The Effect of Pregnancy and Breastfeeding on the Population Pharmacokinetics of Levofloxacin in South Africans with Rifampicin Resistant Tuberculosis

Background

Levofloxacin is a key drug in the prevention and treatment of rifampicin-resistant tuberculosis (RR-TB).¹ However, data on its pharmacokinetics in pregnant and breastfeeding women remain limited, as they have historically been excluded from clinical trials.² We aimed to characterize the pharmacokinetics of levofloxacin in adults with RR-TB, including an evaluation of the effect of pregnancy and lactation.

Methods

We pooled data from two South African studies in adults treated for RR-TB, receiving levofloxacin at 750/1000 mg daily, based on body weight. Blood samples were drawn pre-dose, 2-, 4-, 6-, 8-, 10-, and 24-hours post-dose. Pregnant participants were sampled in the third trimester and again approximately 6-8 weeks postpartum. Breastmilk samples were collected pre-dose, 2-, 4-, 6-, and 8-hours post-dose at the same post-partum visit. A single plasma sample was obtained from breastfed infants within the same 8-hour interval. Levofloxacin concentrations were measured using HPLC-MS/MS. Data were analysed using nonlinear mixed-effects modelling. Disposition parameters were allometrically scaled using total body weight or fat-free mass (FFM).³ A plasma model was developed and expanded with an effect compartment⁴ to represent breastmilk, estimating the milk-to-plasma ratio and equilibration half-life.

Results

We obtained plasma samples from 72 adults (median age: 31 years; weight: 60 kg; serum creatinine: 56 µmol/L). Of 58 female participants, 46 were pregnant, and 37 provided both antepartum and postpartum profiles. Twenty participants contributed paired plasma and breastmilk samples. Additionally, 15 infant plasma samples were available. A one-compartment disposition model with first-order elimination and absorption with transit compartments best described the data. Typical values of clearance and volume of distribution, best scaled using FFM, were 6.06 L/h and 85.9 L respectively. After adjusting for body size and serum creatinine, pregnancy further increased levofloxacin clearance by 38.1%. The levofloxacin milk to plasma ratio was 1.46, with a rapid equilibration half-life of ~7.50 minutes. Assuming a milk intake of 0.15 L/kg/day,⁵ the relative infant dose was 6-8% of the recommended 15-20 mg/kg/day adult and pediatric dose.

Conclusion

Levofloxacin concentrations are reduced during pregnancy and penetrates breastmilk, warranting further evaluation of its implications for breastfeeding infants.

References

1. WHO. WHO Consolidated Guidelines on Tuberculosis Module 4: Treatment Drug-Resistant Tuberculosis Treatment 2022 Update.; 2022.
2. Gupta A, Hughes MD, Garcia-Prats AJ, McIntire K, Hesseling AC. Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons. PLoS Med. 2019;16(8):1-26. doi:10.1371/journal.pmed.1002882
3. Anderson BJ, Holford NHG. Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48(1):303-332. doi:10.1146/annurev.pharmtox.48.113006.094708
4. Savic RM, Ruslami R, Hibma JE, et al. Pediatric Tuberculous Meningitis: Model-Based Approach to Determining Optimal Doses of the Anti-Tuberculosis Drugs Rifampin and Levofloxacin for Children. Clin Pharmacol Ther. 2015;98(6):622-629. doi:10.1002/cpt.202
5. Wilson JT. Determinants and Consequences of Drug Excretion in Breast Milk. Vol 14.; 1983. doi:10.3109/03602538308991402