Evaluation of cytochrome P450-mediated drug–drug interactions based on the strategies recommended by regulatory authorities

Abstract

Herein, we aimed to evaluate the recently proposed risk assessment strategies of a cytochrome P450 (CYP) mediated drug-drug interaction (DDI) according to the European Medicines Evaluation Agency (EMEA) draft guideline, and discuss the differences between this guideline and the Food and Drug Administration (FDA) draft guidance. A retrospective study on reported 35 clinical DDI cases revealed that the EMEA assessment successfully predicts moderate-to-strong DDIs, i.e. drugs that cause more than 2-fold increase in the area under the curve in the presence and absence of CYP inhibitor (AUC(i)/AUC); however, EMEA tends to overlook weak DDIs with AUC(i)/AUC ≤ 2 to > 1.25. For CYP3A4 inhibitors, even clinically insignificant DDIs were overemphasized if the intestinal DDI is considered. The differences between unbound fraction in plasma and microsomes account for the discrepancies in DDI risk assessment results between EMEA and FDA assessments. Comparing two assessment results for CYP2D6 and CYP2C9 inhibitors, the FDA assessment suggested potential DDI risks for sulphinpyrazone and amitriptyline, while the EMEA assessment indicated no potential risk for these drugs. Through a retrospective study, we showed practical differences in the DDI assessment strategies of EMEA and FDA and suggested improvements in their current strategies.

Risk assessment of drug–drug interactions using hepatocytes suspended in serum during the drug discovery process

“…Only fluvoxamine was considered as potential inhibitor, even though it has no effect on the PK of desipramine. Likewise, an optimal cutoff value was examined using K i values obtained from recombinant human CYPs (rhCYPs), which were reported in the previous study (Kosugi et al, 2012). The false-negative and false-positive rates were examined by changing the cutoff value of K i from 0.3 to 100 in rhCYPs ( Figure 1B).…”

“…The clinical DDI datasets involving the reversible inhibition of CYP2C9, CYP2D6 and CYP3A4 were obtained from the published literature (Kosugi et al, 2012). Those of CYP2C8 were collected from the literature after having been searched by the Metabolism and Transport Drug Interaction Database (Copyright University of Washington 1999-2013.…”

Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

“…The [98][99][100] . Using IC 50 values as a surrogate for K i , the ratio of unbound C max values for clotrimazole and fluconazole to their respective inhibition potencies suggest the potential for these two compounds to inhibit CYP26 activity either locally (clotrimazole) or systemically (fluconazole).…”

“Drugs on oxygen”: an update and perspective on the role of cytochrome P450 testing in pharmacology

“…The situation is further complicated by the fact that different regulatory authorities recommend different strategies. The FDA advises the use of total concentrationbased values, while EMA asks to refer to unbound plasma concentrations [41]. There is good reason for both approaches.…”

“…For reversible inhibition there is basic consensus to define a DDI risk index based on the ratio of the inhibitor plasma concentration to the inhibition constant K i whenever possible but the respective experimental strategies to obtain these values remain disputed [31,40,41]. Literature values of the K i for classical CYP3A4 inhibitors such as fluconazole, ketoconazole and itraconazole differ up to 10-fold, probably due to different experimental conditions [41]. The situation is further complicated by the fact that different regulatory authorities recommend different strategies.…”