E. Chigutsa(1), H. McIlleron(1), N.H.G. Holford(2)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa; (2) University of Auckland, New Zealand
Background: An earlier zero-order input model with first order elimination of pyrazinamide[1] poorly described absorption in a new cohort of South African patients with tuberculosis (TB).
Objectives: To improve the model to describe the population pharmacokinetics of pyrazinamide in a new TB treated cohort.
Methods: Seventy-nine patients were sampled 4-8 times during 2 steady state dosing intervals one month apart. All patients were receiving treatment with rifampicin, isoniazid, ethambutol and pyrazinamide with directly observed administration. LC-MS was used for plasma concentration determination. Pharmacokinetic analysis was performed using NONMEM VI. Visual predictive checks were used for model evaluation. The model was validated using an external dataset.
Results: A combination of first order and Michaelis-Menten elimination best described the clearance of pyrazinamide. A sequential, dual, first order process was used to describe drug absorption. A Ka of 0.02/h changing to 1.0/h at 0.71h post-dose was estimated. A time dependent residual error model was used to account for changes in the residual error with respect to time. Vmax for elimination was estimated to be 14.3mg/h/70kg, whilst the Km was 0.52mg/L. First order clearance was 2.64L/h/70kg and volume was 42L/70kg after using allometric functions of weight. Relative bioavailability was 26% higher in females compared to males. Between subject variability (BSV) for the combined elimination was 17% whilst within subject variability (WSV) was 16%. BSV for the change point in Ka was 45% whilst the WSV was 48%. WSV was 82% for Ka. BSV for bioavailability was 16%. As part of model validation, an estimation was performed using this model on another dataset. Similar parameter estimates were obtained, except for higher absorption rate constants, and females having just 3% higher bioavailability than males.
Conclusions: The population pharmacokinetics of pyrazinamide in this population were described by parallel first and mixed order elimination, and a dual absorption rate constant model. This is the first time that mixed order elimination has been noted for pyrazinamide which may become important in small patients given standard doses.
References:
[1] Wilkins, J.J., G. Langdon, H. McIlleron, G.C. Pillai, P.J. Smith and U.S. Simonsson, Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. Eur J Clin Pharmacol, 2006. 62(9): p. 727-35.
Reference: PAGE 19 (2010) Abstr 1946 [www.page-meeting.org/?abstract=1946]
Poster: Applications- Anti-infectives