Population Pharmacokinetics Of Rifampicin In Mexican Patients With Tuberculosis

Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 56–61

doi: 10.1111/jcpt.12016

Pharmacokinetics

Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis
´ ´ ´ ´ ˜ R. C. Milan Segovia*,  PhD, A. M. Domınguez Ramırez* PhD, H. Jung Cookà PhD, M. Magana Aquino§ MD, M. Vigna Perez  PhD, R. C. Brundage– PhD and S. Romano Moreno  PhD
´ ´ ´ ´ ´ *Doctorado enCiencias Biologicas y de la Salud, Universidad Autonoma Metropolitana, Mexico,  Facultad de Ciencias Quımicas, Universidad Autonoma ´ ´ ´ ´ ´ ´ de San Luis Potosı, Mexico, àFacultad de Quımica, Universidad Nacional Autonoma de Mexico, Mexico, §Hospital Central ‘Dr. Ignacio Morones Prieto’ ´ ´ Servicios Coordinados de Salud del Estado de San Luis Potosı, Mexico, and –College of Pharmacy, University ofMinnesota, Minneapolis, MN, USA

Received 23 August 2012, Accepted 24 September 2012

Keywords: antituberculosis drug, non-linear mixed-effect modelling, NONMEM, population pharmacokinetics, rifampicin

SUMMARY What is known and Objective: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic modelto characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. Methods: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic andclinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (NONMEM). Seventy-seven additional patients participated in the validation of the model. Results and Discussion: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/ F = 8Æ17 L/h (1Æ40 ashigh for males), apparent distribution volume Vd/F = 50Æ1 L (1Æ29 as high for males), absorption rate constant KaA = 0Æ391/h, KaB,C,D = 2Æ70/h, relative bioavailability FA = 0Æ468, FB,C,D = 1, lag time in the absorption phase Tlag = 0Æ264 h. The final model improved the precision on the parameter estimates (CL/F, Vd/F and Ka by 31Æ9%, 16Æ7% and 92Æ9%, respectively). The residual variability was27Æ3%. What is new and Conclusion: Gender was associated with changes in CL/F and Vd/F whereas the pharmaceutical formulation was associated with changes in F and altered the Ka. The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients. WHAT IS KNOWN AND OBJECTIVE During 2009, there were >17 000 new cases of tuberculosis (TB)reported in Mexico. There were $2000 deaths and 488 reports of resistance to first-line drugs.1 Tuberculosis is a disease increasingly associated with problems of multidrug resistance, HIV/AIDS and diabetes mellitus
´ ´ Correspondence: R. C. Milan Segovia, Facultad de Ciencias Quımi´ ´ cas, Universidad Autonoma de San Luis Potosı, Avenida Manuel ´ ´ Nava No. 6, 78210 San Luis Potosı, SLP, Mexico.Tel.: +52 (444) 8 26 24 40 ext. 514; fax +52 (444) 8 26 23 72; e-mail: milanros@uaslp.mx

(DM).2–5 Directly observed treatment short course (DOTS) for TB includes rifampicin (RIF) as first-line drug because of its high effectiveness and potency. Reference therapeutic range of RIF is 8–24 lg/mL at 2 or 4 h post-dose of 600 mg.2 Although a close relationship between body weight and exposure to RIFexists, pharmacokinetic–pharmacodynamic studies have documented high inter- and intra-individual variability in reaching the therapeutic range with standard doses3 and non-linear pharmacokinetics with increasing doses.4–7 Several studies have suggested that low RIF plasma concentrations observed in TB patients may be due to, among other factors, differences related to bioavailability of...