Effect of Hepatic Impairment on the Pharmacokinetics of the Novel Glycopeptide Oritavancin

Authors: Fetterly GJ, Owen JS, Bhavnani SM, Ambrose PG, Morello L, Loutit JS, Porter SB
Conference: AAPS
Keywords: adult, anti-infectives, antibiotic, Child-Pugh, gram-positive, infectious disease, intravenous, IV, liver, MRSA, non compartmental, oritavancin, PK
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Purpose: Oritavancin (ORI) is a semisynthetic glycopeptide being developed for the treatment of serious gram-positive infections. Physiochemical properties of ORI lead to extensive tissue distribution, with uptake by the tissues of the reticuloendothelial system, including the liver, lung, and spleen, while there is no evidence of metabolism. Due to ORI uptake by the liver, the effect of hepatic impairment on ORI pharmacokinetics was investigated in subjects with Child-Pugh Class B (moderate) liver insufficiency.

Methods: ORI was administered as a single dose of 800 mg over 90 minutes to 20 healthy subjects and 20 subjects with moderate hepatic impairment. Following the start of the infusion, plasma samples were collected at 45 and 85 minutes during the infusion, and at several timepoints post-infusion up to Day 45. Drug concentration was determined using an LC/MS/MS assay and noncompartmental PK analysis was performed for each group. ANOVA was used to compare the PK parameters (AUC0-∞, AUC0-24, AUC0-t, and Cmax) between subject groups.

Results: AUC and Cmax were lower in hepatically-impaired subjects compared with healthy subjects. Both AUC0-∞ and AUC0-t were 14% lower, AUC0-24 was 11% lower, and Cmax was 16% lower (Table 1). The 90% C.I. for ratios of AUC0- ∞ (0.76–0.98), AUC0-t (0.76–0.98), and AUC0-24 (0.77–1.02) were not within the pre-specified range of 0.80 to 1.25, thus equivalent exposure between subject groups could not be concluded. The 90% C.I. of the ratio for Cmax (0.73–0.96) was within the range of 0.70 to 1.43, indicating that peak exposure was equivalent between treatment groups. Overall, ORI was well tolerated.

Conclusions: While the plasma AUCs were statistically significantly different for hepatically-impaired subjects versus healthy subjects, the observed relative differences are not clinically significant and would not warrant a dose adjustment for moderate hepatic impairment.

American Association of Pharmaceutical Scientists (AAPS), Baltimore, Maryland, November 2004

By G.J. Fetterly, Joel S. Owen, S.M. Bhavnani, P.G. Ambrose, L. Morello, J.S. Loutit, S.B. Porter