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% Cmax and 44% area under the curve (AUC∞ ) increase in piragliatin exposure without affecting glucose AUC0-6h following ketoconazole (400 mg QD × 5 days); 30% Cmax and 72% AUC∞ decrease in piragliatin exposure with a 13% increase in glucose AUC0-6h following rifampicin (600 mg QD × 5 days); and, unexpectedly, a 32% Cmax and 23% AUC0-6h decrease (no change in AUC∞ ) in piragliatin exposure with a 13% increase in glucose AUC0-6h 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.
Roche Innovation Center of New York, New York, NY, USA.
Jianguo
J
Zhi
Roche Innovation Center of New York, New York, NY, USA.
Suoping
S
Zhai
Roche Innovation Center of New York, New York, NY, USA.
Angela
A
Georgy
Roche Innovation Center of New York, New York, NY, USA.
Zhenming
Z
Liang
Roche Innovation Center of New York, New York, NY, USA.
Mark
M
Boldrin
D000328:Adult; D000368:Aged; D044482:Benzeneacetamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism / Q000652:urine; D004311:Double-Blind Method; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology*
D044482:Benzeneacetamides; D001786:Blood Glucose; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007004:Hypoglycemic Agents; D000431:Ethanol; C553963:piragliatin; D007654:Ketoconazole; D012293:Rifampin
glucokinase activator; interaction; pharmacodynamics; pharmacokinetics