Dataset Information

Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.

ABSTRACT: The purpose of this study was to develop and validate a population pharmacokinetic model for Z-endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z-endoxifen-HCl was administered orally once a day on a 28-day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z-endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed-effects modeling to develop a population pharmacokinetic model for Z-endoxifen. A 2-compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight-effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z-endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z-endoxifen and may assist in the design of future clinical trials.

SUBMITTER: Koubek EJ

PROVIDER: S-EPMC9339467 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.

Koubek Emily J EJ Ralya Andrew T AT Larson Thomas R TR McGovern Renee M RM Buhrow Sarah A SA Covey Joseph M JM Adjei Alex A AA Takebe Naoko N Ames Matthew M MM Goetz Matthew P MP Reid Joel M JM

Journal of clinical pharmacology 20220419 9

The purpose of this study was to develop and validate a population pharmacokinetic model for Z-endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z-endoxifen-HCl was administered orally once a day on a 28-day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z-endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed-effects modeling to develop a population p ...[more]

PMID: 35358345

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Project description:Iruplinalkib (WX-0593), a selective oral ALK/ROS1 tyrosine kinase inhibitor, was approved in China as first-line therapy for ALK-positive non-small-cell lung cancer (NSCLC) and for the treatment of locally advanced or metastatic ALK-positive NSCLC that has progressed following crizotinib therapy. Pharmacokinetics (PK) data of iruplinalkib have been collected in healthy subjects and patient populations in several studies. We developed a population PK (PopPK) model for describing iruplinalkib plasma concentrations and for evaluating whether dose adjustments are necessary based on demographic factors or disease characteristics. Plasma concentration-time data were collected from 392 participants (16 healthy volunteers and 372 patients with solid tumors) who received single or multiple doses of iruplinalkib in four trials. Data were analyzed using non-linear mixed-effects modeling. Iruplinalkib plasma concentrations were best described by a two-compartment model with first-order absorption and first-order elimination. Baseline body weight, time-varying albumin, time-varying creatinine clearance, and time-varying lactate dehydrogenase were significant covariates of apparent clearance from the central compartment (CL/F) while baseline body weight was a significant covariate of apparent volume of the central compartment (V1/F). Given the small or modest effect of all statistically significant covariates on iruplinalkib exposure at steady-state, no covariate was expected to have clinically meaningful effects on iruplinalkib exposure. Furthermore, iruplinalkib absorption was delayed 0.472 h after meal, and Ka was 58.8% of that under fasting. However, there was no difference in exposure of iruplinalkib between the fasted and fed states. In conclusion, the PopPK model adequately describes iruplinalkib PK properties in Chinese healthy subjects and patients with solid tumors. No covariate had a clinically meaningful impact on iruplinalkib exposure. These results indicate that dose adjustment of iruplinalkib is not necessary, based on the aforementioned covariates, for ALK-positive NSCLC patients.

Project description:Background and objectiveOveractivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.MethodsPharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.ResultsA total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).ConclusionsCapivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.

Dataset Information

Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.

Publications

Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.

Similar Datasets

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