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Pharmacokinetic Effect of AMD070, an Oral CXCR4 Antagonist, on CYP3A4 and CYP2D6 Substrates Midazolam and Dextromethorphan in Healthy Volunteers

Nyunt, Myaing M ; Becker, Stephen ; MacFarland, Ron T ; Chee, Priscilla ; Scarborough, Robert ; Everts, Stephanie ; Calandra, Gary B ; Hendrix, Craig W

Journal of acquired immune deficiency syndromes (1999), 2008-04, Vol.47 (5), p.559-565 [Periódico revisado por pares]

Hagerstown, MD: Lippincott Williams & Wilkins, Inc

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Título:
Pharmacokinetic Effect of AMD070, an Oral CXCR4 Antagonist, on CYP3A4 and CYP2D6 Substrates Midazolam and Dextromethorphan in Healthy Volunteers
Autor: Nyunt, Myaing M ; Becker, Stephen ; MacFarland, Ron T ; Chee, Priscilla ; Scarborough, Robert ; Everts, Stephanie ; Calandra, Gary B ; Hendrix, Craig W
Assuntos: Administration, Oral ; Adolescent ; Adult ; Antiretroviral drugs ; Bioavailability ; Biological and medical sciences ; CD4-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - metabolism ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 CYP3A - metabolism ; Dextromethorphan - administration & dosage ; Dextromethorphan - pharmacokinetics ; Drug Interactions ; Drug therapy ; Excitatory Amino Acid Antagonists - administration & dosage ; Excitatory Amino Acid Antagonists - pharmacokinetics ; Female ; Fundamental and applied biological sciences. Psychology ; GABA Modulators - administration & dosage ; GABA Modulators - pharmacokinetics ; Heterocyclic Compounds, 1-Ring - administration & dosage ; Heterocyclic Compounds, 1-Ring - blood ; Heterocyclic Compounds, 1-Ring - pharmacokinetics ; HIV ; Human immunodeficiency virus ; Human viral diseases ; Humans ; Infectious diseases ; Leukocytosis - chemically induced ; Male ; Medical sciences ; Microbiology ; Midazolam - administration & dosage ; Midazolam - pharmacokinetics ; Middle Aged ; Miscellaneous ; Pharmacology ; Receptors, CXCR4 - antagonists & inhibitors ; Viral diseases ; Virology
É parte de: Journal of acquired immune deficiency syndromes (1999), 2008-04, Vol.47 (5), p.559-565
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: Hagerstown, MD: Lippincott Williams & Wilkins, Inc
Idioma: Inglês

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Pharmacokinetic Effect of AMD070, an Oral CXCR4 Antagonist, on CYP3A4 and CYP2D6 Substrates Midazolam and Dextromethorphan in Healthy Volunteers

Nyunt, Myaing M ; Becker, Stephen ; MacFarland, Ron T ; Chee, Priscilla ; Scarborough, Robert ; Everts, Stephanie ; Calandra, Gary B ; Hendrix, Craig W

Hagerstown, MD: Lippincott Williams & Wilkins, Inc

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