A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells—using rifampicin as an example

• Published in: European journal of clinical pharmacology Vol. 71; no. 3; pp. 313 - 319
• Main Authors: Clewe, Oskar, Goutelle, Sylvain, Conte, John E., Simonsson, Ulrika S. H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2015; Springer Nature B.V; Springer Verlag
• Subjects: Alveolar cells; Biomedical and Life Sciences; Biomedicine; Bronchoalveolar lavage; Bronchoalveolar Lavage Fluid - chemistry; Epithelial lining fluid; Female; Humans; Life Sciences; Lungs; Male; Models, Biological; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Pharmacometrics; Plasma; Pulmonary Alveoli - cytology; Pulmonary distribution; Rifampin - analysis; Rifampin - blood; Rifampin - pharmacokinetics; Tuberculosis; Pharmacometrics; Epithelial lining fluid; Alveolar cells; Pulmonary distribution; Bronchoalveolar lavage
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-014-1798-3

Purpose The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. Methods Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. Results This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k ELF and k AC , respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio ( R ELF/unbound-plasma ) and unbound AC/plasma concentration ratio ( R AC/unbound-plasma ) which typical values were predicted to be 1.28 and 5.5, respectively. Conclusions The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.