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.

• Authors: Jyoti S Mathad, Rada Savic, Paula Britto, Priya Jayachandran, Lubbe Wiesner, Grace Montepiedra, Jennifer Norman, Nan Zhang, Ellen Townley, Nahida Chakhtoura, Sarah Bradford, Sandesh Patil, Stephanie Popson, Tsungai Chipato, Vanessa Rouzier, Deborah Langat, Amphan Chalermchockcharoentkit, Portia Kamthunzi, Amita Gupta, Kelly E Dooley
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 74 Issue 9 Pg. 1604-1613 (05 03 2022) ISSN: 1537-6591 [Electronic] United States
• PMID: 34323955 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Chemical References

• Antitubercular Agents
• Isoniazid
• Rifampin
• rifapentine

Topics

• Adult
• Antitubercular Agents (adverse effects)
• Child
• Drug Therapy, Combination
• Female
• HIV Infections (drug therapy, prevention & control)
• Humans
• Isoniazid (adverse effects)
• Latent Tuberculosis (drug therapy)
• Male
• Pregnancy
• Pregnant Women
• Rifampin (analogs & derivatives)
• Tuberculosis (complications, drug therapy, prevention & control)