Potential for a Drug Interaction Between Posaconazole and Phenytoin

R. D. COURTNEY, P. STATKEVICH, M. LAUGHLIN, S. PAI, J. LIM, R. P. CLEMENT, V. K. BATRA

Author address: 

Schering-Plough Research Institute, Kenilworth, NJ.

Abstract: 

Background: Posaconazole (POZ) is a broad-spectrum triazole antifungal agent developed to treat a wide variety of invasive fungal infections. POZ inhibits CYP3A4 metabolism, whereas, Phenytoin (PH) is an inducer of CYP3A4 metabolism. Methods: This randomized, open-label, parallel-group, multiple-dose study with POZ and PH was conducted in healthy male and female adult volunteers (n = 36) to assess the potential for a drug interaction between PH and POZ. Each subject was randomized to receive one of the following three treatments: Treatment A: POZ (200 mg QD) for 10 days, Treatment B: PH (200 mg QD) for 10 Days, and Treatment C: POZ (200 mg QD) and PH (200 mg QD) for 10 days. Blood samples were collected on Days 1 and 10 for pharmacokinetic (PK) evaluation of POZ and PH. Plasma data were analyzed by model-independent methods, and PK parameters were evaluated using ANOVA to assess changes in the area under the curve over 24 hr (AUC[0-24hr]), maximum plasma concentration (Cmax) and accumulation ratio (R) between Days 1 and 10 for both POZ and PH. Results: Cmax and AUC(0-24hr) values of POZ on Day 10 when administered alone were approximately 2-fold higher than those on Day 1 (R ~2); the steady state clearance (CL/F) on Day 10 was 30.3L/hr. In the presence of PH, however, the CL/F increased by ~90% and the Cmax and AUC(0-24hr) values of POZ on Day 10 were similar to those on Day 1 (R ~1). Within the limits of variability (%CV ranging from 22-77%), PH Cmax and AUC(0-24 hr) values showed no statistically significant differences (p>0.05) following single and multiple dose administration of PH in the presence or absence of POZ Conclusion: The large variability in the Cmax and AUC(0-24hr) values was due to some individuals with clinically significant increases in exposure of PH in the presence of POZ. Therefore, at this time we cannot recommend co-administration of POZ with PH.
2001

abstract No: 

NULL

Full conference title: 

ICAAC 41st
    • ICAAC 41st