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Pharmacokinetic Interaction between AMD11070 and Substrates of CYP3A4 and 2D6 Enzymes in Healthy Volunteers
M Nyunt1, S Becker2, R MacFarland2, S Everts1, P Chee2, R Scarborough2, and Craig Hendrix*1
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US and 2AnorMED Inc, Langley, Canada
Background:
AMD11070
belongs to a new class of ART, called “entry inhibitors,” with a novel
mechanism of action, binding CXCR4 receptors and inhibiting membrane fusion and
viral entry into CD4+ cells. It is a potent and selective inhibitor
of X4 viral replication in vitro. It
is orally bioavailable. Studies in vitro showed that AMD11070 is a
substrate of cytochrome P450 (CYP) 3A4, has a low potential for induction, but
may have a moderate inhibition of CYP2D6 and a time-dependent inhibition of
CYP3A4. Because many drugs commonly used in the care of HIV-infected patients
are CYP 2D6 and 3A4 substrates, identification of these interactions could have
substantial clinical significance.
Methods: Our objective was to compare the
pharmacokinetic parameters of CYP probe drugs, midazolam (CYP 3A4 substrate)
and dextromethorphan (CYP 2D6 substrate), in the absence and presence of
AMD11070. A cohort of 12 healthy subjects was enrolled. They received a single
oral dose of midazolam 5 mg and dextromethorphan 30 mg on day 1, and twice-daily
dosing of AMD11070 200 mg from day 2 to 9, inclusive. The same dose of the 2 CYP
probe drugs was administered with AMD11070 on day 9. Pharmacokinetic blood
samples for midazolam and dextromethorphan were collected on day 1 and 9, and
AMD11070 on day 9. Pharmacokinetic analyses were performed using validated
analytical methods. Data were analyzed using non-compartmental pharmacokinetic
methods. Interaction was evaluated using geometric mean ratio (90% confidence
interval).
Results: In the
presence of AMD11070, the mean (90% confidence interval) AUC0–24 and
Cmax of dextromethorphan increased 265% (190 to 370) and 252% (177
to 359), respectively, with almost an hour’s delay in time to peak
concentration, while the mean half-life was unchanged. There is also a 32% (13
to 54) increase in the plasma AUC0–24 for midazolam, without
appreciable differences in Cmax, Tmax, or t½. The
relative change in the AUC for both probe drugs was correlated with the AUC for
AMD11070 on day 9.
Conclusions: Increases in
the AUC0–24 for both CYP 2D6 and 3A4 probe drugs, and Cmax
for the CYP 2D6 probe, were statistically significant. Whether this interaction
is clinically beneficial or deleterious and warrants a dosing adjustment
remains to be shown. Interaction between AMD11070 with individual drugs of
clinical importance to HIV-infected patients and which are also substrates of
CYP 2D6 and 3A4 should be further explored.
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