Paolo Denti (1), Anthony Garcia-Prats (2), Heather Draper (2), Lubbe Wiesner (1), H. Simon Schaaf (2), Helen McIlleron (1), Anneke Hesseling (2)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa (2) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
Objectives: The fluoroquinolone levofloxacin is the levo-isomer of ofloxacin and is widely used for treatment and prophylaxis of multi-drug-resistance-tuberculosis (MDR-TB). Limited data on its PK is available in children. The aim of this study is to characterise levofloxacin PK in children to optimise dosing.
Methods: 109 South African children, median age 2.1 yr (range 0.3–8.7) and weight 12 kg (6–22), received daily levofloxacin within a study on MDR-TB treatment/prophylaxis. Samples were collected before dosing and at 1, 2, 4, 6, and 8 hours post-dose. Children received 15 or 20 mg/kg, with exact dosing on the day of PK sampling. Smaller children received crushed tablets, often using a nasogastric tube. NONMEM 7.3 with FOCE-I was used to interpret the PK data. The effect of body size was captured with allometric scaling [1], while the effect of age, HIV status, treatment vs. prophylaxis, and drug administration procedure were evaluated. Simulations from the final model were used to optimise doses across different weight bands, targeting adult exposure.
Results: Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption through transit compartments [2]. After inclusion of allometric scaling, which substantially improved the fit, the model could characterise age-driven maturation of CL with an effect reaching 50% around 2 months after birth. CL in a 12 kg, 2-year-old child was estimated 4.7 L/h. The use of nasogastric tube increased the rate of absorption, but no significant effect on bioavailability could be detected. HIV positive children were found to have 16% slower CL. Levofloxacin exposures in this cohort of children were significantly lower than previously reported in adults dosed 1000 mg daily (a similar mg/kg dose): 45 vs. 129 mg∙h/L [3]. Only part of this difference could be explained by allometric scaling. To achieve exposures similar to adults a dose of 50 mg/kg would be required, with smaller children receiving higher mg/kg doses, except very young children with immature CL (<1 yr old).
Conclusions: Consistently with reports in other paediatric populations [4], children achieve levofloxacin exposures considerably lower than adults using the same mg/kg dose, and this difference cannot be fully explained by allometric scaling. Our report of slightly higher exposure in HIV positive children, of unlikely clinical significance, would need further investigation in other studies.
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] R. M. Savic, D. M. Jonker, T. Kerbusch, and M. O. Karlsson, “Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies.,” J. Pharmacokinet. Pharmacodyn., vol. 34, no. 5, pp. 711–26, Oct. 2007.
[3] C. a. Peloquin, D. J. Hadad, L. P. D. Molino, M. Palaci, W. H. Boom, R. Dietze, and J. L. Johnson, “Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis.,” Antimicrob. Agents Chemother., vol. 52, no. 3, pp. 852–7, Mar. 2008.
[4] S. R. Mase, J. A. Jereb, D. Gonzalez, F. Martin, C. L. Daley, D. Fred, A. Loeffler, L. Menon, S. B. Morris, R. Brostrom, T. Chorba, and C. A. Peloquin, “Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-Resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands,” Pediatr. Infect. Dis. J., p. 1, Dec. 2015.
Reference: PAGE 25 (2016) Abstr 6009 [www.page-meeting.org/?abstract=6009]
Poster: Drug/Disease modeling - Infection