Marie Wijk (1), Kamunkhwala Gausi (1), Samantha Malatesta (2), Sarah E. Weber (3), Tara Carney (4), Bronwyn Myers (4), Lubbe Wiesner (1), C. Robert Horsburgh Jr (5), Frank Kloprogge (6), Richard Court (1), Robin M. Warren (7), Helen McIlleron (1), Paolo Denti (1), Karen R. Jacobson (3)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, (2) Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA, (3) Section of Infectious Diseases, Boston University School of Medicine and Boston Medical Centre, Boston, MA, USA, (4) Alcohol, Tobacco and Other Drug Research Unit, South African Medical Research Council, Tygerberg, South Africa, (5) Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA, (6) Institute for Global Health, University College London, London, UK, (7) Department of Science and Innovation, National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research, South Africa Medical Research Council for Tuberculosis Research, Stellenbosch University, Tygerberg, South Africa
Objectives: Ethambutol is one of four drugs given during the initial two-month intensive phase of drug-susceptible tuberculosis treatment. Ethambutol is minimally metabolized with ~70% excreted unchanged renally.[1] Ethambutol’s addition to the treatment regimen in the early 1960s was mainly to protect against rifampicin resistance development in isoniazid resistant individuals and was usually stopped early if an organism is confirmed as fully drug susceptible.[2] Consequently, few population pharmacokinetic models describing ethambutol in tuberculosis patients have been published. We investigated the population pharmacokinetics of ethambutol in South African patients with drug-susceptible tuberculosis.
Methods: Patients within an observational study in Worcester, South Africa, who had tested negative for HIV received first-line tuberculosis treatment with weight-based dosing (15-25 mg/kg ethambutol once daily). After one month of treatment, blood samples were taken pre-dose, and at 1.5, 3, 5 and 8 h post-dose. Plasma concentrations were measured using a validated liquid chromatography tandem mass spectrometry method and lower limit of quantification (LLOQ) was determined. We used population pharmacokinetic modelling in NONMEM to interpret the data. Doses were adjusted in accordance with the salt factor for ethambutol dihydrochloride. Observations below LLOQ were imputed to LLOQ/2 (0.0422 mg/L), and their additive error component was increased by 50% of LLOQ. Covariates tested were allometry (either total body weight or fat-free mass) and creatinine clearance. Ethics approval was obtained by the South African Medical Research Council, Stellenbosch University Human Research Ethics Committee, and the Boston University Institutional Review.
Results: In total, 471 observations from 96 participants were included in the model. The cohort’s median weight was 52 kg (range 31-80), fat-free mass was 43 kg (24-59) and 71% (n=68) were male. Creatinine clearance was estimated to 119 mL/min (range 51-253), using the Cockcroft-Gault formula. The pharmacokinetics of ethambutol was best described by a two-compartment model with transit compartment absorption and first-order elimination. Between-subject variability was included on clearance, while between-occasion variability was included on absorption parameters. Allometric scaling using fat-free mass best described the effect of body size on disposition parameters. The typical value for clearance was estimated to 46.8 L/h and linearly correlated with creatinine clearance. With each 10 mL/min increase in creatinine clearance, ethambutol clearance increased with 2.9%.
Conclusions: We found a two-compartment model to be the best fit for the data, which is consistent with most published models on ethambutol pharmacokinetics in tuberculosis patients. The clearance values fall within the range of previously reported values. Using fat-free mass on disposition parameters and including creatinine clearance as a covariate on ethambutol clearance significantly improved the model. This has been seen in previously published models and is expected given the renal elimination of ethambutol.
References:
[1] Lee, C. S., Brater, D. C., Gambertoglio, J. G., & Benet, L. Z. (1980). Disposition kinetics of ethambutol in man. Journal of pharmacokinetics and biopharmaceutics, 8(4), 335-346.
[2] Mitchison, D. A. (1985). The action of antituberculosis drugs in short-course chemotherapy. Tubercle, 66(3), 219–225. doi:10.1016/0041-3879(85)90040-6
Reference: PAGE 30 (2022) Abstr 10155 [www.page-meeting.org/?abstract=10155]
Poster: Drug/Disease Modelling - Infection