Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women

Abstract

Background: Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy.

Methods: IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics.

Results: Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants.

Conclusions: 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy.

Clinical trials registration: ClinicalTrials.gov, NCT02651259.

Keywords: HIV; latent tuberculosis; maternal health; pharmacokinetics; rifapentine.

Figure 1.

CONSORT diagram and study schema: CONSORT flow diagram showing participant flow through the IMPAACT 2001 trial. Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; DOT, directly observed therapy; GA/gest age, gestational age; IMPAACT, International Maternal Pediatric Adolescent AIDS Clinical Trial Network; PK, pharmacokinetics; TB, tuberculosis.

Figure 2.

Effect of HIV on clearance of RPT in second-trimester and third-trimester trimester. There were no differences in RPT concentration between second-trimester data (intensive PK from cohort 1; left panel) and third-trimester data (intensive PK from cohort 2, sparse PK from cohort 1; right panel). RPT clearance was 30% higher in pregnant WLHIV (blue) compared with women without HIV (pink) (P < .001). Data deemed to be below the LLOQ are displayed as open black circles as the LLOQ value (0.039 μg/mL). Abbreviations: AUC_SS, steady-state area under the concentration-time curve; HIV, human immunodeficiency virus; IQR, interquartile range; LLOQ, lower limit of quantification; PK, pharmacokinetics; RPT, rifapentine; RSE, relative standard error; WLHIV, women living with HIV.

Figure 3.

Effect of pregnancy and HIV on INH PK: The clearance of isoniazid was comparable between pregnant and postpartum women with HIV (orange) and without HIV (blue). The AUC_SS for the entire population was 78.2 mg × hour/L (IQR, 21.9–78.2) and maximum isoniazid concentration was 7.74 mg/L (IQR, 5.68–10.6). Abbreviations: AUC_SS, steady-state area under the concentration-time curve; HIV, human immunodeficiency virus; IQR, interquartile range.

Figure 4.

Effect of pregnancy on clearance of RPT, by HIV status: In women without HIV (left panel), the postpartum clearance (purple) was 28% higher than antepartum clearance (green). In WLHIV, the clearance of RPT antepartum and postpartum was comparable to each other, and to postpartum clearance in women without HIV. Abbreviations: HIV, human immunodeficiency virus; RPT, rifapentine; RSE, relative standard error; WLHIV, women living with HIV.