Physiological changes in pregnancy can affect drug disposition. Plasma concentrations of several PIs -- including lopinavir, atazanavir and saquinavir -- currently prescribed to HIV-positive pregnant women, are decreased during this period. Pharmacokinetcs (PK) for darunavir (DRV) and fosamprenavir (FPV) in pregnancy are not well characterised. Two posters presented at the paediatric workshop and IAS 2011 showed data from PK studies of these antiretrovirals in pregnant women.1,2
Edmund Capparelli and colleagues from the IMPAACT P1026s study group presented PK and safety data of DRV dosed twice-daily (BID) and once-daily (QD) during the third trimester of pregnancy, at delivery and post partum. These data were shown at the paediatric workshop in Rome.
IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral PK in pregnancy. It comprises of two groups of women receiving ritonavir-boosted DRV either as 600/100mg BID, or 800/100 mg, QD, as part of an ART regimen during pregnancy and 6-12 weeks postpartum (PP).
All women had received at least two weeks of ART at the time of the evaluation. Intensive steady-state 12 or 24-hour PK profiles were performed during the 3rd trimester and PP. Cord blood and maternal samples were taken at delivery when possible. DRV concentrations were measured by HPLC (limit of detection 0.09 mcg/mL). The minimum exposure targets were DRV AUC0-12 or 24 of 43.6 or 56.5 mcg*hr/mL, for BID or QD, respectively. This represents >70% median for non-pregnant adults.
PK data were available for 31 women (19 BID, 12 QD). Two PP PK evaluations (1 BID and 1 QD) were excluded for non-adherence with no detectable DRV concentrations. Geometric mean 3rd trimester/PP ratios were 0.74 (90% CI 0.54-0.92) and 0.76 (90% CI 0.64-0.91) for AUC and 1.42 (90% CI 1.09-1.84) and 1.31 (90% CI1.10-1.55) for CL/Fs with BID and QD dosing respectively.
For the PK parameters presented below for 3rd trimester and PP the investigators indicated values with p<0.05 compared to PP with an asterisk (*). They found, AUC0-12 were median 50.7 (range 23.8-102)* mcg*hr/mL for 3rd trimester and 70.0 (range 40.3-175.5) mcg*hr/mL PP for women who received DRV/r 600/100mg BID. Of those with PK parameters available, 13/19 (68%) and 11/13 (85%) met the AUC-12 target. CL/F was 11.82 (range 7.58-26.4)* L/h and 8.57 (range 3.42-14.89) L/hr. C12h was 3.13 (range 0.78-8.85) mcg/mL and 2.81 (range 1.61-5.50) mcg/mL.
AUC0-24 were 67.7 (range 30.3-105.5) mcg*hr/mL and 87.9 (77.5- 150.2) mcg*hr/mL, for the women who received DRV/r 800/100mg QD. Of these 8/12 and 7/7 met the AUC0-24 target. CL/F was 11.82 (7.58-26.4) L/h and 9.10 (5.33-10.32) L/hr. C24h was 1.37 (0.15-3.49) mcg/mL and 2.59 (<0.09-3.96) mcg/mL.
A total of 20 paired samples of maternal delivery and cord blood were collected. Of these, 6 pairs had concentrations below the limit of detection. For the remainder (n=14) median cord blood DRV concentrations were 0.19 (<0.09-1.1) mcg/mL. Maternal delivery plasma DRV concentrations were 1.42 (<0.09-5.62) mcg/mL. The median ratio of cord blood/maternal delivery plasma concentrations was 0.24 (0.062-0.58) indicating limited transplacental transport of DRV.
The investigators concluded that lower troughs and AUC with QD compared to BID dosing combined with pregnancy lowering DRV exposure suggests BID dosing should be used in pregnancy and higher doses may be required.
Of note, not all women achieved viral suppression in both dosing groups (at delivery overall, 57% and 79% <50 and <400 copies/mL respectively), and there was at least one vertical transmission among 24 (77%) infants with data available at the time of this analysis.
There are limited data describing safety and outcomes of FPV in pregnancy or plasma concentrations of FPV's active metabolite, amprenavir (APV), during pregnancy, PP and in cord blood.
Michelle Cespides and colleagues from New York University School of Medicine showed findings from a phase I, open-label, single-centre study to evaluate APV PK following dosing of ritonavir boosted FPV 700/100mg BID in pregnant women. The investigators evaluated steady-state PK in the second and/or third trimesters and 4-12 weeks PP. Maternal plasma and cord blood samples were taken at the time of delivery. APV concentrations were measured by LC-MS/MS, and PK were determined using WinNonlin. This study was presented at IAS 2011.
The study evaluated 10 women receiving DRV/r based regimens. Cord blood samples were available from six deliveries. The median ratio of cord blood/maternal APV concentrations was 0.27, again, indicating limited transplacental transfer of this PI. Individual APV AUC was 22-34% lower, Cmax 9-41% lower and C12 27-28% lower in pregnancy than PP. See Table 1: Amprenanvir concentrations during pregnancy.
|Table 1: Amprenavir Concentrations During Pregnancy|
|Phase||2nd trimester n=6||3rd trimester n=9||Postpartum n=9|
|AUC ug*h/mL Median (range)||26.80
|Cmax ug/mL Median (range)||4.32
|C12h ug/mL Median (range)||1.35
The investigators noted that although APV C12 was 27-28% lower in pregnancy, HIV was well suppressed for all subjects at delivery. Maternal and cord blood concentrations were above mean protein binding-adjusted IC50 (0.146 ug/mL) for wild-type virus.
Safety and outcomes data showed that FPV was well tolerated in this small study with no hepatic, renal, or adverse events attributed to ART.
At delivery, all women had viral loads <400 copies/mL and nine women had <50 copies/mL. All infants were HIV PCR negative.
The recommendation from the first study that higher doses of DRV may be required is consistant with US recomendations with other PIs such as lopinavir and atazanavir.
BHIVA guidelines do not recommended a dose increase.
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