Clinical pharmacokinetics · 2026
Pharmacokinetics of Efavirenz in Pregnancy and Postpartum with and Without First-line Tuberculosis Drugs: Results from IMPAACT P1026s.
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Van Schalkwyk Marije, Wang Jiajia, Bekker Adrie, Decloedt Eric, Theron Gerhard B, Cotton Mark F, Cressey Tim R, Wabwire Deo, Stotz Chelsea, Knowles Kevin, George Kathleen, Browning Renee, Rungruengthanakit Kittipong, Wiesner Lubbe, Capparelli Edmund V, Stek Alice M, Mirochnick Mark, Shapiro David E, Best Brookie M, Eke Ahizechukwu C, IMPAACT P1026s Protocol Team
Аннотация
BACKGROUND AND OBJECTIVE: Efavirenz (EFV) pharmacokinetics (PK) may be influenced by both pregnancy-related physiological changes and concurrent treatment for drug-sensitive tuberculosis (DS-TB), and intensive 24-h EFV PK data during rifampin (RIF)/ isoniazid (INH) treatment in pregnant women living with HIV (PWLHIV) and TB disease are lacking. We evaluated EFV PK in a prospective cohort of PWLHIV receiving WHO-recommended oral daily EFV alongside RIF and INH (with or without ethambutol [EMB] and pyrazinamide [PZA]).
METHODS: Participants enrolled between 20 and 37+6 weeks gestation and underwent steady-state intensive 24-h PK sampling during second trimester (2T), third trimester (3T), and 2-8 weeks postpartum (PP) when eligible. PK parameters (AUC0-24, Cmax, Cmin and CL/F) were characterized using noncompartmental analysis, and paired comparisons across pregnancy stages were made using geometric mean ratios (GMR) with 90% confidence intervals (CI); α = 0.10. PK outcomes were compared with a previously published cohort of PWLHIV without TB and evaluated against protocol-defined therapeutic targets.
RESULTS: Of 22 participants, PK data were available for 12, 21 and 13 participants in 2T, 3T and PP, respectively. In 3T (3T↔PP: n = 13), EFV exposure was lower than PP: AUC0-24 was 19% lower (GMR 0.81 [0.69-0.95]; p = 0.008), Cmax 16% lower (GMR 0.84 [0.76-0.94]; p = 0.033), Cmin 25% lower (GMR 0.75 [0.63-0.90]; p = 0.003), and apparent oral clearance (CL/F) 24% higher (GMR 1.24 [1.06-1.46]; p = 0.057). 2T GMRs were directionally similar to 3T but were underpowered (2T↔PP: n = 4). Although median EFV concentrations exceeded therapeutic thresholds, 38% of participants did not meet target AUC0-24 or Cmin. In contrast, in the non-TB group, the EFV AUC0-24 and Cmax were similar in pregnancy and postpartum (3T AUC0-24 GMR 0.94 [0.86-1.02]; p = 0.373 and Cmax GMR 1.07 [0.95-1. 02]; p = 0.167). No infants acquired HIV during follow-up.
CONCLUSIONS: Late pregnancy combined with DS-TB treatment is associated with lower EFV exposure. Further investigation is needed to determine the clinical significance of these findings, but frequent viral load monitoring is advised in PWLHIV with TB disease receiving EFV-based antiretroviral treatment.
GOV IDENTIFIER: NCT00042289.
METHODS: Participants enrolled between 20 and 37+6 weeks gestation and underwent steady-state intensive 24-h PK sampling during second trimester (2T), third trimester (3T), and 2-8 weeks postpartum (PP) when eligible. PK parameters (AUC0-24, Cmax, Cmin and CL/F) were characterized using noncompartmental analysis, and paired comparisons across pregnancy stages were made using geometric mean ratios (GMR) with 90% confidence intervals (CI); α = 0.10. PK outcomes were compared with a previously published cohort of PWLHIV without TB and evaluated against protocol-defined therapeutic targets.
RESULTS: Of 22 participants, PK data were available for 12, 21 and 13 participants in 2T, 3T and PP, respectively. In 3T (3T↔PP: n = 13), EFV exposure was lower than PP: AUC0-24 was 19% lower (GMR 0.81 [0.69-0.95]; p = 0.008), Cmax 16% lower (GMR 0.84 [0.76-0.94]; p = 0.033), Cmin 25% lower (GMR 0.75 [0.63-0.90]; p = 0.003), and apparent oral clearance (CL/F) 24% higher (GMR 1.24 [1.06-1.46]; p = 0.057). 2T GMRs were directionally similar to 3T but were underpowered (2T↔PP: n = 4). Although median EFV concentrations exceeded therapeutic thresholds, 38% of participants did not meet target AUC0-24 or Cmin. In contrast, in the non-TB group, the EFV AUC0-24 and Cmax were similar in pregnancy and postpartum (3T AUC0-24 GMR 0.94 [0.86-1.02]; p = 0.373 and Cmax GMR 1.07 [0.95-1. 02]; p = 0.167). No infants acquired HIV during follow-up.
CONCLUSIONS: Late pregnancy combined with DS-TB treatment is associated with lower EFV exposure. Further investigation is needed to determine the clinical significance of these findings, but frequent viral load monitoring is advised in PWLHIV with TB disease receiving EFV-based antiretroviral treatment.
GOV IDENTIFIER: NCT00042289.