Exploratory Effects of a Strong CYP3A Inhibitor (Ketoconazole), a Strong CYP3A Inducer (Rifampicin), and Concomitant Ethanol on Piragliatin Pharmacokinetics and Pharmacodynamics in Type 2 Diabetic Patients

Piragliatin is a CYP3A substrate; its inactive metabolite M4, formed through cytosolic reductase, is reversibly metabolized back to piragliatin through CYP3A. The impact of concomitant CYP3A modifiers thus cannot be predicted. Drinking alcohol under fasting conditions is associated with a recognized glucose-lowering effect, which might be synergistic with piragliatin's hypoglycemic effect. Two exploratory studies were conducted to examine these potential interactions in type 2 diabetes (T2D) patients: 16 completed an open-label, sequential 2-way crossover, 2-arm (randomized to ketoconazole and rifampicin) CYP3A study; another 18 participated in a double-blind, placebo-controlled, randomized 3-way crossover ethanol study. Administration of piragliatin (100-mg single dose) resulted in a 32% C-max and 44% area under the curve (AUC infinity) increase in piragliatin exposure without affecting glucose AUC(0-6h) following ketoconazole (400mg QDx5 days); 30% C-max and 72% AUC infinity decrease in piragliatin exposure with a 13% increase in glucose AUC(0-6h) following rifampicin (600mg QDx5 days); and, unexpectedly, a 32% C-max and 23% AUC(0-6h) decrease (no change in AUC infinity) in piragliatin exposure with a 13% increase in glucose AUC(0-6h) following alcohol (40-g single dose). In conclusion, a strong CYP3A modifier or concomitant alcohol could lead to a change in exposure to piragliatin with a potential alteration in glucose-lowering effect.