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Antimicrobial Agents and Chemotherapy, May 2008, p. 1630-1634, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01460-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers ^,

Ying Jun Cao,^1* Charles W. Flexner,¹ Shelia Dunaway,² Jeong-Gun Park,³ Karin Klingman,⁴ Ilene Wiggins,¹ Jeanne Conley,² Christine Radebaugh,¹ Angela D. Kashuba,⁵ Ron MacFarland,⁶ Stephen Becker,⁶ and Craig W. Hendrix¹

Johns Hopkins University School of Medicine, Baltimore, Maryland,¹ University of Washington and Harborview Medical Center, Seattle, Washington,² Frontier Science and Technology Research Foundation/Harvard School of Public Health, Boston, Massachusetts,³ Division of AIDS, NIAID/NIH, Bethesda, Maryland,⁴ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,⁵ AnorMED, Inc., Langley, British Columbia, Canada⁶

Received 11 November 2007/ Returned for modification 14 January 2008/ Accepted 11 February 2008

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C_max), 934 h·ng/ml (313 to 2,127 h·ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC_0-), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the 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 to 89%) and the AUC_0- by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.

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* Corresponding author. Mailing address: Osler 501, 600 N. Wolfe Street, Baltimore, MD 21287. Phone: (410) 502-3252. Fax: (410) 614-9978. E-mail: ycao3{at}jhmi.edu

Published ahead of print on 19 February 2008.

AIDS Clinical Trial Group study A5191.

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Antimicrobial Agents and Chemotherapy, May 2008, p. 1630-1634, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01460-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.