Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis

Abstract

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Keywords: NONMEM; allometric scaling; dosing recommendations; fluoroquinolones; maturation; pediatric; population PK modeling.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Maturation function of levofloxacin clearance. The percent maturation achieved versus postnatal age, assuming a standard duration of gestation (9 months), is shown.

FIG 2

Visual predictive check of the levofloxacin concentration versus time after dose, stratified by either the administration method (top) or HIV infection status (bottom). The solid and dashed lines represent the 50th, 5th, and 95th percentiles of the observed data, while the shaded areas represent the model-predicted 95% confidence intervals for the same percentiles. The dots are the observed concentrations.

FIG 3

Simulated levofloxacin steady-state AUC from time zero to 24 h (AUC0–24) (top) and Cmax (bottom) versus body weight. (Left) The concentrations achieved with dosing at 20 mg/kg; (right) the suggested optimized dosing. The dashed lines for Cmax (15.55 mg/liter) are the median values observed by Peloquin et al. (15) with dosing at 1,000 mg daily, while the dashed lines for AUC (96.8 mg · h/liter) represent the median exposure from the same study, after rescaling of the dose from 1,000 mg to 750 mg daily, the dose currently recommended for the treatment of tuberculosis in adults.