Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.

TitleEffect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.
Publication TypeJournal Article
Year of Publication2008
AuthorsCao YJun, Flexner CW, Dunaway S, Park J-G, Klingman K, Wiggins I, Conley J, Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW
JournalAntimicrob Agents Chemother
Date Published2008 May
KeywordsAdolescent, Adult, Area Under Curve, Dose-Response Relationship, Drug, Heterocyclic Compounds, 1-Ring, HIV Protease Inhibitors, Humans, Male, Metabolic Clearance Rate, Middle Aged, Receptors, CXCR4, Ritonavir

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 x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 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-infinity) 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.

Alternate JournalAntimicrob. Agents Chemother.
PubMed ID18285477
PubMed Central IDPMC2346642
Grant ListAI038855 / AI / NIAID NIH HHS / United States
M01RR000052 / RR / NCRR NIH HHS / United States
M01RR00037 / RR / NCRR NIH HHS / United States
U01AI027668 / AI / NIAID NIH HHS / United States
U01AI27664 / AI / NIAID NIH HHS / United States