Pharmacokinetics of saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women

Abstract

The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng. h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC(12)s) during gestation (29,373 +/- 17,524 ng. h/ml [mean +/- standard deviation]), during labor and delivery (26,189 +/- 22,138 ng. h/ml), and during the postpartum period (35,376 +/- 26,379 ng. h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC(12), 7,811 and 13,127 ng. h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P </= 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.

FIG. 1.

SQV and RTV concentration-time curves for subjects receiving SQV at 800 mg b.i.d. in combination with RTV at 100 mg b.i.d. (A) Results for SQV during gestation (n = 13); (B) results for SQV during labor and delivery (n = 7); (C) results for SQV during the postpartum period (n = 12); (D) results for RTV during gestation (n = 13); (E) results for RTV during labor and delivery (n = 5); (F) results for RTV during the postpartum period (n = 12). The thick solid curve in each plot represents the median.

FIG. 2.

Median SQV and RTV concentration-time curves for gestation (line with large dashes), labor and delivery (line with small dashes), and the postpartum period (solid line).