Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers
The expression of P-glycoprotein, a transporter protein present in enterocytes as well as
other cells involved in the absorption and distribution of HIV protease inhibitors, has been
linked to a single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T.
Individuals homozygous for the T allele have reduced P-gp expression compared to CC
individuals. Preliminary studies by other investigators to determine the influence of MDR1
genotype on HIV protease inhibitor pharmacokinetics have yielded inconclusive results. The
primary purpose of this study is to determine the relationship, if any, between MDR1
genotypes and plasma concentrations of the HIV protease inhibitors indinavir and saquinavir.
Secondary objectives of this investigation will (1) assess the relationship between CYP3A4
activity and indinavir and saquinavir exposure and (2) characterize the relationship, if
any, between P-gp expression on lymphocyte surfaces and MDR1 genotype. Up to 150 subjects
will be screened to enroll a total of 63 healthy volunteers (21 subjects each in the CC, TT,
and CT groups). Each subject will have blood drawn for P-gp expression analysis and MDR1
genotyping at screening. Next, subjects will receive oral midazolam 8 mg for CYP3A4
phenotyping; a single blood sample will be collected 4 hours after midazolam administration
for determination of midazolam and 1-hydroxymidazolam. Between 7 and 28 days after midazolam
administration, subjects will receive indinavir 800 mg every 8 hours for one day and a
single 800 mg dose the next morning (dose #4). Between 7 and 28 days after indinavir
administration, subjects will receive saquinavir soft-gel capsules 1200 mg three times daily
for 3 days and a single dose on the morning of day 4 (dose # 10). Post-dose blood samples
will be collected over 8 hours following dose #4 of indinavir and dose #10 of saquinavir.
Indinavir and saquinavir pharmacokinetic parameters (primarily AUC and Cmax) will be
compared across MDR1 genotype groups using ANOVA with post-hoc testing. 1-hydroxymidazolam:
midazolam ratios will be correlated to indinavir and saquinavir AUCs as well as compared
across MDR1 genotype groups. P-gp expression on lymphocyte surfaces will be determined by
flow cytometry, quantified, and compared across MDR1 genotype groups. Data from this
investigation will determine whether MDR1 genotype influences protease inhibitor plasma
Primary Purpose: Treatment
Nicolas Wentzensen, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|