Oskar Clewe, Mats O. Karlsson, Ulrika S. H. Simonsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Bronchoalveolar lavage (BAL) is a semi-invasive method that enables sampling and quantification of drug concentrations from epithelial lining fluid (ELF) and alveolar cells (AC). Information about lung pharmacokinetic (PK) distribution is important in diseases such as tuberculosis where the site of action is primarily in the pulmonary tract and where plasma PK may not be a good marker when obtaining pharmacokinetic/pharmacodynamic relationships. Due to the semi-invasive nature of the BAL technique, repeated sampling within a narrow time frame from the same subject is difficult [1,2]. This poses a problem, as a characterization of the whole distribution profile then requires a large study population. This becomes even more difficult for a novel compound where the distribution characteristics might be unknown. The aim of this work was thus to develop and assess a general study design framework aimed at BAL studies in order to quantify the rate and extent of drug distribution to the pulmonary tract for a new compound using a limited number of samples.
Methods: A general PK distribution model [3], developed using rifampicin as an example was used in this work. In the model, the distribution from plasma to ELF is characterized by the extent (Rplasma/ELF) and rate (kELF) of distribution, driven by a plasma PK model. Two hypothetical drugs, one with instant and the second with slow distribution from plasma to ELF along with different number of BAL samples per subject were evaluated with only known plasma PK profile and limit of quantification (LOQ) in plasma and ELF. The evaluation was carried out using the stochastic simulation and estimation (SSE) tool provided in the Perl speaks NONMEM (PsN) [4] software.
Results: The best study BAL design for a drug with unknown lung distribution PK, is to obtain one very early and one late BAL sampling time point. The exact time points are chosen given the plasma PK profile and LOQ in plasma and ELF. Both single sample approach as well as two samples/subject designs are adequate although the latter provides less bias and lower imprecision in parameter estimates.
Conclusions: The developed study design framework is drug unspecific and enables characterization of both the rate and the extent of drug distribution from plasma to ELF. The framework includes as little as one or two samples per subject and relies only on prior information about the plasma PK profile and LOQ in ELF and plasma.
References:
[1] Zeitlinger M, Muller M, Joukhadar C. Lung microdialysis: a powerful tool for the determination of exogenous and endogenous compunds in the lower respiratory tract (mini-review). AAPS J 2005; 7: E600-8
[2] Dhanani J, Roberts JA, Chew M, et al. Antimicrobial chemotherapy and lung microdialysis: a review. Int J Antimicrob Agents 2010; 36; 491:500
[3] Clewe, O., Karlsson, M.O., Goutelle, S., Conte, J.E.Jr., Simonsson, U. S.H., A model predicting penetration of rifampicin from plasma to epithelial lining fluid and alveolar cells. Population Approach Group Europe, Glasgow 2013 (Abstract no. 2777)
[4] PsN-Toolkit – A collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM, Lindbom, L., Pihlgren, P., Jonsson, N. 2005 Computer Methods and Programs in Biomedicine 79 (3), pp. 241-257
Acknowledgments: The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (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 23 () Abstr 3182 [www.page-meeting.org/?abstract=3182]
Poster: Methodology - Study Design