title: Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban.
abstract: Argatroban, a direct thrombin inhibitor, is metabolized in vitro by CYP3A4/5 and therefore may be susceptible to clinically relevant CYP3A drug interactions. The effect of erythromycin, a potent CYP3A4/5 inhibitor, on the pharmacokinetics and pharmacodynamics of argatroban was evaluated in 14 healthy male volunteers in an open-label, crossover study with a 5-day washout between regimens. Argatroban 1 microgram/kg/min was infused alone for 5 hours (regimen A) and again on day 6 of a 7-day oral regimen of 500 mg erythromycin four times daily (regimen B). Serial blood samples for the determination of activated partial thromboplastin time (aPTT) and argatroban concentrations were collected for up to 48 hours following infusion. Mean values for argatroban area under the concentration-time curves (AUC0-inf), maximum concentration (Cmax), and half-life (t1/2) were similar between regimens. Mean aPTT values were not affected significantly by the concomitant administration 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 important in vivo elimination pathway for argatroban. Therefore, coadministration of CYP3A4/5 inhibitors should not require a modification in the dosage of argatroban.
authors.affiliation: SmithKline Beecham Clinical Pharmacology Unit, Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, USA.
authors.forename: J Q
authors.initials: JQ
authors.lastname: Tran
authors.forename: R A
authors.initials: RA
authors.lastname: Di Cicco
authors.forename: S B
authors.initials: SB
authors.lastname: Sheth
authors.forename: M
authors.initials: M
authors.lastname: Tucci
authors.forename: L
authors.initials: L
authors.lastname: Peng
authors.forename: D K
authors.initials: DK
authors.lastname: Jorkasky
authors.forename: M J
authors.initials: MJ
authors.lastname: Hursting
authors.forename: L J
authors.initials: LJ
authors.lastname: Benincosa
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000991:Antithrombins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001120:Arginine / Q000031:analogs & derivatives; D018592:Cross-Over Studies; D004347:Drug Interactions; D004917:Erythromycin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010875:Pipecolic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013449:Sulfonamides
chemical_list: D000900:Anti-Bacterial Agents; D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D004917:Erythromycin; D001120:Arginine; C031942:argatroban