title: Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers.
abstract: 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.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ycao3@jhmi.edu
authors.forename: Ying Jun
authors.initials: YJ
authors.lastname: Cao
authors.forename: Charles W
authors.initials: CW
authors.lastname: Flexner
authors.forename: Shelia
authors.initials: S
authors.lastname: Dunaway
authors.forename: Jeong-Gun
authors.initials: JG
authors.lastname: Park
authors.forename: Karin
authors.initials: K
authors.lastname: Klingman
authors.forename: Ilene
authors.initials: I
authors.lastname: Wiggins
authors.forename: Jeanne
authors.initials: J
authors.lastname: Conley
authors.forename: Christine
authors.initials: C
authors.lastname: Radebaugh
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Ron
authors.initials: R
authors.lastname: MacFarland
authors.forename: Stephen
authors.initials: S
authors.lastname: Becker
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines; D019540:Area Under Curve; D001562:Benzimidazoles; D002082:Butylamines; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D019438:Ritonavir / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D001562:Benzimidazoles; D002082:Butylamines; D017320:HIV Protease Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor; D019438:Ritonavir