Pregnancy-related PK studies

1 May 2003. Related: Conference reports, Pregnancy, PK and drug interactions, PK Workshop 4th Cannes 2003.

Polly Clayden, HIV i-Base

Two small French studies at this meeting looked at maternal-foetal aspects of pharmacokinetics and genomics. Again the findings were intriguing but the clinical implications are unclear.

Over-expression of MDR-1 in the placenta

An oral presentation from Dr Maryse Camus was based on the hypothesis that P-glycoprotein (P-gp) may play an important role in limiting the materno-foetal transfer of antiretroviral drugs.[1] P-gp is a transporter of a large number of agents including PIs, which are now more frequently given to HIV-positive women during pregnancy. P-gp is expressed in the placenta and localised on the foetal side of trophoblastic cells.

Dr Camus explained that in France (similar to much of Western Europe) 36% of women were diagnosed during pregnancy and 50% of these women were between 30 and 39 years of age. HIV in pregnancy presents the unique challenge of treating maternal disease and preventing mother to child transmission.

This investigation evaluated P-gp expression in placentas from HIV-positive and negative women (n=24 and n=18 respectively). The HIV-positive women gave their informed consent for the use of their placentas in this study.

The investigators found a mean of seven-fold statistically significant increase in MDR1 expression in the placentas from HIV-positive women. This over-expression was similar with ZDV monotherapy or with more complex therapy.

They suggest that this upregulation of MDR-1 in placentas from HIV positive women might contribute to “…diminish the foetal exposure to antiretroviral treatments or to other P-gp substrates and modulate their materno-foetal transport across the placental barrier”.

Maternal-foetal transfer and amniotic fluid accumulation of ARVs

A study from Dr Chuppuy and colleagues (only in abstract form at this workshop) investigated placental transfer and amniotic fluid concentrations of antiretroviral drugs given to HIV positive pregnant women [2].

Maternal plasma, cord blood plasma and amniotic fluid samples were obtained from mother-infant pairs at time of delivery (n=103).

The investigators evaluated the most frequently used combinations in this cohort – AZT/3TC/NFV (n=20), AZT/3TC/NVP (n=13), AZT/3TC (n=8), ddI/d4T/NFV (n=7). They found a significant relationship between maternal and cord blood plasma concentrations for AZT/3TC, ddI, d4T, NFV and NVP.

Cord/maternal plasma concentration ratio was reported to be high for AZT (R=1.22), d4T (R=1.32), 3TC(R=0.93) and NVP (R=0.88). They were low for ddI (R=38) and NFV (R=0.24). They also found concentrations of 3TC in amniotic fluid to be higher than in maternal and cord blood plasma with median of 0.45, 0.41 and 1.68mg/L respectively.

These findings regarding the NRTIs are consistent with previous reports. NFV crosses the placenta with a cord/maternal plasma ratio of NFV. The investigators conclude “our findings could have important implications for the choice of the drugs during pregnancy.”

References:

1. Camus M, Delomenie C, Faye A et al. Overexpression of MDR-1 in placentas from HIV-infected women. 4th International Workshop on Clinical Pharmacology of HIV Therapy, Cannes 27th-29 March 2003. Abs 8:P 2.5
2. Chappuy H, Treluyer JM, Dimet J et al. Maternal-fetal transfer and amniotic fluid accumulation of antiretroviral drugs in HIV infected pregnant women. 4th International Workshop on Clinical Pharmacology of HIV Therapy, Cannes 27th-29 March 2003. Abs 12:P 3.3

Comment

The biological function of P-gp is to exclude drugs and toxins from drug sensitive anatomical sites, such as the brain and testes and foetus. Hence overexpression of P-gp in the placenta is understandable reaction to the presence of drugs.

In most therapy situations maximal drug penetration into all anatomical body sites would be desirable. However, pregnancy may be an exception. It could be argued that as long as the mother’s systemic viral load is fully suppressed, then excluding drug from the baby may not be a bad thing, certainly with respect to reducing foetal toxicity. Obviously, the drugs won’t have the same PEP effect within the baby but as most transmissions occur at or around birth it is questionable how important this is.