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A multistate platform model was developed to describe time-to-event (TTE) endpoints in an oncology trial through the following states: initial, tumor response (TR), progressive disease (PD), overall survival (OS) event (death), censor to the last evaluable tumor assessment (progression-free survival [PFS] censor), and censor to study end (OS censor), using an ordinary differential equation framework. Two types of piecewise functions were used to describe the hazards for different events. Piecewise surge functions were used for events that require tumor assessments at the scheduled study visit times (TR, PD, and PFS censor). Piecewise constant functions were used to describe hazards for events that occur evenly throughout the study (OS event and OS censor). The multistate TTE model was applied to describe TTE endpoints from a published phase III study. The piecewise surge functions well-described the observed surges of hazards/events for TR, PD, PFS, and OS occurring near scheduled tumor assessments and showed good agreement with all Kaplan-Meier curves. With the flexibility of piecewise hazard functions, the model was able to evaluate covariate effects in a time-variant fashion to better understand the temporal patterns of disease prognosis through different disease states. This model can be applied to advance the field of oncology trial design and optimization by: (1) enabling robust estimations of baseline hazards and covariate effects for multiple TTE endpoints, (2) providing a platform model for understanding the composition and correlations between different TTE endpoints, and (3) facilitating oncology trial design optimization through clinical trial simulations., (© 2023 Amgen Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV-infected subjects with cirrhosis (Child-Pugh A; GLE area under the plasma concentration-time curve was 160% higher, and PIB area under the plasma concentration-time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end-stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors., (© 2019, The American College of Clinical Pharmacology.)

This first-in-human dose-ascending study investigated pharmacokinetics, safety, and tolerability of pibrentasvir following single and multiple doses in healthy volunteers. Additionally, the effects of food and ritonavir on pibrentasvir were assessed in a crossover study design. The starting dose of pibrentasvir was selected based on the no-observed-adverse-effect-level exposure from preclinical studies. Dose escalations of subsequent cohorts were dependent on reviews of the safety, tolerability, and pharmacokinetic data from previous dose cohorts. Pibrentasvir exposures increased in a greater than dose-proportional manner across the 1.5- to 120-mg dose range and became linear across the 120- to 600-mg dose range. Following multiple dosing, pibrentasvir steady state was attained by day 5 with an accumulation ratio of 25% to 35%. Pibrentasvir harmonic mean terminal half-life ranged from 20 to 22 hours. Food had minimal effect (<14%) on pibrentasvir bioavailability, but ritonavir increased pibrentasvir peak concentration and area under the concentration-time curve by 60% and 89%, respectively. All adverse events were assessed by the investigator as mild, and no clinically significant vital signs, electrocardiogram, or clinical laboratory values were observed. The pharmacokinetic results from this study support once-daily dosing and administration of pibrentasvir without regard to food. A maximum tolerated dose was not attained in the single- and multiple-ascending-dose assessments for pibrentasvir., (© 2017, The American College of Clinical Pharmacology.)