Polymorphic Effects of Cytochrome P450 3A5 on Pharmacokinetics of Maraviroc and Its Metabolites

This study aims to evaluate the effects of CYP3A5 genotype on pharmacokinetics of maraviroc
and its oxidative metabolites. A single oral dose of 300 mg maraviroc will be given to 24
eligible healthy individuals who will be screened and determined to have specific CYP3A5
genotype - 8 homozygous wild type (2 CYP3A5*1 alleles), 8 heterozygous (1 CYP3A5*1 allele
and 1 mutant allele), and 8 without wild type genotype (2 mutant alleles). Blood samples
will be drawn and urine samples will be collected immediately before and during a 32-hr
period following the dose. The concentrations of maraviroc and its oxidative metabolites
from the blood and urine samples will be measured and the pharmacokinetics of maraviroc and
its metabolites will be compared among the three groups with different CYP3A5 polymorphic
status.

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Inclusion Criteria:

- Healthy with no acute medical illness

- Willing to provide written informed consent

- Age 18-65 years

- Negative serum pregnancy test (females only) at screening and a negative urine
pregnancy test (females only) on day of dosing

- HIV seronegative at screening, as determined by any licensed ELISA

- At screening, no evidence of hepatic or renal impairment (LFT's < 1.5 Upper Limit of
Normal (ULN), creatinine clearance > than 60 ml/min, total bilirubin below ULN, AST
and ALT below 1.5 ULN)

- 8 subjects with homozygous CYP3A5 allele *1 (wild type)

- 8 subjects with 1 CYP3A5*1 allele and 1 mutant allele

- 8 subjects with CYP3A5 allele other than *1

Exclusion Criteria:

- Concomitant medication (prescription or over-the-counter) or herbal supplements for
which there is a known risk of pharmacokinetic or pharmacodynamic drug interactions,
including those that inhibit CYP3A4 as listed on the P450 Drug Interaction Table
(http://medicine.iupui.edu/clinpharm/ddis/table.aspx)

- History of postural hypotension or cardiovascular disease

- Active medical or psychological condition that, in the opinion of the investigator,
might put the volunteer at undue risk or interfere with the participation of the
study