Women achieve higher blood concentrations of saquinavir than men, and thus appear to derive more benefit from the drug, according to an American study published in the April 1st edition of the Journal of Infectious Diseases.
AIDS Clinical Trials Group study 359, one of the first to look at subsequent regimens in patients for whom prior therapy had failed, evaluated the effectiveness of soft-gel saquinavir (Fortovase) plus either ritonavir or nelfinavir in patients who had previously used indinavir. After 16 weeks, virological response was seen in fewer than 30% of patients, so investigators decided to further explore factors that might contribute to therapeutic success or failure.
The present study included 277 participants randomly assigned to one of six arms (saquinavir/ritonavir/delavirdine, saquinavir/ritonavir/adefovir, saquinavir/ritonavir/delavirdine/adefovir, saquinavir/nelfinavir/delavirdine, saquinavir/nelfinavir/adefovir, or saquinavir/nelfinavir/delavirdine/adefovir). Participants receiving saquinavir plus ritonavir took 400 mg of each twice daily, while those receiving saquinavir plus nelfinavir took 800 mg of the former and 750 mg of the latter three times daily.
Baseline patient characteristics were similar in all six arms. Pharmacokinetic data were available for 186 participants, who were included in the statistical analyses. In this subset, 157 (about 84%) were men, 29 (about 16%) were women, just over half were white, about 27% were black, and about 17% were Hispanic.
Saquinavir concentrations were measured at weeks 4, 8, and 16. More intensive pharmacokinetic assessment was done for a smaller number of patients to determine drug level changes over time. Individual pharmacokinetic data were used to estimate total 24-hour area under the curve (AUC) and minimum or trough concentrations (Cmin) of saquinavir, as well as inhibitory quotient (IQ), an individualized measure of drug exposure and HIV susceptibility as determined by phenotypic resistance testing.
The investigators found no statistically significant differences in saquinavir concentration between the different racial/ethnic groups.
Women had significantly higher total and trough saquinavir concentrations than men, even after adjusting for lower average body weight. The median AUC was 20.0 mg x h/L for the women and 14.9 mg x h/L for the men (p=.004); the corresponding median Cmin values were 0.30 for the women and 0.13 for the men (p=.0001). Saquinavir clearance in the women was about half that seen in the men. The researchers suggested that the observed differences may be related to variations in how women and men metabolise drugs via the cytochrome P450 liver enzyme system and/or p-glycoprotein (which, in effect, pumps drugs out of cells).
Comparing drug regimens, saquinavir levels were higher in those who also took ritonavir compared with those who took nelfinavir, even though the latter received higher and more frequent saquinavir doses. Overall, saquinavir bioavailability increased by 90% and clearance decreased by 37% when administered with ritonavir. In contrast (and unexpectedly), saquinavir concentrations were lower and clearance increased by 49% when used with adefovir.
Not surprisingly, higher saquinavir concentration predicted better virological response. Higher total and trough levels were associated with a significantly greater likelihood of achieving an HIV RNA level below 500 copies/mL (p=.008 for AUC, p=.02 for Cmin). Given their higher saquinavir concentrations, women were about twice as likely as men to achieve an undetectable viral load at week 16 (42% vs 28%, respectively). After adjusting for baseline viral load and body weight, sex was an independent predictor of virological response.
While these findings might appear to imply that men should receive higher doses of saquinavir than women, drug concentrations in this study varied dramatically between individuals. Thus, the authors suggested, therapeutic drug monitoring may be a better way to maximise benefits while minimising adverse effects for each patient. They also emphasised the need to include more women in clinical trials: “These data provide a compelling argument that trial designs with sufficient power to allow investigations of sex-based differences in pharmacokinetics and pharmacodynamics should be routinely employed in the development of antiretroviral drugs.”
Reference
Fletcher C et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group study 359. Journal of Infectious Diseases 189 (7): 1176-1187, April 1, 2004.