Effect of pregnancy on PK of protease inhibitors
Polly Clayden, HIV i-Base
Previous studies investigating the PK of protease inhibitors show reduced exposure during pregnancy. M. Regazzi and coworkers from a multicentre cohort in Italy evaluated nelfinavir and lopinavir plasma levels in a group of HIV-positive pregnant women after receiving multiple doses.
A group of 29 women in the 3rd trimester of pregnancy were selected from an ongoing national surveillance study. All women achieved steady-state plasma concentrations while on a HAART regimen containing nelfinavir (1250 mg BD, n=20) or lopinavir/r (400/100 mg, BD, n=9).
Nelfinavir samples were obtained pre-dose (Ctrough) and 0.5, 1, 2, 3, 4, 5, 6, 8,12 hours post-dose. For lopinavir, Ctrough and 3 hour plasma samples were obtained. The results were compared to results from a control group of HIV positive non-pregnant women (nefinavir, n=21; lopinavir: n=12).
Additionally, the investigators evaluated placental transfer in a subgroup of 6/20 mother/infant pairs receiving nelfinavir and 6/9 receiving lopinavir/r by comparing drug concentrations in samples collected at delivery.
They found median nelfinavir PK values were: AUC (0-12h) 25.76 mcg.h/mL (range:12.61-42.74) in pregnant women vs. 32.49 mcg.h/mL (range:19.16-63.81) in controls (p<0.05). CL/F was significantly higher in pregnant women than in controls, 48.5 L/h (range: 29.3- 99.1) vs 38.5 L/h (range:19.6-65.2), but the difference did not remain after CL/F was adjusted for patient weight. Additionally, median Ctrough was significantly (p<0.01) lower in pregnant vs controls, 0.8 mcg/mL (range: 0-2.6) vs 1.5 mcg/mL (range: 0.5-4.9). In the 6 women evaluated at delivery, the median plasma concentration was 0.15 mcg/mL (range: 0-1.82) and 3 women (50%) had undetectable levels.
Median lopinavir Ctrough levels were similar in pregnant women and controls: 4.3 mcg/mL (range: 3.0-8.3) and 5.2 mcg/mL (range: 0.3-16.0). Only 1/9 pregnant women had Ctrough level below the recommended lopinavir target of 4.0mcg/mL. The median C3h was significantly lower (p<0.01) in pregnant women: 4.2 mcg/mL (range: 2.2-9.7) vs 9.8 mcg/mL (7.0-20.5). At delivery the median lopinavir concentration was 0.22 mcg/mL (range: 0-6.8), with 5/6 women having levels below 4.0mcg/mL. No measurable nelfinavir or lopinavir or nelfinavir and concentrations were found in any of the cord blood samples.
The investigators concluded that HIV positive pregnant women receiving nelfinavir without any concomitant PIs frequently show subtherapeutic levels of nelfinavir in late pregnancy. They found that lopinavir showed better PK, with similar Ctrough levels in the two groups.
They wrote; The difference between the two drugs in achieving therapeutic levels may be explained by the inclusion of ritonavir in lopinavir regimen. Nelfinavir and lopinavir did not cross the placenta to an appreciable extent and thus should not be expected to provide any direct protection for the newborn.
Concordant with previous findings some presented at CROI and covered in April HTB [2, 3, 4, 5].
- Regazzi R, Villani P, Floridia M et al. Effect of pregnancy on protease Inhibitors (PIs) pharmacokinetics in HIV-1 infected women. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 27.
- Khuong-Josses M-A, Boussairi A et al. Nelfinavir plasma concentrations in 40 pregnant women. 13th CROI. Abstract 707.
- Stek A, Mirochnick M, Capparelli E et al. Reduced lopinavir exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV Intl AIDS Conference, Bangkok. Abstract LbOrB08.
- Lyons F, Lechelt M, Magaya V et al. Adequate trough lopinavir levels with standard dosing in pregnancy. 13th CROI 2006, Denver. Abstract 709.
- Mirochnick M, Stek A, Capparelli E et al. Adequate lopinavir exposure achieved with a higher dose during the third trimester of pregnancy. 13th CROI, Denver. Abstract 710.