Extrapolation of pharmacokinetic interaction data of proton pump inhibitors obtained in healthy subjects for oral targeted therapies in cancer patients

摘要

During the drug-development process, it is essential to evaluate the potential for any drug-drug interaction (DDI) during early clinical Phase I stage based on the in vitro absorption distribution metabolism excretion (ADME) data gathered during the discovery-development transition phase leading to the IND filing of the new chemical entity [1,2]. Such an evaluation becomes critical for anticancer therapy due to a higher risk of the occurrence of clinical DDI if the novel chemical entity is a victim or a perpetrator drug of cytochrome P450 enzyme (CYP) and/or uptake (liver/renal) transporters because of the existence of polypharmacy in the treatment of cancer patients [3,4], In this context, a recent article describes the dilemma observed in the PK data interpretation when rifampicin was used as a tool drug to study the induction of CYP3A4 enzyme in cancer patients [5]. Because rifampicin contributes for DDI via additional mechanisms such as P-glycoprotein (Pgp)/UDP glucuronosyl transferase (UGT) induction and uptake transporter inhibition, the interpretation of the PK data poses a challenge [5].