Mechanistic pharmacokinetic enzyme model for the characterisation of rifampicin pharmacokinetics in South African pulmonary TB infected adults
W Smythe, H McIlleron, P Smith and USH Simonsson
University of Cape Town & Uppsala University
Introduction: The treatment of TB requires the use of multiple drug containing regimens. As rifampicin (RMP) has the ability to eliminate persisting Mycobaterium organisms within TB lesions it forms the backbone of most first line regimens (1). Nonetheless RMP is known to have highly variable absorption (2, 3) and to induce its own metabolism (4). These characteristics, coupled with potential drug-drug interactions and low RMP concentrations (5), may increase the likelihood of treatment failure and the emergence of drug resistance.
Objectives: The primary objective of this pharmacokinetic analysis was to determine the population pharmacokinetics of rifampicin using nonlinear mixed-effects modelling amongst African patients with pulmonary tuberculosis. Subsequently, population PK models will be developed for the remaining drugs used within the study's multi-drug regimens and potential drug-drug interactions will be assessed.
Methods: Pulmonary tuberculosis infected adult patients were randomized to receive once daily doses of rifampicin, isoniazid, pyrazinamide and ethambutol with or without gatifloxacin for 6 days of the week. Blood samples were taken for pharmacokinetic determination after the first dose (pre-induction) and after approximately 28 days (steady state). In total, 1 142 rifampicin plasma concentration-time data points collected from 195 patients were included in the analysis. A mechanistic pharmacokinetic model incorporating an enzyme turn over model to address rifampicin's auto-inductive properties, together with a multiple dosing transit absorption compartment model to describe the drugs highly variable absorption was developed using the first order conditional method in NONMEM.
Results: A multiple dose transit absorption compartment model (3, 6) was used to describe the highly variable absorption characteristics of rifampicin. The transfer of drug through the transit compartments followed by first order absorption allowed for the model to mimic a delay in absorption observed occasionally in patients taking rifampicin. Rifampicin's propensity to induce its own metabolism was modelled by an enzyme compartment where the amount of drug within the central compartment was allowed to influence the production of enzyme. As more enzyme was produced within the enzyme compartment so the oral clearance (CL/F) of drug from the central compartment was increased. The CL/F was around one fold higher at the steady state compared to the pre-induced state. The predicted enzyme turn-over half-life was predicted to be approximately 62 hours.
Conclusions: The developed mechanistic model described the pharmacokinetics of rifampicin and will be extended to include potential drug-drug interactions seen between rifampicin and the other drug components of the anti-tuberculosis regimens.
References:
[1] Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs. 2002; 62: 2169-83.
[2] Peloquin CA, Jaresko GS, Yong CL, et al. Population Pharmacokinetic Modeling of Isoniazid, Rifampin, and Pyrazinamide. Antimicrobial Agents Chemother. 1997; 41: 2670-9.
[3] Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G,. Smith PJ, and USH Simonsson. Antimicrobial Agents Chemother. 2008; 52: 2138-48.
[4] Loos U, Musch E, Jensen JC, Schwabe H K, and M Eichelbaum. Influence of the enzyme induction by rifampicin on its presystemic metabolism. Pharmacol. Ther. 1987; 33: 201-4.
[5] Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000; 4: 796-806.
[6] Wilkins JJ, Langdon G, McIlleron H, Pillai G, Smith PJ and USH Simonsson. PAGE 13 (2004) Abstr 538 [www.page-meeting.org/?abstract=538]
