Pharmacokinetics of antiretrovirals in pregnant women

Antiretroviral treatment of HIV-infected pregnant women is widely used to prevent mother-to-child HIV transmission and as primary therapy of maternal HIV infection. The physiological changes associated with pregnancy have a large impact on drug disposition. and changes in antiretroviral pharmacokinetics during pregnancy must be understood for these drugs to be used safely and effectively in pregnant women. Zidovuine and didanosine, two of the nucleoside reverse transcriptase inhibitors, demonstrate an increase in clearance and decrease in area under the concentration-time curve during pregnancy. The clinical significance of these changes is unknown due to the lack of a clear relationship between plasma concentrations of nucleoside reverse transcriptase inhibitors and clinical effects. Pharmacokinetic parameters of lamivudine, stavudine and abacavir are not significantly changed during pregnancy. There are no data describing the effect of pregnancy on the pharmacokinetics of the other nucleoside/nucleotide analogues (zalcitabine, emtricitabine and tenofovir). Pregnancy does not appear to have a significant effect on the pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor nevirapine and there are no data describing the pharmacokinetics of the other non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) during pregnancy. Reduced plasma concentrations during pregnancy have been described for several of the protease inhibitors, including nelfinavir (with administration of 750mg three times daily), indinavir, saquinavir and Kaletra(R) (a co-formulation of lopinavir and ritonavir). Plasma concentrations equivalent to those in nonpregnant adults have been reported in pregnant women receiving nelfinavir at doses of 1250mg twice daily, and the addition of ritonavir to saquinavir greatly increases saquinavir exposure to therapeutic concentrations in pregnant women. No pregnancy pharmacokinetic data are available for the newer protease inhibitors atazanavir and fosamprenavir, or with other dual protease inhibitor combinations that include low dose ritonavir to boost concentrations of the coadministered protease inhibitor. Further investigations of antiretroviral pharmacology during pregnancy, including protein binding studies, are urgently needed.