17 March 2020
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.
Publication
The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus.
Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alba-Alejandre I, van Crevel R, Colbers A, Burger D; Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women Network .
In Clinical infectious diseases RIHS researchers Pauline Bollen, Jolien Freriksen, Angela Colbers and David Burger with collaborative researchers of the PANNA network were the first to report the effect of pregnancy on both unbound and total dolutegravir levels and described the pregnancy effect on the main glucuronide metabolite. They showed that dolutegravir use in pregnancy results in effective plasma concentrations when dolutegravir is taken with food.
Abstract
BackgroundPharmacokinetic 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.
Publication
The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus.
Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alba-Alejandre I, van Crevel R, Colbers A, Burger D; Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women Network .
-
Want to know more about these subjects? Click on the buttons below for more news.
Related news items
The European Hector Research Award in HIV 2021 awarded to Angela Colbers and David Burger
2 November 2021 On Friday 29 October 2021, during the 18th European AIDS Conference in London, the Hector Research Award for the best scientific article related to clinical or epidemiological HIV research was presented to Angela Colbers and David Burger, both working in the Pharmacy of the RadboudUMC. read moreRob Aarnoutse is appointed as professor in Translation pharmacology of antimicrobial agents in particular drugs for tuberculosis
25 January 2021Hospital pharmacist and clinical pharmacologist Rob Aarnoutse is appointed as professor in ‘Translation pharmacology of antimicrobial agents, in particular drugs for tuberculosis’ at Radboud University / Radboudumc, starting 16 November 2020.
read more