A Bayesian Pharmacokinetics Integrated Phase I-II Design To Optimize Dose-Schedule Regimes

Authors

Mengyi Lu
Ying Yuan
Suyu Liu

Publication Date

12-31-2024

Journal

Biostatistics

DOI

10.1093/biostatistics/kxae034

PMID

39275895

PMCID

PMC11823184

PubMedCentral® Posted Date

9-13-2024

PubMedCentral® Full Text Version

Post-print

Abstract

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. Conditional on the drug concentration in plasma, we jointly model toxicity and efficacy as a function of the concentration. We quantify the risk-benefit of regimes using utility-continuously updating the estimates of PK, toxicity, and efficacy based on interim data-and make adaptive decisions to assign new patients to appropriate dose-schedule regimes via adaptive randomization. The simulation study shows that the PKIDS design has desirable operating characteristics.

Keywords

Bayes Theorem, Humans, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Pharmacokinetics, Dose-Response Relationship, Drug, Drug Administration Schedule, Computer Simulation, Models, Statistical, Research Design, dose-schedule finding, dose optimization, phase I–II trials, risk-benefit trade-off

Published Open-Access

yes

Recommended Citation

Mengyi Lu, Ying Yuan, and Suyu Liu, "A Bayesian Pharmacokinetics Integrated Phase I-II Design To Optimize Dose-Schedule Regimes" (2024). Faculty, Staff and Student Publications. 5187.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5187