Lukas Löfling (1), Anthony Garcia-Prats (3), H. Simon Schaaf (3), Sandra Castel (2), Lubbe Wiesner (2), Helen McIlleron (2), Anneke Hesseling (3), Paolo Denti (2)
(1) Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden (2) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa (3) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
Objectives: Multidrug-resistant tuberculosis (MDR-TB) is an emerging problem, increasingly affecting children. Ofloxacin is a fluoroquinolone widely used in the treatment and prophylaxis of MDR-TB, but with limited PK data in children.
The study aim was to describe ofloxacin PK in the paediatric population, to optimise future dosing regimens.
Methods: 88 South African children (age 3.5 yr, 0.5–15, and weight 15 kg, 7–66) were routinely receiving daily ofloxacin as part of MDR-TB treatment or prophylaxis. Blood samples were collected pre-dose, and at 1, 2, 4, and 6-8 or 8-11 hr post-dose. Children were dosed exactly 20 mg/kg of ofloxacin on the day of PK sampling, with smaller children receiving crushed tablets, sometimes by naso-gastric tube.
MONOLIX 4.3.3 was used to analyse the PK data. Allometric scaling [1] was employed to account for differences in body weight. The effect of age, HIV status, treatment vs. prophylaxis, and drug administration procedure was evaluated using drops in objective function value (OFV) and goodness of fit plots. The final model was then used to optimise doses across different weight bands, targeting previously reported ofloxacin exposures in adults [2, 3].
Results: Ofloxacin PK was best described by a 1-compartment model with 1st-order elimination and 1st-order absorption with a lag time. The inclusion of allometric scaling substantially improved the model. For a 15 kg child, the model estimated CL of 5.2 L/h and V of 25 L. Crushing tablets or use of naso-gastric tube affected the rate of absorption, but not bioavailability. Age, HIV status, and treatment vs. prophylaxis did not significantly affect PK.
Children in this cohort achieved exposures lower than previously reported in adults on the standard 800 mg daily dose (median AUC of 58 mg∙h/L vs. roughly 100 mg∙h/L). As predicted by allometric scaling, lower weight children achieved lower concentrations. Dose simulations from the model show that to obtain similar median AUCs to those in adults, paediatric doses should be in the range of 25-50 mg/kg, with smaller children receiving higher mg/kg doses.
Conclusions: With the current “constant mg/kg” dosing approach, children achieve ofloxacin exposures considerably lower than adults and smaller children are even more severely under-dosed and exposed. However, allometric scaling does not account for the entire difference with adult exposures. No maturation effect of age on CL was detected in this cohort, possibly due to the low number of children <1 yr.
References:
[1] B. J. Anderson and N. H. G. Holford, “Mechanism-based concepts of size and maturity in pharmacokinetics.,” Annu. Rev. Pharmacol. Toxicol., vol. 48, pp. 303–32, Jan. 2008.
[2] E. Chigutsa, S. Meredith, L. Wiesner, N. Padayatchi, J. Harding, P. Moodley, W. R. Mac Kenzie, M. Weiner, H. McIlleron, and C. M. J. Kirkpatrick, “Population pharmacokinetics and pharmacodynamics of ofloxacin in South African patients with multidrug-resistant tuberculosis.,” Antimicrob. Agents Chemother., vol. 56, no. 7, pp. 3857–63, Jul. 2012.
[3] M. Zhu, J. J. Stambaugh, S. E. Berning, A. E. Bulpitt, E. S. Hollender, M. Narita, D. Ashkin, and C. a Peloquin, “Ofloxacin population pharmacokinetics in patients with tuberculosis,” Int. J. Tuberc. Lung Dis., vol. 6, no. 6, pp. 503–509, 2002.
Reference: PAGE 24 (2015) Abstr 3624 [www.page-meeting.org/?abstract=3624]
Poster: Drug/Disease modeling - Paediatrics