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Dose-finding methods for Phase I clinical trials using pharmacokinetics in small populations
Moreno Ursino1, Sarah Zohar1, Frederike Lentz2
1INSERM, UMRS 1138, team 22, CRC, University Paris 5, University Paris 6, Paris, France.
Biometrical Journal. Biometrische Zeitschrift
|March 22, 2017
Summary
Integrating pharmacokinetic (PK) measures into phase I clinical trial dose allocation improves the estimation of the dose-toxicity relationship. This approach enhances dose recommendations for future studies without compromising maximum tolerated dose selection.
Area of Science:
- Clinical Pharmacology
- Drug Development
- Biostatistics
Background:
- Phase I clinical trials aim to determine drug safety, tolerability, pharmacokinetics (PK), and mechanism of action to establish the maximum tolerated dose (MTD).
- Current phase I trial designs often analyze dose-finding and PK separately, limiting efficiency, especially in rare diseases or pediatric studies.
- Integrating PK data into dose allocation can optimize trial design and information gathering.
Purpose of the Study:
- To propose, study, and compare methods for incorporating PK measures into the dose allocation process of phase I clinical trials.
- To evaluate the impact of PK-guided dose allocation on dose-finding efficiency and dose-toxicity curve estimation.
- To assess the utility of PK information in optimizing MTD selection and subsequent dose recommendations.
Main Methods:
- Development and comparison of methods integrating PK observations as covariates, dependent variables, or within hierarchical models.
- Conducting a large-scale simulation study to evaluate the performance of different PK-integrated dose allocation strategies.
- Assessing trial efficiency based on the number of observed dose-limiting toxicities and the probability of correct MTD selection.
Main Results:
- Incorporating PK measurements solely as a covariate did not improve dose-finding trial efficiency regarding dose-limiting toxicities or MTD selection probability.
- Integrating PK measures significantly enhanced the estimation of the dose-toxicity curve.
- PK-integrated designs maintained performance in MTD selection compared to traditional dose-finding methods.
Conclusions:
- Using PK information in dose allocation enriches understanding of the dose-toxicity relationship.
- PK-integrated approaches facilitate better dose recommendations for subsequent clinical trials.
- This strategy is particularly valuable in scenarios with limited patient populations, such as rare diseases or pediatric studies.
Keywords:
Dose-findingDose-toxicity relationshipMaximum tolerated dosePharmacokineticsPhase I clinical trialsMore Related Videos
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