Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s.

BACKGROUND AND OBJECTIVE

Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB.

METHODS

Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth.

RESULTS

A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin.

CONCLUSIONS

Levofloxacin AUC was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.