Nelfinavir levels a third lower in pregnant women

Michael Carter
Published: 31 August 2004

Plasma levels of the protease inhibitor nelfinavir (Viracept) were 34% lower in HIV-positive pregnant women than HIV-positive women taking the drug who were not pregnant, according to a Dutch study published in the September 1st edition of Clinical Infectious Diseases. Nevertheless, all but one of the pregnant women maintained an undetectable viral load, and none of the women’s babies was infected with HIV.

Although nelfinavir is now rarely used in first-line anti-HIV treatment regimens it is still widely used during pregnancy on the basis of its safety, efficacy and side-effect profile. Diarrhoea, the side-effect most commonly associated with the drug, seldom occurs when used by pregnant women, possibly due to a tendency towards constipation during pregnancy.

Dutch investigators were concerned however that two studies had shown that blood concentrations of nelfinavir may be reduced to sub-therapeutic levels in HIV-positive women.

Accordingly, doctors measured plasma concentrations of nelfinavir in 27 pregnant women and 48 non-pregnant women two months after starting treatment with the drug as part of a HAART regimen and every month thereafter.

If plasma levels were suboptimal, individuals were counselled about adherence, and the importance of taking nelfinavir with food. If plasma levels of the drug did not increase the dose of the drug was increased from the standard 1250mg twice a day to 1500mg twice daily.

Investigators determined the individuals’ plasma concentration ratios of nelfinavir, with a plasma concentration ratio below 0.90 indicating suboptimal blood levels of the drug. The investigators compared the mean and median concentration ratios for pregnant and non-pregnant women.

HIV-positive pregnant women had significantly lower mean concentration ratio of the drug (0.88 versus 1.19, p = 0.02), and median concentration ratio (0.88 versus 0.99, p = 0.04). Over half (51%) of the pregnant women had a plasma concentration ratio of the drug below 0.90 compared to 35% of non-pregnant women.

The investigators also found that levels of M8, the pharmacologically active metabolite of nelfinavir, were significantly lower in the HIV-positive pregnant women (p = 0.05).

Using a linear regression model, the investigators established that mean nelfinavir concentration ratios were 35% lower in HIV-positive pregnant women than non-pregnant women. A low plasma concentration ratio of nelfinavir was significantly correlated with both a high viral load and a low CD4 cell count.

Of the 14 HIV-positive women who had a nelfinavir plasma concentration ratio below 0.90, one gave birth with a viral load of 701 copies/ml. All the other women had an undetectable viral load at delivery, and no baby was infected with HIV.

“Concentration ratios were significantly lower in pregnant women, compared with non-pregnant women” write the investigators, adding that concentration ratios of the drug are particularly low during the last three months of pregnancy.

The investigators speculate that low concentrations of the drug during pregnancy could be because the liver metabolises nelfinavir faster during pregnancy as the production of CYP3A4, which plays a key role in processing the protease inhibitor, is increased.

Plasma concentration ratios of nelfinavir can be increased to the target 0.90 by stressing the importance of adherence and eating food with nelfinavir, the investigators suggest.

They conclude that plasma concentrations of nelfinavir should be closely monitored during pregnancy. Should concentrations of the drug fail to reach therapeutic levels a possible option is to increase the twice-daily dose of the drug to 1500mg.

Reference

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