Clinical Drug Interactions Due to Metabolic Inhibition: Prediction, Assessment, and Interpretation

Mechanisms and Consequences of Drug‐Drug Interactions

“…Inhibition of substrate metabolism by the perpetrator results in decreased substrate clearance, increased area under the plasma concentration curve (AUC) after single doses, and increased steady‐state plasma concentrations during multiple dosage (Table , Figure ) . A principal clinical concern is potential toxicity due to excessively high plasma levels of substrate, although deliberately enhanced substrate exposure through an intentionally‐produced inhibitory DDI (“boosting” or “enhancement”) is commonly applied in treatment of HIV and HCV infections.…”

“…Though inhibition and induction of metabolism have opposite pharmacokinetic outcomes, the two phenomena are mechanistically distinct and do not represent the same process operating in opposite directions. Metabolic inhibition results from the direct effect of a chemical inhibitor on the enzyme itself . The onset of an inhibitory DDI occurs rapidly or immediately following exposure of the enzyme to the perpetrator.…”

“…With co‐addition of candidate inhibitors, metabolic rates may be modified. Quantitative parameters, such as the inhibition constant (K i ) or the 50% inhibitory concentration (IC 50 ), can be used to compare inhibitors or to attempt extrapolative predictions of clinical DDIs . In vitro studies of this type are relatively straightforward and inexpensive.…”

“…Many of these drugs also are substrates for transport by P‐gp. For such drugs, oral bioavailability and systemic exposure may be limited by a combination of enteric and hepatic presystemic extraction, together with efflux transport by enteric mucosal cells . An early example of pharmacokinetic boosting involves cyclosporine as the target substrate.…”

Liver injury associated with ketoconazole: Review of the published evidence

“…If a candidate drug is identified as a possible or probable substrate for biotransformation via CYP3A isoforms, a controlled ketoconazole drug interaction study can address critical clinical and safety issues. In a typical study of this type, the candidate (substrate) drug is administered to healthy volunteers once in the control state with no inhibitor, and on another occasion during co‐treatment with ketoconazole during which the subjects assume what has been termed “human CYP3A phenotypic knockout status.” The increase in systemic exposure to the substrate (AUC) due to ketoconazole co‐treatment provides quantitative data on the contribution of CYP3A to net clearance, and well as the “worst case” drug interaction scenario in which concentrations of the substrate drug then reflect those achievable under maximal CYP3A inhibition . If the candidate drug itself is a suspected CYP3A inhibitor, its inhibitory potency can be compared to ketoconazole in a similarly designed study in which the CYP3A substrate drug is a known index compound such as midazolam, triazolam, or buspirone.…”