Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE credits
Introduction: Multidrug-resistant tuberculosis (MDR-TB) is an emerging problem among children. Ofloxacin is a fluoroquinolone that has been frequently used in treatment of MDR-TB in South Africa. Despite this ofloxacin pharmacokinetics has not been studied before in a South African paediatric population with MDR-TB.
Aim: The aim of this study was to describe ofloxacin pharmacokinetics in a South African paediatric population with MDR-TB, in order to optimise the dose regimens.
Materials and Methods: Eighty-eight South African children (median age 3.5, range 0.5 – 15 years, median weight 15, range 7 – 66.3 kg) with MDR-TB treatment or on prophylaxis were dosed 20 mg/kg of ofloxacin and samples were collected at 0, 1, 2, 4, 8, 11, or 0, 1, 2, 4, 6, 8 hours. Smaller children were dosed using crushed tablets, and sometimes with a naso-gastric tube. MONOLIX 4.3.3 (Lixoft) was used to analyse PK data. Allometric scaling was employed to account for differences in body weight and the effect of other covariates amongst which age and administration procedure was explored. Since no time of dose was available for the day before PK, this was estimated in the model. The final model was then used to optimise the dose across different weights using adult exposures as a target.
Results: The pharmacokinetics of ofloxacin was best described by a one-compartment model, with first-order elimination and first-order lagged absorption. The typical values of clearance was found to be 5.24 L/h. Age, HIV status, and study arm (disease treatment or prophylaxis treatment) were not found to significantly affect PK. Crushing the tablet or using a naso-gastric tube were found to affect the speed of absorption, but not the bioavailability of ofloxacin. The dose simulation show that children are currently under-dosed and the ideal values should be in the range of 15-33 mg/kg, with smaller children receiving higher mg/kg doses. This would also result in patients above 40 kg receiving a dose higher than 800 mg, which is the maximum dose today.
Conclusions: With the current mg/kg dosing approach, children achieve ofloxacin exposures lower than adults. According to the dose simulation the doses should be higher, compared to the recommended 15-20 mg/kg, for most of the younger children and for the ones above 40 kg.
2014. , 28 p.
Population pharmacokinetics, multi drug-resistant TB, Ofloxacin, paediatric, South Africa