Alessandro Schipani (1), Henry Pertinez (1), Rachel Mlota (2), Nuria Lopez (2), Paul Tembo (2), Steve Ward (3), Saye Khoo (1), Gerry Davies (1)
(1) Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK. (2) Department of Paediatrics, College of Medicine, Blantyre, Malawi. (3) Liverpool school of tropical medicine, Liverpool, UK
Objectives: Rifampicine (RIF) is considered a key drug for the treatment of pulmonary infections caused by M. tuberculosis. It rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy.
Low RIF plasma exposure can lead to a delayed, incomplete response to treatment or to increased risk of developing drug resistance. RIF has known high variability in reaching the therapeutic range with standard doses and for this reason the World Health Organization (WHO) recently increased the recommended oral dosage from 10 to 15 mg/kg body weight. However in most parts of Africa patients still receive the 10mg/kg dosage, particularly affecting children, who typically show lower levels of RIF than in adults, for a given dose.
The objectives of this study were to:
- Evaluate the PK of RIF in Malawian children with tuberculosis
- Assess the new WHO dosing recommendation for the use of currently available fixed dose combination tuberculosis medicines in children
- Investigate the use of surrogates for weight (age and height), as indicators of body size for dosing bands
Methods: A total of 151 RIF concentrations from 55 patients, aged 0.58 to 17 years and weighing 4.8 to 45kg, were included to build a population pharmacokinetic model using non-linear mixed effects modelling (NONMEM7).
Results: A one-compartment model with first-order absorption best described the data. The typical population estimate of oral clearance was 6.80L/h, while the volume of distribution was estimated to be 179L. Interindividual variability was estimated to be 36% for clearance and 134% for volume of distribution. Body weight was included as a covariate in the final model using allometric scaling. Models with the inclusion of age and height covariates were evaluated separately. Simulations of the dosing bands using age and height as surrogates for weight showed similar results.
Simulations for the new WHO doses generate a better exposure especially for younger children compared with the present weight band dosage in Malawi.
Conclusion: The final model successfully described RIF PK in the population studied and is suitable for simulation in this context. The data have shown that children have low plasma concentrations, indicating a need for new formulations. Simulations from dosing bands based on height and age show these can be used as alternatives to weight to set doses in clinical settings where weight may be hard to assess.
Reference: PAGE 22 (2013) Abstr 2782 [www.page-meeting.org/?abstract=2782]
Poster: Infection