Why, when, and how should pharmacogenetics be applied in clinical studies?: current and future approaches to study designs.

The growing interest in incorporating pharmacogenetics (PGx) into drug development and clinical practice raises several questions: which study designs best reveal relevant pharmacogenetic biomarkers, best clarify specific hypotheses in PGx, and result in the largest gain of clinical evidence in this field? In this review, we present and compare a variety of PGx-related study designs. The type and quality of evidence gained by each category of study design is evaluated, and an appropriate timeline for the integration of pharmacogenetic studies into drug development is proposed. A summary of the pros and cons of the different study designs might help investigators decide how best to incorporate PGx into drug research. Using different scenarios to explain how genetic polymorphisms influence drug action, we illustrate how this knowledge can be translated into individualized drug choices, individualized dosage determination based on pharmacogenetic diagnostics, and other types of monitoring in order to make drug therapies safer and more effective.

Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients.

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.