Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients
Siv J÷nsson(2), Alistair Davidse(1), Justin Wilkins(2,3), Jan-Stefan Van der Walt(1,2), Ulrika SH Simonsson(2), Mats O Karlsson(2), Helen McIlleron(1), Peter Smith(1)
(1)Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa; (2)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (3)Modelling & Simulation, Clinical Development & Medical Affairs, Novartis Pharmaceuticals AG, Basel, Switzerland
Objectives: Ethambutol (EMB) is one of four drugs in the first-line antitubercular regimen and is used to protect against rifampicin resistance in the event of a pre-existing resistance to isoniazid . The aim was to describe the population pharmacokinetics (PK) of EMB in South African tuberculosis patients.
Methods: Data were obtained from patients with pulmonary tuberculosis treated with EMB (oral doses 800-1500 mg qd) combined with standard anti-tubercular medication from 2 centres employing different dosing and sampling schedules. Blood samples were collected following multiple dosing and plasma concentrations of EMB were determined using a validated HPLC-tandem MS method. A population PK model was developed in NONMEM VI (FOCE INTER)  with a covariate model established using the scm procedure in PsN 3.0.0 [3, 4]. The model was qualified using visual predictive checks and non-parametric bootstrapping.
Results: PK observations were obtained from 189 patients (54% male, 46% female) weighing 47 kg on average (range 29-86) and with a mean age of 36 years (range 16-72). Twelve percent were HIV positive. The estimated creatinine clearance (CLCR) was 79 mL/min (range 23-150). A two-compartment model with one transit compartment prior to first-order absorption and elimination described the data. Allometric body weight scaling was introduced on all clearance and volume terms. Oral clearance (CL/F), central and peripheral volume of distribution in a patient weighing 50 kg were 40.3 L/h, 96.2 L and 593 L, respectively. Presence of HIV decreased bioavailability by 16%. Inter-occasion variability exceeded inter-individual variability for oral clearance (45 vs 16 %CV).
Conclusions: The estimated typical CL/F concur with Lee , but is roughly half of CL/F reported by Peloquin  and Zhu . The latter can partially be due to differences in body weight between studies. The decrease in bioavailability is consistent with earlier findings [7, 8]. CLCR and body weight were positively correlated and most patients (86%) had CLCR greater or equal to 60 mL/min, possibly explaining why renal function was not identified as a covariate although EMB is mainly excreted unchanged in urine.
 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America (2003). Treatment of tuberculosis. American Journal of Respiratory and Critical Care Medicine 167:603-662.
 Beal SL et al. (1989-2006). NONMEM Users' Guides, Icon Development Solutions, Ellicott City, Maryland, USA.
 Lindbom L et al. (2004). Perl-speaks-NONMEM (PsN)--a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 75(2):85-94.
 Lindbom L et al. (2005). PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 79(3):241-57.
 Lee CS et al (1977) Kinetics of oral ethambutol in the normal subject. Clin Pharmacol Ther 22(5 Pt 1):615-21.
 Peloquin CA et al. (1999). Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids. Antimicrobial Agents and Chemotherapy 43(3):568-572.
 Zhu M et al. (2004). Pharmacokinetics of ethambutol in children and adults with tuberculosis.á Int J Tuberc Lung Disá 8(11):1360-1367.
 McIlleron H et al. (2006). Determinants of rifampin, isonaizid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrobial Agents and Chemotherapy 50(4):1170-1177.