PANNA

7

Sep, 2020

The effect of pregnancy on the pharmacokinetics of total and unbound Dolutegravir and its main metabolite in women living with Human Immunodeficiency Virus

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Authors: Bollen P, Freriksen J, Konopnicki D, Weizsäcker K , et al; on behalf of the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women Network

Published in: Clin infect Dis2020;26.ciaa006

Background Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents.

Methods Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected.

Results Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68-1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77-1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49-1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants).

Conclusions Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy.

7

Sep, 2020

Clinically significant lower elvitegravir exposure during third trimester of pregnant patients living with HIV: data from the PANNA study

 

Authors: Bukkems V, Necsoi C, Hidalgo Tenorio C, et al. PANNA Network

Published in: Clin infect Dis2020; 24;ciaa488.

Abstract This phase-IV study investigated the influence of pregnancy on the pharmacokinetics of elvitegravir/cobicistat in 14 HIV-1-positive women. The results support the recommendation against elvitegravir/cobicistat use during pregnancy, as the elvitegravir Ctrough was reduced by 77%, with 85% of pregnant women having a Ctrough below the EC90.

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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