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Ritonavir Increases Concentrations of the CXCR4 Antagonist AMD070 in Healthy Volunteers
Ying-Jun Cao*1, C Flexner1, S Dunaway2, J G Park3, K Klingman4, I Wiggins1, J Conley2, C Radebaugh1, S Becker5, C Hendrix1, and the A5191 Study Team
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 2Univ of Washington Harborview Med Ctr, Seattle, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Div of AIDS, NIAID, NIH, Bethesda, MD, US; and 5AnorMED Inc, Langley, Canada
Background: Many HIV-infected patients either do not
tolerate available antiretroviral drugs or develop virologic
failure due to incomplete suppression of viral replication and development of
antiviral resistance. Thus, the identification of new classes of antiretroviral
drugs with unique mechanisms of action is an important goal of antiretroviral
drug development. AMD070, a CXCR4 antagonist, inhibits the replication of HIV-1
in vitro. It is rapidly absorbed
following oral administration and represents a new class of antiretroviral drug
for the management of HIV infection. Since AMD070 is a substrate of CYP3A4 and
P-glycoprotein and will be likely co-administered with ritonavir (RTV), we
tested the hypothesis that co-administration of RTV favorably alters the
pharmacokinetic (PK) profiles of AMD070.
Methods: A total of 23 healthy male subjects were given
a single 200-mg dose of AMD070 on day 1.
RTV (100 mg every 12 hours) was given from day 3 to
day 18. A single 200-mg AMD070 dose was given simultaneously with the first
dose of RTV on day 3 and with the morning dose of RTV on day 17. Blood samples
were collected for the determination of AMD070 concentration for 48 hours after
each administration of AMD070 on days 1, 3, and 17. Safety of AMD070 alone and
during co-administration with RTV was also assessed. Non-compartmental pharmacokinetic
analyses were performed with WinNonlin. Paired
comparison and the calculation of mean (95% confidence interval) were carried
out on the log scale for the quantification of drug interaction.
Results: Of the 23 subjects, 21 completed the study and
were included in the final pharmacokinetic analysis; 2 discontinued for reasons
other than safety. All adverse events were < grade 2. AMD070 alone
had the following pharmacokinetic features: 2.9 (2.4 to 3.6) hours for time to peak blood
concentration (Tmax), 231 (163 to 329) ng/mL for peak concentration (Cmax),
876 (701 to 1094) hr·ng/mL for 48-hour AUC (AUC0-48),
16 (14 to 18) hours for terminal half-life (t1/2), and 216 (173 to 270)
L/hour for total body clearance (CL/F). The initial dose of RTV decreased Tmax by 29% (10 to 44%) and CL/F by 38% (19 to 52%)
while increasing Cmax by 39% (–4 to 102%),
AUC0-48 by 55% (18 to 103%), and t1/2 by 20% (–4 to 49%). RTV at steady-state decreased Tmax by 25% (0 to 43%) and CL/F by 27% (2 to 46%)
while increasing Cmax by 47% (1 to 114%),
AUC0-48 by 24% (–1 to 82%), and t1/2 by 16% (–2 to 38%).
Conclusions: AMD070 concentrations were increased with
concomitant RTV dosed to steady state (14 days) in healthy volunteers.
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