Steady state PK of nelfinavir and M8 in pregnancy

A study from Rolf van Heeswijk and colleagues from the Ottawa Health Research Institute in Canada evaluated the pharmacokinetics and its active metabolite M8 during pregnancy and post partum.

A group of 11 women receiving 1,250 mg BID of nelfinavir and two nucleosides were assessed in this longitudinal study. Twelve hour nelfinavir and M8 levels were analysed by LC/MS/MS at a median of 33 weeks during the third trimester and a second analysis was performed post partum at a median of eight weeks following the first sampling.

The investigators reported the post partum geometric mean nelfinavir AUC 0-12h, Cmax and C12h to be 31.0 h mg/L, 4.84 mg/L and 1.21 mg/L respectively (comparable with population values). The geometric mean ratio (GMR) third trimester/post partum (90% CI) for nelfinavir AUC 0-12h, Cmax and C12h was 0.76 (0.54–1.06), 0.81 (0.57–1.15) and 0.43 (0.25–0.76) respectively.

For the M8 AUC 0-12h, Cmax and C12h GMR (90% CI) was 0.32 (0.18-0.55), 0.31 (0.19-0.51), and 0.30 (0.14-0.64) respectively. The median ration of the AUC 0-12h of M8 and NFV during the third trimester and post partum was 11% and 27% respectively and the GMR and 90% CI was 0.42 (0.33–0.53).

The investigators noted a trend towards reduced exposure to nelfinavir during pregnancy (AUC reduced by 24%) that they suggest is due to induction of CYP3A4 and/or CYP2D6. They also reported significant reductions in concentrations of the active metabolite M8 (reduced by 70%) during pregnancy, which may be due to induction of CYP3A4 and/or inhibition of CYP2C19 and the clinical implications of which are unclear.

All women in this study maintained an undetectable plasma viral load and a stable CD4 cell count during pregnancy and post partum.

Comment

These and other data (Kosel et al, AIDS 2003;17:1195-9) indicate that total plasma concentrations of nelfinavir are reduced during the later stages of pregnancy. This may be due to physiological changes in the volume of distribution and in clearance. Kosel et al also noted individual variability, which suggests that a universal increase in nelfinavir dose is unlikely to be possible. The effect seen of pregnancy on M8 concentrations is even greater which seems to support dose adjustment in pregnancy, however, the virological outcome of undetectable plasma viral load in all eleven mothers, is consistent with clinical experience.

The move away from using nevirapine, particularly for those mothers with high viral loads and CD4 counts greater than 250 cells/mm3 requiring short course antiretroviral therapy, is likely to result in greater use of protease inhibitors. There is an urgent need for data on how best to prescribe these in pregnancy, an area which to date has been neglected. Meanwhile, there is a strong case for TDM in pregnancy with cautious dose adjustment.

Van Heeswijk R, Khaliq Y, Gallicano K et al. The steady state pharmacokinetics of nelfinavir and M8 during pregnancy and postpartum. Abstract 9. Poster 3.2.