Increased Clearance of Protease Inhibitors in Pregnant Women

Strategic Insights -

Recent research from the United States has discovered that protease inhibitors (PIs), a class of antiretroviral drugs used to treat HIV/AIDS, are cleared from the body at a faster rate in pregnant women. Specifically, the apparent oral clearance of PIs is increased by 3.14-fold in pregnant women compared to postpartum women. This phenomenon is attributed to an increase in systemic clearance and a decrease in bioavailability of the drugs during pregnancy. Furthermore, in vitro studies have shown that pregnancy enhances the rate of PI depletion in hepatic S-9 fractions, but not intestinal S-9 fractions.

Key Takeaways:

  • The apparent oral clearance of protease inhibitors (PIs) is increased by 3.14-fold in pregnant women compared to postpartum women.
  • The increased clearance of PIs during pregnancy is due to an increase in systemic clearance and a decrease in bioavailability of the drugs.
  • In vitro studies have shown that pregnancy enhances the rate of PI depletion in hepatic S-9 fractions, but not intestinal S-9 fractions.
  • Human CYP3A inhibitors, such as erythromycin, ketoconazole, and troleandomycin, significantly inhibited the depletion of PIs in hepatic S-9 fractions and expressed rhesus CYP3A64 enzyme.
  • The nonhuman primate, Macaca nemestrina, is being investigated as a model to study the mechanisms by which the clearance of PIs is increased during pregnancy.
  • H.X. Zhang and colleagues at the University of Washington conducted the study, which was published in the Journal of Pharmacology and Experimental Therapeutics in 2009.
  • The researchers concluded that increased hepatic activity of NFV-metabolizing enzymes (perhaps CYP3A enzymes) results in increased clearance of PIs during pregnancy in the macaques.

Statistics:

  • 3.14-fold increase in the apparent oral clearance of nelfinavir (NFV) in pregnant women compared to postpartum women.
  • 1.9-fold increase in systemic clearance of NFV during pregnancy.
  • Similar to 45% decrease in bioavailability of NFV during pregnancy.
  • 0.5 mM, 0.5 mc M, and 0.01-1 mM concentrations of erythromycin, ketoconazole, and troleandomycin, respectively, significantly inhibited the depletion of NFV in hepatic S-9 fractions.

Sources:

  • H.X. Zhang et al. (2009). As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina. Journal of Pharmacology and Experimental Therapeutics, 329(3), 1016-1022.
  • University of Washington, Dept. of Pharmaceutical, Box 357610, Seattle, WA 98195, USA.
  • American Society Pharmacology Experimental Therapeutics, 9650 Rockville Pike, Bethesda, MD 20814-3995, USA.