J.M. Borghardt (1, 2), B. Weber (2), A. Staab (2), C. Kloft (1)
(1) Dept. Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany; (2) Dept. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Objectives: Pulmonary absorption of inhaled drugs is a complex process influenced by pulmonary deposition patterns and dissolution (1, 2). Parallel first-order absorption processes were demonstrated for inhaled drugs applying empirical models (3, 4). In those models the total estimated fraction absorbed (lung dose) was constrained to be between zero and one. Proportionality factors for each absorption process (PFi) were estimated. The contribution of each process to the lung dose was calculated as PFi/sum(PF1-n). Variability of PFi was assumed to be log-normally distributed before normalisation, which is in contrast to the usually applied logit-transformation, for which variability is assumed to be normally-distributed on the logit-scale. The objective was to develop an alternative parameterisation applying logit-transformations, which allow modelling fractions directly on a zero to one scale.
Methods: The new parameterisation for pulmonary absorption was inspired by “Advanced Compartmental Absorption and Transit“ models applied to describe gastrointestinal (GI) absorption (5). In these models, transport through transit GI absorption compartments is described by transit rate constants. In the lung, inhaled particles have to pass different airways, possibly represented by multiple absorption compartments. In contrast to the GI tract, drug distribution across pulmonary absorption compartments was assumed to be instantaneous. Hence, fractions (Fi) on a logit-scale were estimated instead of transit rate constants. While Fi represented drug input to absorption compartment i, 1-Fi represented the remaining amount of drug available for subsequent absorption compartments. The lung dose was estimated as a fraction of the nominal inhaled dose. The new and previously proposed parameterisations were applied to data (plasma and urine) of inhaled olodaterol.
Results: Without allowing for interindividual variability (IIV), both parameterisations provided numerically identical description of the data. This was expected since it can be shown that the parameterisations are mutually transformable functions. When including IIV, the new parameterisation provided a numerically better description of the data.
Conclusions: A new parameterisation for parallel pulmonary absorption processes was successfully developed. The parameterisation allowed to adequately describe PK data after olodaterol inhalation. Additionally the new parameterisation might also facilitate interpretation of parameters.
References:
[1] Patton JS, Brain JD, Davies LA, Fiegel J, Gumbleton M, Kim KJ, et al. The particle has landed – characterizing the fate of inhaled pharmaceuticals. J Aerosol Med Pulm D. 2010;23 Suppl 2:S71-87.
[2] Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discovery. 2007;6(1):67-74.
[3] Parra-Guillen Z, Weber B, Sharma A, Freijer J, Retlich S, Borghardt JM, et al. Population Pharmacokinetic Analysis of Tiotropium in Healthy Volunteers after Intravenous Administration and Inhalation. J Pharmacokinet Phar. 2014;41(1):S54.
[4] Bartels C, Looby M, Sechaud R, Kaiser G. Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach. Br J Clin Pharmacol. 2013;76(6):868-79.
[5] Huang W, Lee SL, Yu LX. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009;11(2):217-24.
Reference: PAGE 24 () Abstr 3607 [www.page-meeting.org/?abstract=3607]
Poster: Drug/Disease modeling - Absorption & PBPK