Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum

Abstract

Objectives: Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.

Methods: The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC(0-12)) was >or=10th percentile NFV AUC(0-12) in non-pregnant historical controls (18.5 microg h/mL).

Results: Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C(max)), 12-h post-dose concentration (C(12)) and AUC(0-12) were significantly lower during the third trimester compared to postpartum (P<or=0.03). The metabolite hydroxyl-tert-butylamide (M8) AUC(0-12) and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC(0-12) exceeded the AUC(0-12) target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C(min)) was above the suggested minimum trough concentration (0.8 mug/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV-1 RNA copies/mL in 81% of patients at delivery.

Conclusions: These results suggest that higher doses of NFV should be considered during pregnancy.

Fig. 1

Nelfinavir and hydroxyl-tert-butylamide (M8) plasma concentrations during pregnancy: (a) second trimester (n = 4), (b) third trimester (n = 27) and (c) postpartum (n = 22) (nelfinavir 1250 mg twice daily). Solid lines in (a), (b) and (c) represent individual nelfinavir profiles; the dashed line represents the typical (50th percentile) concentrations in non-pregnant historical controls. Solid lines in (d), (e) and (f) represent individual M8 profiles (d) during the second trimester (n = 4), (e) during the third trimester (n = 27) (f) and postpartum (n = 22).

Fig. 2

Nelfinavir and hydroxyl-tert-butylamide (M8) area under the plasma concentration–time curves (AUCs). (a) Antepartum and postpartum nelfinavir AUCs, second trimester (n = 4), to third trimester (n = 27) to postpartum (n = 22) in the same patients. The horizontal line indicates the 50th percentile AUC in non-pregnant adults (26 μg h/mL). (b) Antepartum and postpartum M8 AUCs, second trimester (n = 4), to third trimester (n = 27) to postpartum (n = 22) in the same patients.

Fig. 3

Hydroxyl-tert-butylamide (M8) area under the plasma concentration–time curve (AUC)/nelfinavir AUC ratio, antepartum and postpartum.