Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution

• Published in: Journal of pharmacokinetics and pharmacodynamics Vol. 42; no. 6; pp. 699 - 708
• Main Authors: Clewe, Oskar, Karlsson, Mats O., Simonsson, Ulrika S. H.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2015; Springer Nature B.V
• Subjects: Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Bronchoalveolar lavage; Bronchoalveolar Lavage - methods; Bronchoalveolar Lavage Fluid - chemistry; Computer Simulation; Drug Administration Routes; Drug Administration Schedule; Epithelial Cells - metabolism; Humans; Lung - metabolism; Models, Biological; Models, Statistical; Original Paper; Pharmacology/Toxicology; Pharmacometrics; Pharmacy; Pulmonary Alveoli - metabolism; Pulmonary distribution; Sampling design; Specimen Handling - methods; Tissue Distribution; Veterinary Medicine/Veterinary Science; Pharmacometrics; Pulmonary distribution; Sampling design; Bronchoalveolar lavage
• ISSN: 1567-567X; 1573-8744; 1573-8744
• DOI: 10.1007/s10928-015-9438-9

Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.