Darunavir use during pregnancy

Polly Clayden, HIV i-Base

Evidence based guidance for PI use in pregnancy is scarce, particularly with the newer drugs. Three posters at CROI 2012 showed findings from studies looking at safety, efficacy and pharmacokinetics (PK) of darunavir/ritonavir (DRV/r) in pregnant women. [1, 2, 3]

A prospective, multicentre study conducted in Paris by Eve Courbon and colleagues enrolled 33 HIV positive pregnant women receiving DRV/r-containing regimens. Women were a median of 35 years old with a median CD4 of 440 cells/mm3. Nearly a third (n=12) were hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infected, and the majority (n=27) treatment experienced.

Their background regimens were: 2 NRTI (n = 25), 2NRTI+raltegravir (RAL) (n=3), 2NRTI+enfuvirtide (T-20) (n=2), 3 NRTI (n=2). Some received 800/100 mg DRV/r once daily (n=11) and others 600/100 mg twice daily (n=17). To achieve greater DRV/r exposure, a small number switched once daily to twice daily in their second (n = 1) and third trimesters (n=3).

Of the 33 pregnancies, there were 26 live births (of which 4 were pre-term), 1 elective abortion and 1 death in utero. The remaining women were still pregnant at the time of analysis.

The investigators reported DRV trough plasma concentrations of: 1973 ng/mL (1533 – 3118 ng/mL, n= 6) at first trimester, 1485 ng/mL (961 – 2240, n=12) at second trimester, 1575 ng/mL (625 – 2181, n=25) at third trimester, 1702 ng/mL (486 – 2426, n=18) at delivery.

All women except one (who was believed to be non-adherent), had median trough plasma concentrations were above the DRV 10 fold EC50 for resistant HIV (approx 550 ng/mL) whether they received once or twice daily regimens.

The median ratio of cord blood to maternal DRV concentration was 0.18 (IQR 0.10 to 0.24, n=8). DRV plasma concentrations reductions were -25% between first and second trimesters and -20% between first and third trimesters for women who remained on the same dose of DRV/r.

At delivery, 4/8 and 13/18 of women receiving DRV/r once and twice daily respectively had viral load <50 copies mL (6/8 and 18/18 were <400 copies/mL). All babies for whom data were available (19/19) were HIV negative.

A second study, conducted by Carmen Zorrila and investigators in Puerto Rico and the US on behalf of the manufacturer, evaluated the PK of total and unbound (DRV) in pregnant women receiving 600/100 mg DRV/r containing twice daily regimens. This multicentre phase 3b study enrolled women in the second trimester and plasma concentrations were obtained pre-dose and 1, 2, 3, 4, 6, 9, and 12 hours post-dose both second and third trimesters and then 6-12 weeks postpartum.

Total DRV and ritonavir (RTV) plasma concentrations were measured using HPLC-MS/MS with a lower limit of quantification 5.00 ng/mL for both DRV and RTV. The investigators measured unbound DRV by fortifying plasma samples with 14C DRV and separating total and unbound DRV using ultrafiltration. Total and unbound 14C DRV were measured using liquid scintillation counting.

The study enrolled 16 women of a median age of 24 years and CD4 count of 421 cells/mm3. Of these, 11 had evaluable PK data.

The investigators found total DRV Cmax was 28% and 19% lower during second and third trimesters, respectively, compared to postpartum; but total DRV Cmin increased respectively by 43% and 86% in comparison to postpartum. AUC12h was 24% and 17% lower in the second and third trimesters compared to post partum.

The free fraction of DRV was slightly higher compared to post partum in both trimesters. This meant the difference in unbound Cmax and AUC12h was less than for total DRV.

The investigators suggested that the deceased drug exposure of DRV in pregnancy might be partially compensated for by this increased proportion of free drug as albumin and a1-acid glycoprotein (AAG) concentrations were decreased by 22% to 29% during pregnancy. Unbound DRV was >EC50 (27.5 ng/mL) for protease inhibitor-resistant HIV in all women.

Total Cmax for RTV was 34% and 37% lower; total Cmin was 8% and 22% higher and AUC12h was 28% and 33% lower, respectively for second and third trimesters compared to postpartum.

As the unbound concentrations of DRV were relatively unchanged during pregnancy and postpartum, the investigators suggested no dose adjustment is needed with 600/100 mg twice daily.

Overall the women’s viral load decreased over time, with 90% <50 cells/mm3 in the third trimester (100% <400 cells/mm3). The investigators reported one serious adverse event (increased transaminase). Of 12 infants, 4 were born preterm and all were HIV negative by standard PCR testing.

This ongoing trial will also evaluate the effects of pregnancy on DRV/r 800/100 mg once daily, etravirine, and rilpivirine PK.

The third poster showed data from PANNA – a European network established to study the PK of new ARV drugs during pregnancy. Angela Colbers and colleagues looked at third trimester exposure to DRV, atazanavir (ATV), and RTV used as booster.

In this phase 4 study women receiving DRV/r 600 mg/100 mg twice daily or 800 mg/100 mg once daily, or ATV/r 300 mg/100 mg once daily during pregnancy were enrolled. Plasma concentrations were obtained pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours in the third trimester and at least 2 weeks postpartum. Where possible a cord blood sample and matching maternal blood sample were taken at delivery. Plasma concentrations were determined using a validated UPLC method.

Women were a median of 33.5 years of age. Their background regimens were: TDF+3TC (n=12), AZT+3TC (n=4), ABC+3TC (n=3), AZT+3TC+TDF (n=3) and one woman received DRV/r monotherapy.

Data were available for 6 women receiving DRV/r 800/100 mg once daily (3 did not have postpartum concentrations) and 3 receiving 600/100 mg twice daily. For ATV/r 300/100 mg once daily, data were available for 13 women. Cord blood and maternal samples were available for 5 women receiving DRV/r and 7 ATV/r.

This study found exposure (AUCtau) during pregnancy to DRV, ATV and RTV was decreased by respectively 36%, 33% and 53% compared to post-partum. The investigators suggested that increased volume of distribution or decreased absorption could explain this. They added that as the half-life seems to be similar during and after pregnancy, increased elimination is less likely to be the reason.

They noted that concomitant use of tenofovir (used by 14 patients) did not appear to influence DRV or ATV exposure.

In this study 2/9 women receiving DRV had concentrations below the target concentration in the 3rd trimester.

The ratio of cord blood/maternal concentrations ranged from 0.11-0.67 (n=7) and was <0.76 for DRV (n=5).

All children were HIV-negative and no birth defects were reported.

comment

Data from these studies suggest that twice daily dosing with darunavir 600mg/ritonavir 100 mg provides adequate drug exposure during pregnancy.

However, the data from the PANNA study on a small sample of women taking once daily darunavir 800mg/ritonavir 100mg and data from Capparelli et al presented at the Rome paediatric workshop last year show much lower trough concentrations, which in some cases are below that recommended to achieve viral suppression. [4, 5]

Until more data are available twice-daily darunavir at the standard dose should be prescribed and TDM used to monitor the use of once daily darunavir during pregnancy.

References:

Courbon E et al. Safety, efficacy, and pharmacokinetic of darunavir/ritonavir-containing regimen in pregnant HIV+ women. 19th Conference on Retroviruses and Opportunistic Infections, 5 – 8 March, Seattle. Poster abstract 1011.
Zorrilla C et al. Total and unbound darunavir pharmacokinetics in HIV-1+ pregnant women. 19th Conference on Retroviruses and Opportunistic Infections, 5 – 8 March, Seattle. Poster abstract 1012.
Colbers A et al. A comparison of the pharmacokinetics of darunavir, atazanavir, and ritonavir during pregnancy and post-partum. 19th Conference on Retroviruses and Opportunistic Infections, 5 – 8 March, Seattle. Poster abstract 1013.
Capparelli E et al. Pharmacokinetics of Darunavir Once or Twice Daily During and After Pregnancy. 3rd International Workshop on HIV Pediatrics. 15-16 July, 2011. Rome, Italy. Poster abstract P_72.
HTB. Pharmacokinetics of darunavir and fosamprenavir in pregnancy
https://i-base.info/htb/15489