2010 - Berlin - Germany

PAGE 2010: Applications- Anti-infectives
Paolo Denti

Parallel first order and mixed order elimination of pyrazinamide in South African patients with tuberculosis

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.

[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
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