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First report of dolutegravir unbound plasma concentrations during pregnancy in HIV-positive women - Unbound dolutegravir trough similar in third trimester and postpartum
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19th International Workshop on Clinical Pharmacology of Antiviral Therapy
Mark Mascolini
Unbound dolutegravir minimum concentration (Cmin) proved similar in the third trimester and after delivery in a small multicenter European study [1]. Women taking regimens containing this integrase inhibitor had an undetectable viral load when approaching delivery.
A prior 29-woman study found total dolutegravir plasma levels 25% to 51% lower during pregnancy than postpartum in women taking 50 mg of the integrase inhibitor once daily [2]. But in that study Cmin during pregnancy lay well above the 90% effective concentration (EC90) for dolutegravir (0.064 ug/mL). European PANNA Network researchers who conducted the new study noted that more than 99% of dolutegravir is protein-bound. It is important to know unbound levels of highly protein-bound drugs during pregnancy.
PANNA enrolls and monitors HIV-positive pregnant women in Europe. This analysis focused on women taking 50 mg of dolutegravir once daily during pregnancy. All had intensive drug-level monitoring during the third trimester of pregnancy and 3 to 7 weeks after delivery. Researchers used a validated method to determine total and unbound dolutegravir concentrations during and after pregnancy. Then they calculated geometric mean ratios (GMRs) comparing third-trimester levels with postpartum levels.
The study initially included 9 women, 7 black and 2 white, with a median age of 30 years (range 21 to 42). Because 3 women did not return for a postpartum visit, the dolutegravir concentration analysis focused on 6 women with a median gestational age of 38 weeks (range 34 to 40) at delivery. As these 6 women approached delivery, all had a plasma viral load below 50 copies.
Among 4 women tested for albumin protein concentrations in plasma, median albumin proved lower in the third trimester (36.5 g/L, range 36 to 37) than after delivery (39.0 g/L, range 37 to 43). In the third trimester geometric mean total and unbound dolutegravir Cmin measured 710 and 4.0 ug/L. Respective postpartum geometric means were 1070 and 4.2 ug/L.
GMR (and 90% confidence interval) for total dolutegravir Cmin in the third trimester versus postpartum was 0.72 (0.40 to 1.29). But for unbound dolutegravir, Cmin GMR for the third trimester versus postpartum was 0.98 (0.55 to 1.75), indicating virtual equivalence in the two periods. Median (interquartile range) free fraction Cmin was 0.63% (0.43 to 0.73) in the third trimester and 0.33% (0.28 to 0.70) after delivery, a nonsignificant difference (P = 0.345).
Despite differences in total dolutegravir Cmin during pregnancy and after delivery, unbound dolutegravir Cmin was similar in the two periods. That finding, "coupled with the undetectable viral loads at delivery," the researchers concluded, "suggests uncompromised efficacy of dolutegravir 50 mg once daily in pregnancy."
References
1. Bollen P, Colbers A, Schalkwijk S, et al. First report of dolutegravir unbound plasma concentrations during pregnancy in HIV-positive women. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. May 22-24, 2018. Baltimore. Abstract 8.
2. Mulligan N, Best BM, Wang J, et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS. 2018;32:729-737.
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