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Antimicrob. Agents Chemother. doi:10.1128/AAC.01460-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Effect of Low-dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

Johns Hopkins University School of Medicine, Baltimore, MD, USA; University of Washington and Harborview Medical Center, Seattle, WA, USA; Frontier Science and Technology Research Foundation/Harvard School of Public Heath, Boston, MA, USA; Division of AIDS, NIAID/NIH, Bethesda, MD, USA; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; AnorMED, Inc., Langley, British Columbia, CA

^* To whom correspondence should be addressed. Email: ycao3{at}jhmi.edu.

	Abstract

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in HIV-infected patients. Since AMD070 is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were dosed with a single 200-mg AMD070 on Day 1, 3, and 17. Ritonavir (100 mg q12h) was dosed from Day 3 to Day 18. Blood samples for AMD070 concentration were collected for 48 hours after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study; two were discontinued for reasons other than safety. All adverse events were grade 2. AMD070 alone had the following pharmacokinetic features [median (range)]: 3 (0.5-4) hours for time to peak blood concentration, 256 (41-845) ng/ml for peak concentration (C_max), 934 (313-2127) hr•ng/ml for area under the concentration-time curve (AUC_0-), 214 (94-639) L/hr for apparent body clearance (CL/F), and 4201 (1996-9991) L for apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C_max of AMD070 [geometric mean (90% confidence interval)] by 39 (3-89) % and AUC_0- by 60 (29-100) %. After 14 days of ritonavir dosing, the pharmacokinetics changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir was consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.