| Reference | 1. Antimicrob Agents Chemother. 2008 May;52(5):1630-4. doi: 10.1128/AAC.01460-07.
Epub 2008 Feb 19.
<br><br>
Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist
AMD070 in healthy volunteers.
<br>
Cao YJ(1), Flexner CW, Dunaway S, Park JG, Klingman K, Wiggins I, Conley J,
Radebaugh C, Kashuba AD, MacFarland R, Becker S, Hendrix CW.
<br>
Author information: <br>
(1)Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
[email protected]
<br>
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.
<br><br>
2. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):559-65. doi:
10.1097/QAI.0b013e3181627566.
<br><br>
Pharmacokinetic effect of AMD070, an Oral CXCR4 antagonist, on CYP3A4 and CYP2D6
substrates midazolam and dextromethorphan in healthy volunteers.
<br><br>
Nyunt MM(1), Becker S, MacFarland RT, Chee P, Scarborough R, Everts S, Calandra
GB, Hendrix CW.
<br>
Author information: <br>
(1)Johns Hopkins University School of Medicine, Division of Clinical
Pharmacology, Baltimore, MD, USA.
<br>
BACKGROUND: Many antiretroviral drugs used in HIV care involve complex drug
metabolism by CYP3A4 and CYP2D6 enzymes, and drug interactions are problematic
clinically. AMD070, a novel entry inhibitor, is an inhibitor of X4-tropic HIV
virus. In vitro data suggested that it is a CYP3A4 substrate and may inhibit
CYP2D6 and CYP3A4.<br>
METHODS: Twelve healthy subjects were given a single oral dose of 5 mg of
midazolam and 30 mg of dextromethorphan on day 1 and 9, and 200 mg of AMD070
twice daily on days 2 through 9 (inclusive). Pharmacokinetic parameters of
midazolam and dextromethorphan were assessed alone and in the presence of AMD070.
RESULTS: The mean AUC0-24 and Cmax of dextromethorphan increased 2.86-fold (2.20
to 5.10, 90% confidence interval [CI]) and 2.52-fold (1.99 to 4.24, 90% CI),
respectively, in the presence of AMD070. Plasma AUC0-12 of midazolam increased
1.33-fold (1.15 to 1.61, 90% CI) without change in Cmax. The half-life did not
change for both drugs, but significant, parallel decrease in apparent oral
clearance and volume of distribution was observed.
CONCLUSIONS: The data support an alteration in bioavailability due to an
AMD070-mediated inhibition of presystemic metabolism, though an intestinal
P-glycoprotein effect could also be contributing. Interactions between AMD070
with CYP3A4 and, especially, 2D6 substrates of clinical importance in HIV care
should be further explored.
<br><br>
3. Antimicrob Agents Chemother. 2007 Jul;51(7):2351-8. Epub 2007 Apr 23.
<br><br>
Multiple-dose escalation study of the safety, pharmacokinetics, and biologic
activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.
<br>
Stone ND(1), Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S, Cao YJ,
Wiggins IP, Conley J, MacFarland RT, Park JG, Lalama C, Snyder S, Kallungal B,
Klingman KL, Hendrix CW.
<br>
Author information: <br>
(1)Johns Hopkins University School of Medicine, Division of Clinical
Pharmacology, Harvey 502, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
<br>
Erratum in<br>
Antimicrob Agents Chemother. 2007 Aug;51(8):3047.
<br>
AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human
immunodeficiency virus type 1. Thirty fasting healthy male volunteers received
oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given
every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior
to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was
well tolerated, without serious adverse events. Transient headaches (13 subjects)
and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were
the most common complaints. Seven subjects had sinus tachycardia, and two were
symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing.
The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose
proportionality was not demonstrated. Less than 1% of the drug appeared unchanged
in the urine. Food reduced the maximum concentration of drug in serum and the
area under the concentration-time curve from 0 to 24 h by 70% and 56%,
respectively (P < or = 0.01). A dose-dependent elevation of white blood cells
(WBC) demonstrated a maximum twofold increase over baseline (95% confidence
interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was
well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced
drug exposure. AMD070 induced a dose-related elevation of WBC which was
attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4
inhibition, this dose-response relationship suggests that the doses used in this
study were active in vivo, though not maximal, throughout the dosing interval.
Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro
90% effective concentration of AMD070.<br>
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