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Abstract:
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Genetic variations can lead to huge inter-individual differences in drug efficacy and toxicity, so it is desirable to individualize chemotherapy. Genetic variations that affect drug metabolism are expected to affect all pharmacodynamic (PD) processes downstream, including both efficacy and toxicity, while other genetic variations may affect only one PD process. This suggests that a hierarchical model could help in designing an improved Phase I trial incorporating specific genetic information and prior belief. On the other hand, Phase I trials are small and may not contain enough information to support a highly adaptive design. The question is whether such a design could be helpful. We propose an adaptive Bayesian design based on a three-level hierarchical PK/PD model, incorporating patient response, toxicity, genotype and prior belief. Preliminary simulation results are encouraging.
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