Background:  Pregnancy may lead to alterations in protein binding of drugs due to changes in the plasma concentration of albumin, α-1 acid glycoprotein (AAG), and steroid and placental hormones. In non-pregnant adults, the protein binding of the protease inhibitor lopinavir (LPV) is ≥99% and small changes in protein binding could have a large effect on the fraction of drug unbound, which exerts pharmacological effect. We have previously reported a significant reduction in total plasma LPV plasma concentration with standard dosing during pregnancy. We now report LPV protein binding during the third trimester and at 2 to 6 weeks post-partum.

Methods:  P1026s is an ongoing, prospective, non-blinded study of ART pharmacokinetics in HIV-1-infected pregnant women receiving ≥1 ART for routine clinical care, and has enrolled 2 cohorts of women receiving LPV/ritonavir (Kaletra) 400/100 mg or 533/133 mg twice daily as the soft gel capsule formulation. LPV pharmacokinetics, AAG, and albumin were determined during the third trimester and post-partum. Plasma samples from each pharmacokinetic study day were pooled into low concentration (0 and 12 hours post dose) and high concentration (1 to 8 hours post dose) for LPV protein binding determination via ultrafiltration using radiolabeled LPV. Linear models were used to correlate LPV fraction of drug unbound with covariates.

Results:  Samples during the third trimester and postpartum were available from 28 and 25 women, respectively (10 black non-Hispanic, 13 Hispanic, 3 white, 3 other; median age 31 years). Mean plasma protein concentrations were reduced during the third trimester (AAG = 576 mg/L, albumin = 3.28 mg/dL) vs post-partum (AAG = 931 mg/L, albumin = 3.85 mg/dL) (p <0.0001). LPV plasma binding was reduced during pregnancy, resulting in higher fraction of drug unbound (mean 0.96±0.16% during the third trimester vs 0.82±0.21% postpartum, p = 0.002). Albumin concentration had no effect on LPV binding. AAG concentration was significantly correlated with the extent of LPV binding; each 100 mg/L increase in AAG was associated with an increase in LPV binding of 0.04%. Higher LPV concentration (after correction for AAG) were also associated with reduced binding and higher fraction of drug unbound. Time postpartum had no effect on the fraction of drug unbound comparing measurements ≤4 weeks to those >4 weeks post-partum.

Conclusions:  AAG concentration was lower and LPV fraction of drug unbound higher during pregnancy compared to postpartum. The 17% relative increase in LPV fraction of drug unbound during pregnancy is much smaller than the reduction in total LPV concentration. Therefore, reduced protein binding will only compensate for a portion of the decrease in LPV exposure associated with pregnancy.