INTERACTION BETWEEN AMD 11070 AND SUSTRATES OF CYP3A4 AND 2D6 ENZYMES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase I, single center, open label, multiple dose, sequential design drug interaction study that explores the potential for AMD11070 to inhibit cytochrome P450 (CYP) 3A4 and/or 2D6 probe drugs in healthy volunteers. The objective of this study is to compare the pharmacokinetics (PK) of single dose midazolam and dextromethorphan in the absence and presence of AMD11070 in healthy subjects. Enrolled subjects will be administered a single oral dose of dextromethorphan (CYP2D6 probe substrate) 30 mg, and a single oral dose of midazolam (CYP3A4 probe substrate) 5 mg, on Day 1. On Days 2-9, subjects will be administered twice daily (BID) oral doses of AMD11070. On Day 9, subjects will be administered, in addition to oral AMD11070 doses, a single oral dose of dextromethorphan, 30 mg and midazolam, 5 mg. Blood samples will be collected for midazolam and dextromethorphan PK analyses on Day 1 and Day 9. Blood samples will also be collected for AMD11070 PK analysis before the morning dose on Days 2, 3, 5 and 7, and over the 24-hour period on Day 9. Pre-dose blood samples will also be analysed by FACS t measure CD4+/CD8+ levels. Additional samples will also be collected on Days 10, 11, 12, and 15 for the same measurements. Subjects will be admitted to the study center on Day 0 and will be discharged on the morning of Day 10. Subjects will be asked to return for a follow up visits on Days 11,12, and 15. The safety and tolerability of oral midazolam, dextromethorphan, and AMD11070 and co-administration of these three drugs will be evaluated throughout the study. The study may consist of up to three cohorts of healthy subjects. The first cohort will receive AMD11070, 200 mg BID. Depending on the results from a concurrent safety and activity dose finding study of AMD11070, a subsequent cohort may be opened where the dose level of AMD11070 will be escalated or de-escalated to reflect the optimized dose level as determined by the concurrent study. If only one cohort is required, the cohort will consist of 12 healthy subjects. However, if more than one cohort is required, 9 healthy subjects will be included in the subsequent cohort (s).