical trials maximize the information that can be obtained regarding the clinical pharmacology of a drug and, in turn, can streamline and enhance the drug development process. Until recently, little emphasis has been placed on integrating the role of variability in individual patterns of drug-taking into the drug development process. With the use of electronic monitoring, the temporal relationship between an individual's pattern of dosing and the prescribed regimen may be examined, and individual drug exposure may be estimated based on the actual history of dosing. As a result, accurate estimation of exposure-response relationships (or surrogate markers of response) can be obtained. Considerations in the design of clinical trials must therefore be expanded to include appropriate methods to measure compliance, sufficient frequency of monitoring to allow the time course of response to be mapped, and the use of statistically valid methods of data analysis.

For population pharmacokinetic analysis of multiple oral doses one of the key issues is knowing as precisely as possible the dose inputs in order to fit a model to the input-output (dose-concentration) relationship. Recently developed electronic monitoring devices, placed on pill containers, permit precise records to be obtained over months, of the time/date opening of the container. Such records are reported to be the most reliable measurement of drug taking behavior for ambulatory patients. To investigate strategies for using and summarizing this new abundant information, a Markov chain process model was developed, that simulates compliance data from real data from electronically monitored patients, and data simulations and analyses were conducted. Results indicate that traditional population pharmacokinetic analysis methods that ignore actual dosing information tend to estimate biased clearance and volume and markedly overestimate random interindividual variability. The best dosing information summarization strategies consist of initially estimating population pharmacokinetic parameters, using no covariates and only a limited number of dose records, the latter chosen based on an a priori estimate of the half-life of the drug in the compartment of interest; then resummarizing the dose records using either population or individual posterior Bayes parameter estimates from the first population fit; and finally reestimating the population parameters using the newly summarized dose records. Such summarization strategies yield the same parameter estimates as using full dosing information records while reducing by at least 75% the CPU time needed for a population pharmacokinetic analysis.

Medical students were introduced to issues relating to medication noncompliance in a simulated clinical setting. Compliance with either a twice-a-day or a three-times-a-day regimen was monitored with use of electronic monitoring devices for a 2-week interval. Compliance with the twice-a-day regimen was higher than compliance with the three-times-a-day regimen, although the difference was not significantly different. Overall, 71% of the prescribed doses were taken by the medical student participants; however, only 46.5% of the doses were taken at the prescribed dosing frequency and 28.5% were taken at the prescribed intervals. The majority of students linked dose taking with routine daily activities and reported that their hectic lifestyles adversely influenced compliance. Similar factors might be expected to influence compliance in patient populations. The goal of this exercise was to demonstrate to future physicians the difficulties that patients have with compliance to prescribed medications.

Purpose: CCNU (lomustine) and other nitrosourea compounds are rapidly metabolized to alkylating moieties, which are active against various malignancies. In humans, CCNU undergoes biotransformation to the geometric isomers of 4'-hydroxyCCNU. The pharmacokinetics of trans-and cis-4'-hydroxyCCNU were determined in five patients with Hodgkin's or non-Hodgkin's lymphoma receiving sequential doses of CCNU (15 mg/kg), etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg) prior to autologous bone marrow transplantation., Methods: Plasma concentrations of the isomeric forms of the metabolites were determined by high-performance liquid chromatography. Data were analysed using noncompartmental pharmacokinetic methods., Results: Formation of the trans-isomer predominated over that of the cis-isomer, with an average exposure ratio of 1.4 (range 1.0-2.1). Peak plasma concentrations occurred between 1 and 4.1 h postdosing and averaged 1.56 mg/l for the trans-isomer and 1.10 mg/l for cis isomer. Peak plasma concentrations and systemic exposures varied approximately six- and ninefold, respectively, reflecting significant interindividual variability in alkylating activity after high doses of CCNU. Plasma half-lives of the metabolites were 3.1 h (range 1.1-4.5 h) for the trans-isomer and 3.5 h (range 1.3-6.4 h) for the cis- isomer, and varied linearly with increasing patient body weight. There was no significant difference in plasma half-lives after high-dose CCNU administration observed in this study and those reported previously after the administration of substantially lower doses of CCNU., Conclusion: Despite linearity in the pharmacokinetics of the isomeric forms of 4'-hydroxyCCNU at high doses, large interindividual variability in exposure to the CCNU metabolites was observed. Potential saturation of metabolic pathways to the isomers at these doses may manifest as toxic symptoms since alkylating moieties formed directly from the parent, CCNU, may be associated with greater toxicity than those formed from the isomeric forms of the 4'-hydroxylated metabolite.

Background: This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies., Methods: Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0., Results: Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months)., Conclusion: The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

After routine inguinal herniorrhaphy we gave 12 patients a wound infiltration regimen of bolus doses of 20 ml of 0.5% bupivacaine via a catheter within the wound and rectally administered indomethacin (100 mg). Peak venous plasma bupivacaine concentrations ranged from 0.07 mg.l-1 to 1.14 mg.l-1 (mean (SD) 0.47 (0.33) mg.l-1), and occurred at between 0.25 and 2 h after the first dose. Plasma concentrations were well below the toxic threshold of 4 mg.l-1 and there was no accumulation. The regimen provided satisfactory analgesia. There were no wound infections nor signs of toxicity.

A high-performance liquid chromatographic method with ultraviolet detection at 210 nm for quantitation of bupivacaine and two of its metabolites from plasma and urine is described. The compounds are extracted into n-hexane-isopropanol (5:1), evaporated and the reconstituted residue injected onto a reversed phase C18 column. Standard curves for all compounds were linear (r2 greater than 0.999) in the range 20-2000 ng/ml, with a limit of detection of 10 ng/ml. The inter-day coefficients of variation ranged between 2.7 and 12.2%. The method was applied to analyse bupivacaine and metabolite concentrations in patients on long-term epidural bupivacaine-fentanyl infusions.