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 - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue European Journal of Clinical Pharmacology Année : 2015

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

O. Clewe
  • Fonction : Auteur
Jr. Conte
  • Fonction : Auteur
Ush. Simonsson
  • Fonction : Auteur

Résumé

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. 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. 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. 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.

Dates et versions

hal-02044963 , version 1 (21-02-2019)

Identifiants

Citer

O. Clewe, Sylvain Goutelle, Jr. Conte, Ush. Simonsson. 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. European Journal of Clinical Pharmacology, 2015, 71 (3), pp.313-9. ⟨10.1007/s00228-014-1798-3⟩. ⟨hal-02044963⟩
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