Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information.
The aim of the present paper was to present an overview of the current status of the methods used to predict the magnitude of pharmacokinetic drug-drug interactions (DDIs) which are caused by apparent changes in cytochrome P450 (CYP) activity with an emphasis on a method using in vivo information. In addition, more than a hundred representative CYP substrates, inhibitor and inducer drugs involved in significant pharmacokinetic DDIs were selected from the literature and are listed. Although the magnitude of DDIs has been conventionally predicted based on in vitro experiments, their predictability is restricted occasionally due to several difficulties, including a precise determination of the unbound inhibitor concentrations at the enzyme site and a reliable in vitro measurement of the inhibition constant (K(i)). Alternatively, a simple method has been recently proposed for the prediction of the magnitude of DDIs based on information fully available from in vivo clinical studies. The new in vivo-based method would be applicable to the adjustment of dose regimens in actual pharmacotherapy situations although it requires a prior clinical study for the prediction. In this review, theoretical and quantitative relationships between the in vivo- and the in vitro-based prediction methods are considered. One of the interesting outcomes of the consideration is that the K(i)-normalized dose (dose/in vitro K(i)) of larger than approximately 20L (2-200L, when variability is considered) may be a pragmatic index which predicts significant in vivo DDIs. In the last part of the article, the relevance of the inclusion of the in vivo-based method into the process of new drug development is discussed for good prediction of in vivo DDIs.
Hisaka
Akihiro
A
Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ohno
Yoshiyuki
Y
Yamamoto
Takehito
T
Suzuki
Hiroshi
H
D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004794:Enzyme Repression / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D010599:Pharmacokinetics
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human