Pharmacokinetic effect of AMD070, an Oral CXCR4 antagonist, on CYP3A4 and CYP2D6 substrates midazolam and dextromethorphan in healthy volunteers.
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.


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.
Nyunt
Myaing M
MM
Johns Hopkins University School of Medicine, Division of Clinical Pharmacology, Baltimore, MD, USA.
Becker
Stephen
S
MacFarland
Ron T
RT
Chee
Priscilla
P
Scarborough
Robert
R
Everts
Stephanie
S
Calandra
Gary B
GB
Hendrix
Craig W
CW
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines; D001562:Benzimidazoles; D002082:Butylamines; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007964:Leukocytosis / Q000139:chemically induced; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
D000634:Aminoquinolines; D001562:Benzimidazoles; D002082:Butylamines; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam