Oskar Clewe (1), Mats O Karlsson (1), Sylvain Goutelle (2, 3), John E. Conte, Jr. (4, 5), Ulrika SH Simonsson (1)
(1) Uppsala Pharmacometric Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Hospices Civils de Lyon, Hôpital A. Charial, Service Pharmaceutique, ADCAPT, Francheville, France; (3) Université Lyon 1, UMR CNRS 5558, Biométrie et Biologie Evolutive, Villeurbanne, France; (4) Department of Epidemiology and Biostatistics, Infectious Disease Research Group, University of California, San Francisco, California; and (5) American Health Sciences, San Francisco, California
Objectives: In a non-tuberculosis infected population describe rifampicin´s (RIF) autoinduced plasma concentrations and predict the concentration ratios between epithelial lining fluid, alveolar cells and plasma.
Methods: Data from a previously published study (1) were used in this population analysis. The data analysis was performed with a nonlinear mixed-effects approach as implemented in the software NONMEM, version 7.2 (ICON Development Solutions). The model building process was performed in a stepwise fashion, starting from a previously published rifampicin pharmacokinetic enzyme turn-over model (2). Rifampicin's autoinduction was described with an enzyme turn-over-model, where rifampicin's plasma concentration increase the enzyme production rate which in turn increases the enzyme pool in a non-linear fashion by means of an EMAX-model. The epithelial lining fluid and alveolar cell drug penetration were described using effect compartments (3), where the penetration coefficients between plasma and epithelial lining fluid (Pelf) and plasma and alveolar cells (Pac) were estimated. The time rate constants kelf and kac were fixed to a value mimicking an almost instantaneous transfer of drug from plasma to epithelial lining fluid or alveolar cell due to the sparse sampling design.
Results: The final RIF plasma model was a one compartment model with transit absorption compartments and an enzyme turn-over model describing rifampicin's autoinduction. Parameters related to the absorption and enzyme turnover was fixed to previously published values (2). Oral clearance and volume of distribution were estimated to 4.8 L/h and 50 L respectively. The data supported inclusion of inter individual variability on oral clearance (69%). At four hours post dose the RIF's penetration coefficients for epithelial lining fluid and alveolar cells were estimated to 0.27 and 1.17 respectively. This resulted in a mean epithelial lining fluid to plasma ratio of 1.36 and a mean alveolar cell to plasma ratio of 5.81 when compensating for the free fraction (0.2) of RIF concentration in plasma (4).
Conclusions: The final model propose a way to describe the often sparse data originating from the use of bronchoalveolar lavage, where only one or a few samples are possible to withdraw from each subject. The model characterizes RIF's plasma pharmacokinetic properties including auto-induction as well as the penetration of drug from plasma to epithelial lining fluid and alveolar cells.
References:
[1] Conte JE, Golden JA, Kipps JE, Lin ET, Zurlinden E. Effect of sex and AIDS status on the plasma and intrapulmonary pharmacokinetics of rifampicin. Clinical pharmacokinetics. 2004;4 (6):395-404. Epub 2004/04/17.
[2] Smythe W, Khandelwal A, Merle C, Rustomjee R, Gninafon M, Bocar Lo M, et al. A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients. Antimicrobial agents and chemotherapy. 2012;56(4):2091-8. Epub 2012/01/19.
[3] Kjellsson MC, Via LE, Goh A, Weiner D, Low KM, Kern S, et al. Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions. Antimicrobial agents and chemotherapy. 2012;56(1):446-57. Epub 2011/10/12.
[4] Moffat, A. C., M. D. Osselton, and B. Widdap (ed.). 2004. Clarke's analysis of drugs and poisons, 3rd ed. Pharmaceutical Press, London, United Kingdom.
Acknowledgments: The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertakin (www.imi.europe.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution.
Reference: PAGE 22 (2013) Abstr 2777 [www.page-meeting.org/?abstract=2777]
Poster: Infection