Kaletra dose may need to rise in late pregnancy

The protease inhibitor Kaletra (lopinavir/ritonavir) may need to be taken at a higher dose during the last trimester of pregnancy, US paediatric HIV researchers suggest in the October 3^rd edition of the journal AIDS, after a small pharmacokinetic study found that pregnant women had lopinavir levels half those seen in non-pregnant adults taking a standard dose of the drug. Inadequate drug levels could result in viral rebound and drug resistance for the mother, and HIV transmission to the infant.

Kaletra is widely used in pregnant HIV-positive women in the developed world, and its use has also been proposed in South Africa as an alternative to nevirapine-containing regimens for women previously exposed to single dose nevirapine in a past pregnancy. In such cases it has been feared that lingering resistance to nevirapine acquired at the time of exposure to a single dose might compromise later maternal treatment, hence the suggestion that a protease inhibitor like Kaletra be used instead of nevirapine.

However little is known about its safety or pharmacokinetics during pregnancy, nor how much reaches the foetus during pregnancy. Levels of many drugs have the potential to change during pregnancy, the authors point out, due to increased gastrointestinal transit time (which can alter absorption and drug exposure), changes in body weight that affect drug distribution, decreased albumin and increased alpha-acid glycoprotein levels (which affect protein binding of drugs), and changes in the activity of hepatic enzymes responsible for drug metabolism.

As part of an ongoing multicentre study looking at safety and pharmacokinetics of all antiretroviral drugs during pregnancy called PACTG 1026s, investigators conducted an intensive pharmacokinetic study of lopinavir levels in 17 pregnant women between weeks 30 and 36 of pregnancy, and again six to twelve weeks postpartum. They also obtained maternal and umbilical cord blood samples at the time of delivery to analyse drug levels.

Preliminary findings from this study were reported at this year’s Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver.

Sampling took place at a median of 35 weeks into pregnancy, after participants had received a median of 25 weeks of Kaletra. Two-thirds of participants were taking AZT/3TC at the same time, with the remainder using other nucleoside analogue combinations. The proportion of participants with viral load below 400 copies at the time of third trimester sampling was not stated, but at the time of delivery 14 of 16 women had viral load below 400 copies/ml, one viral load was not available and one woman had a viral load of 10,313 copies/ml.

Pharmacokinetic sampling took place immediately before taking the morning dose and then one, two, four, six, eight and twelve hours after dosing. A single maternal plasma sample was taken around the time of delivery for comparison with drug levels in umbilical cord blood and placenta, as a measure of lopinavir transfer to the placenta.

Third trimester samples showed that only three of 17 women achieved plasma lopinavir levels above 53µg h/ml, a drug level which historical data show should be achieved by 90% of adults receiving Kaletra. None of the women reached the median drug exposure for non-pregnant adults. Surprisingly only one woman agreed to increase here Kaletra dose after being told that her drug levels were suboptimal.

Umbilical cord and maternal blood samples were compared, and the mean ratio of cord/maternal lopinavir concentration was 0.2 (in three cases maternal lopinavir concentrations were below the limit of detection), indicating a relatively poor placental transfer and very limited fetal exposure to lopinavir

However, postpartum sampling available for 13 of the 17 women showed that target drug exposure was achieved in 75% of women, and postpartum drug exposure was around twice the level achieved during the third trimester.

The authors say that induction of the cytochrome p450 3A4 enzyme responsible for metabolising lopinavir is one likely explanation; induction of this enzyme has been observed previously in pregnant women, and would be expected to increase the speed of drug clearance. They also speculate that increased intestinal p-glycoprotein activity could result in poorer lopinavir absorption.

The researchers are now investigating the pharmacokinetics of the new tablet formulation, as well as the pharmacokinetics of higher Kaletra doses during pregnancy.