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

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, So...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy Vol. 62; no. 2
Main Authors: Denti, Paolo, Garcia-Prats, Anthony J, Draper, Heather R, Wiesner, Lubbe, Winckler, Jana, Thee, Stephanie, Dooley, Kelly E, Savic, Rada M, McIlleron, Helen M, Schaaf, H Simon, Hesseling, Anneke C
Format: Journal Article
Language:English
Published: United States 01.02.2018
Subjects:
Anti-HIV Agents - therapeutic use
Antiretroviral Therapy, Highly Active
Antitubercular Agents - blood
Antitubercular Agents - pharmacokinetics
Antitubercular Agents - pharmacology
Area Under Curve
Child
Child, Preschool
Coinfection
Drug Administration Schedule
Drug Dosage Calculations
Female
HIV - drug effects
HIV - growth & development
HIV Infections - blood
HIV Infections - drug therapy
HIV Infections - virology
Humans
Infant
Levofloxacin - blood
Levofloxacin - pharmacokinetics
Levofloxacin - pharmacology
Male
Models, Statistical
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - growth & development
Prospective Studies
South Africa
Tablets
Tuberculosis, Multidrug-Resistant - blood
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
South Africa
allometric scaling
maturation
dosing recommendations
fluoroquinolones
population PK modeling
NONMEM
pediatric
ISSN:1098-6596, 1098-6596
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Summary: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.
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ISSN:1098-6596
1098-6596
DOI:10.1128/AAC.01521-17