Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban

Argatroban, a direct thrombin inhibitor is metabolized in vitro by CYP3A4/5 and therefore may be susceptible to clinically relevant CYP3A drug interac tions. The effect of erythromycin, a potent CYP3A4/5 inhibitor, on the phar macokinetics and pharmacodynamics of argatroban was evaluated in 14 healthy male volunteers in an open-label, crossover study with a 5-day washout bet ween regimens. Argatroban 1 mu g/kg/min was infused alone for 5 hours (regi men A) and again on day 6 of a 7-day oral regimen of 500 mg erythromycin fo ur times daily (regimen B). Serial blood samples for the determination of a ctivated partial thromboplastin time (aPTT) and argatroban concentrations w ere collected for up to 48 hours following infusion. Mean values for argatr oban area under the concentration-time curves (AUC(0-inf)), maximum concent ration (C-max), and half-life (t(1/2)) were similar between regimens. Mean aPTT values were not affected significantly by the concomitant administrati on of argatroban and erythromycin compared to argatroban alone. No serious adverse events or bleeding episodes occurred during the study These results suggest that oxidative metabolism by CYP3A4/5 is unlikely to be an importa nt in vivo elimination pathway for argatroban. Therefore, coadministration of CYP3A4/5 inhibitors should not require a modification in the dosage of a rgatroban. (C) 1999 the American College of Clinical Pharmacology.