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Emerging evidence

Several studies have recently provided evidence that women have higher blood levels or greater total exposure to certain drugs, in turn potentially explaining higher rates of certain toxicities in women.

In the case of saquinavir, evidence from a randomised study called ACTG 359 showed that women had 50% greater exposure to saquinavir than men. Participants in this study received either 400mg of saquinavir with 400mg of ritonavir twice daily, or 800mg of saquinavir with 750mg of nelfinavir twice daily, plus delavirdine or adefovir or both. Women cleared saquinavir 50% more slowly than men, extending the half-life of the drug to 6.1 hours (Brundage 2002). A significantly higher proportion of women had viral load below 500 copies/ml at week 16 compared to men (52 vs 33%, p=0.01) (Fletcher 2003).

Lopinavir levels have also been found to be higher in women. 130 patients with available plasma samples taken 4-12 hours after lopinavir dosing were tested; women were found to have significantly higher lopinavir levels (11.7 vs 7.0mg/L, p=0.02) (Burger 2002b). This difference was independent of body weight, suggesting that a gender difference in lopinavir exists.

A UK study found that lopinavir plasma levels were significantly higher among men with lower body mass, but could not draw conclusions about gender differences due to the small number of women tested. Data from 245 men and 49 women were studied. Individuals were stratified by gender and according to body weight (above or below 70kg). The investigators found that a greater proportion of males with low body weight had a trough level of lopinavir above 10,000ng/ml than men with a body weight above 70kg (17.2% versus 4.8%). However, the proportion of patients with trough concentrations of lopinavir below the therapeutic range did not differ significantly between the high and low weight individuals (Gibbons 2004).

Nevirapine exposure has also been assessed by gender and found to differ. This evaluation took place in 11 men and 11 women, who underwent sampling over a 24-hour period to assess total exposure as accurately as possible. The Cmax was 44% higher in women (p=0.042), but the difference in total exposure was not significant, leading researchers to suggest that higher peak drug levels in women account for the higher incidence of rash in women. However, the researchers were unable to determine whether gender was an independent risk factor in this study, since women also had significantly lower body weight (Regazzi 2002).

Women have also been shown to experience a significantly higher rate of renal toxicity with indinavir treatment, a side effect known to be caused by high peak drug levels (Burger 2002a).

Nelfinavir drug levels have been shown to be lower in pregnant women; a comparison of 19 pregnant women and 48 non-pregnant women showed that pregnant women were significantly more likely to have concentration ratios below 0.9 (level associated with virological failure) (63% vs 33%, p=0.032) (Nellen 2004).

References

Burger DM et al. Pharmacokinetic variability caused by gender: do women have higher indinavir exposure than men? JAIDS 29: 101, 2002.

Burger DM et al. Lopinavir plasma levels are significantly higher in female than in male HIV-1 infected patients. Third International Workshop on Clinical Pharmacology of HIV Therapy, Washington, abstract 6.5, 2002.

Brundage RC et al. Quantitation of sex differences and drug interactions: pharmacologic studies of saquinavir (SQV) in ACTG 359. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 779, 2002.

Fletcher CV et al. Sex differences in virological response and saquinavir pharmacology in ACTG 359. Antiviral Therapy 8 (suppl 1): S214, 2003.

Gibbons S et al. Is there evidence for weight-adjusted dosing of Kaletra? Tenth Anniversary Conference of the British HIV Association, Cardiff, abstract P75, 2004.

Nellen JFJB et al. Nelfinavir plasma concentrations are low during pregnancy. Clin Infect Dis 39: 736-740, 2004.

Regazzi MB et al. Analysis of potential gender difference in nevirapine disposition in HIV-infected patients. Third International Workshop on Clinical Pharmacology of HIV Therapy, Washington, abstract 4.4, 2002.