Lowered Rilpivirine Exposure During the Third Trimester of Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women
Authors: Schalkwijk S, Colbers A, Konopnicki D, et al.
Published in: Clin Infect Dis. 2017; 65(8):1335-1341.
Authors: Schalkwijk S, Colbers A, Konopnicki D, et al.
Published in: Clin Infect Dis. 2017; 65(8):1335-1341.
Authors: Blonk MI, Colbers AP, HidalgoTenorio C, et al.
Published in: Front Pharmacol. 2016 Aug 4;7:239.
Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women.
Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL).
Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred.
Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available.
Authors: Schalkwijk S, Feiterna-Sperling C, Weizsacker K, et al.
Published in: AIDS. 2016; 30(12):1999-2001.
No Abstract available
Authors: Schalkwijk S, Colbers A, Konopnicki D, et al. For PANNA network
Published in: AIDS. 2016;30(8):1239-44.
Objective To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum.
Design A nonrandomized, open-label, multicentre, phase-IV study.
Methods HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care were included. Intensive 24-h pharmacokinetic sampling was performed during the third trimester and at least 2 weeks after delivery. Pharmacokinetic parameters were calculated by noncompartmental analysis. Paired cord blood and maternal blood samples were taken at delivery when feasible.
Results A total of 14 women were included in the analysis. Geometric mean ratios (90% confidence intervals) of third trimester versus postpartum were 1.05 (0.92–1.19) for AUC0–24h and 1.00 (0.83–1.21) for Cmax. The median (range) ratio of abacavir cord plasma to maternal plasma was 1.0 (0.7–1.0, n = 3). Viral load at the third trimester visit was less than 50 copies/ml in 13 participants (93%; one unknown). In total, 13 (93%; one unknown) children were tested HIV-negative.
Conclusion The pharmacokinetics of abacavir 600 mg q.d. during pregnancy are equivalent to postpartum. No dose adjustments are required during pregnancy and similar antiviral activity is expected.
Authors: Schalkwijk S, Colbers A, Konopnicki D, Greupink R, Russel FG, Burger D; PANNA network.
Published in: AIDS. 2016;30(5):807-8.
Abstract not available
Authors: Blonk MI, Colbers AP, Hidalgo-Tenorio C, et al. Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women PANNA Network; PANNA Network.
Published in: Clin Infect Dis. 2015; 61(5):809-816.
BackgroundThe use of raltegravir in human immunodeficiency virus (HIV)–infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women.
Methods An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated.
Results Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53–.96) for AUC0–12h and 0.64 (.34–1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02–2.17; n = 9).
Conclusions Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women.
Authors: Colbers A, Best B, Schalkwijk S, et al. PANNA Network and the IMPAACT 1026 Study Team.
Published in: Clin Infect Dis. 2015; 61(10):1582-1589.
Objective To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)–infected women during pregnancy and post partum.
Methods HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.
Results Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60–.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58–0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03–0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.
Conclusions Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctroughwas reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.
Authors: Colbers A, Molto J, Ivanovic J, et al. PANNA Network
Published in: J Antimicrob Chemother. 2015; 70(2):534-542
Objectives To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum.
Patients and Methods This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929.
Results Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported.
Conclusions Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.
Authors: Colbers A, Hawkins D, HidalgoTenorio C, et al.
Published in: Antivir Ther. 2015; 20(1):57-64
Background We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.
Methods This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.
Results 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.
Conclusions Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effectiveconcentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis
Authors: Colbers AP, Hawkins DA, Gingelmaier A, et al.
Published in: Aids. 2013; 27(5):739-748.
Objective To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum.
Design A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe.
Methods HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovirdisoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0.
Results Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200 copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported.
Conclusion Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.