Using physiologically-based pharmacokinetic modeling and simulation, researchers predicted multiple-dose exposure levels and optimized the design of a drug-drug interaction study for a compound exhibiting auto-inhibition.
A small biotechnology company had begun early clinical development of a candidate therapy with promise in multiple indications. The drug was metabolized and eliminated primarily through the cytochrome P-450 3A4 (CYP3A4) pathway.
In vitro studies had indicated the possibility of complex drug-drug interactions (DDI). The candidate exhibited both competitive and time-dependent inhibition of CYP34A, the key enzyme in its own metabolism. In Phase 1 trials, non-linear pharmacokinetics observed following multiple oral dosing were attributable to the study drug’s ability to inhibit its own metabolism (auto-inhibition), increasing exposure levels over time.