PANNA

30

Aug, 2019

Dolutegravir pharmacokinetics during pregnancy and postpartum

 

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D; on behalf of the PANNA network

Published: 26th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2019– Seattle. P_758.

 

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30

Aug, 2019

Dolutegravir pharmacokinetics during pregnancy and postpartum

 

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D.

Published: Oral presentation at 9th edition of the International Workshop on HIV & Women, March 2nd-3rd 2019, Seattle

 

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30

Aug, 2019

Efavirenz pharmacokinetics during pregnancy and infant washout

 

Authors: Kreitchmann R, Schalkwijk S, Best B, et al.

Published in: Antivir Ther. 2019;24(2):95-103

Background Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.

Methods HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C24 h) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).

Results Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target.

Conclusions Efavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants.

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30

Aug, 2019

Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling

 

Authors: Schalkwijk S, Ter Heine R, Colbers A, et al.

Published in: J Antimicrob Chemother. 2019;30 [Epub ahead of print]

Background Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available.

Objectives To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women.

Patients and Methods A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure.

Results Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%).

Conclusion The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

30

Aug, 2018

First report of dolutegravir unbond plasma concentrations during pregnancy in HIV-positive women

 

Authors: Bollen P, Colbers A, Schalkwijk S, Velthoven-Graafland K, Konopnicki D, Weizsacker K, Hidalgo Tenorio C, van Crevel R, Burger D, on behalf of the PANNA network

Published: Oral presentation at 19th edition of the International Workshop on Clinical Pharmacology of Antiviral Therapy, May 22nd-24th 2018, Baltimore

 

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30

Aug, 2018

Elvitegravir pharmacokinetics during pregnancy and postpartum

 

Authors: Colbers A, Schalkwijk S, Konopnicki D, Rockstroh  J, Burger D, on behalf of the PANNA network

Published: Oral presentation at 19th edition of the International Workshop on Clinical Pharmacology of Antiviral Therapy, May 22nd-24th 2018, Baltimore.

 

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15

Oct, 2017

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.

Background The use of antiretroviral therapy during pregnancy is important for control of maternal human immunodeficiency virus (HIV) disease and the prevention of perinatal HIV transmission. Physiological changes during pregnancy can reduce antiretroviral exposure. We studied the pharmacokinetics of rilpivirine 25 mg once daily in HIV-1–infected women during late pregnancy.
Methods We conducted a nonrandomized, open-label, multicenter, phase 4 study. HIV-infected pregnant women receiving rilpivirine 25 mg once daily were included. Intensive 24-hour pharmacokinetic sampling was performed in the third trimester and at least 2 weeks postpartum. Pharmacokinetic parameters were calculated by noncompartmental analysis.
Results Sixteen subjects were included. Geometric mean ratios of third trimester vs postpartum were 0.55 (90% confidence interval [CI], .46–.66) for the 24-hour area under the concentration-time curve (AUC0-24h); 0.65 (90% CI, .55–.76) for the maximum concentration; and 0.51 (90% CI, .41–.63) for the minimum observed concentration (Cmin). Four of 16 (25%) subjects had Cmin below the target concentration (0.04 mg/L) in the third trimester of pregnancy. No subtherapeutic levels were observed postpartum. No detectable viral loads were observed in this study. All newborns tested negative for HIV. No birth defects were reported. The median (range, n = 5) rilpivirine cord-to-maternal plasma concentration ratio was 0.50 (range, .35–.81).
Conclusions Rilpivirine exposure is substantially lowered during late pregnancy. Despite lower exposure, virologic suppression was maintained and no perinatal transmission was observed. Overall, these results suggest that rilpivirine 25 mg once daily may be an alternative treatment option for HIV-1–infected pregnant women who are virologically suppressed, in settings where therapeutic drug monitoring and/or close viral load monitoring are feasible to detect suboptimal antiretroviral therapy.
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30

Aug, 2017

Substantially lower rilpivirine plasma concentrations during pregnancy

 

Authors: Colbers A, Schalkwijk S, Konopnicki D, Gingelmaier A, Lambert J, van der Ende I, Moltó J, Burger D.

Published: 24th Conference on Retroviruses and Opportunistic Infections, February 13th – 16th, 2017 – Seattle. Abstract number 754.

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30

Dec, 2016

Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy

 

Authors: Colbers A, Best B, Schalkwijk S, et al. PANNA Network and the IMPAACT 1026 Study Team.

Published in: Clin Pharmacokinet. 2016;55(3):381-96

Abstract Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.

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30

Aug, 2016

Is pregnancy a barrier to the proposed lower dose of efavirenz?

 

Authors: Schalkwijk S, ter Heine R, Colbers A,  Huitema A, Denti P, Dooley K, Capparelli E, Best B, Cressey T, Greupink R, Russel F, Mirochnick M, Burger D.

Published: 17th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, June 8th-10th 2016, Washington DC.  P_26

 

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