Lack of sex-related differences in saquinavir pharmacokinetics in an HIV-seronegative cohort.
OBJECTIVE
To examine the influence of sex on steady-state saquinavir pharmacokinetics in HIV-seronegative volunteers administered saquinavir without a concomitant protease inhibitor.


METHODS
Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady-state conditions. Following administration of the 10th dose, blood was collected serially over 8 h for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using noncompartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences.


RESULTS
There was no significant difference in saquinavir AUC(0-8) or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC(0-8) was 29.9 (95% confidence interval 15.5, 44.3) and 29.8 (18.6, 40.9) ng h(-1) ml(-1) kg(-1) for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females.


CONCLUSIONS
In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications.
Robertson
Sarah M
SM
Clinical Research Center, Department of Critical Care Medicine, National Institutes of Health, Bethesda, MD 20892, USA. robertsonsa@cc.nih.gov
Formentini
Elizabeth
E
Alfaro
Raul M
RM
Natarajan
Ven
V
Falloon
Judith
J
Penzak
Scott R
SR
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018023:HIV Seronegativity / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood; D008875:Middle Aged; D010641:Phenotype; D019258:Saquinavir / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012737:Sex Factors
D017320:HIV Protease Inhibitors; D051544:Cytochrome P-450 CYP3A; D019258:Saquinavir; D008874:Midazolam