The importance of drug-drug interactions in the DAA era

Abstract

With the licensing of the direct acting antivirals telaprevir and boceprevir the topic of drug-drug interactions has come to the forefront. These first generation hepatitis C virus protease inhibitors are metabolized by and inhibit the key drug metabolizing enzyme CYP3A4, which means that knowledge of drug-drug interactions has become an essential component of the evaluation of a patient starting triple therapy. The number of potential co-medications means that many drugs will be used in hepatitis C virus patients where there are no pharmacokinetic study data. Here we have to use the data that are available and seek to extrapolate to unstudied drugs using key principles of clinical pharmacology (disposition characteristics, concentration-effect relationships, therapeutic window) in order to give some guidance for management of patients. This is a rapidly moving area in hepatitis C therapy, both in terms of understanding the drug interaction profile of telaprevir and boceprevir, interaction mechanisms that sometimes appear counterintuitive and that may involve enzymes other than CYP3A4 or transporters, but then seeking to understand the interaction potential of the next wave of drugs that will soon be with us.

Keywords: AKR; AUC; BID; BOC; Boceprevir; CYP; DAAs; Drug–drug interactions; HCV; HIV; Hepatitis C virus infection; IFN; P-glycoprotein; P-gp; Pharmacokinetics; RBV; SPCs; TVR; Telaprevir; UDP-glucuronosyltransferase; UGT; aldo-ketoreductases; area under the plasma concentration vs. time curve; boceprevir; cytochrome P450; direct-acting antivirals; hepatitis C virus; human immunodeficiency virus; interferon; ribavirin; summary of product characteristics; telaprevir; twice daily.