Benjamin Weber (1) and Jens Markus Borghardt (2)
(1) Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany, (2) Department Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
Background/Objectives: Orally inhaled drug products are the preferred treatment options for pulmonary diseases [1, 2]. However, their pulmonary fate is often poorly understood. PBPK approaches may be an option for overcoming this knowledge gap. For inhaled drugs, however, PBPK approaches are often limited by missing in vitro in vivo correlation and an incomplete understanding of pulmonary PK processes, e.g. pulmonary deposition, dissolution and absorption[3-6]. Empirical modeling of PK data after intravenous (IV) and inhalational (INH) administration has recently been proposed as alternative for studying the pulmonary fate of inhaled drugs [7]. The objective of this work is to highlight how empirical modeling has recently helped to increase the understanding of the pulmonary fate of inhaled drugs [8-10].
Methods: Plasma and urine data after INH (in form of a solution via a soft mist inhaler) and IV administration of two inhaled drugs (olodaterol and tiotropium) from a total of 199 healthy volunteers obtained in six clinical studies were available. Model development was performed in a stepwise fashion for both drugs independently (NONMEM 7.3.0). Systemic disposition parameters were fixed to estimates obtained from the data after IV administration. Oral bioavailability was assumed to be negligible for both drugs.
Results: Plasma and urine PK of both substances were adequately described by three parallel pulmonary depot compartments with associated first-order absorption processes on top of four or five compartment systemic disposition models. An extended pulmonary residence time (absorption half-lives of at least 21h) of a large fraction of the pulmonary available dose (~ 70% and 85% for olodaterol and tiotropium, respectively) was demonstrated.
Conclusions: Empirical modeling was successfully applied to increase the understanding of the pulmonary fate of two inhaled drugs. It was the first time that an extended pulmonary residence time for olodaterol and tiotropium was demonstrated in humans. This finding is particularly interesting as pulmonary absorption of dissolved drug is commonly assumed to be fast (expected absorption half-life ~ 5 – 60 min) [11] and certainly not in the range of one day. Thus, empirical modeling seems to be an attractive option for studying and improving the understanding of the pulmonary fate of inhaled drugs when adequately implemented. The additional knowledge might also be used to improve PBPK models for inhaled drugs.
References:
[1] Global Initiative for Chronic Obstructive Lung Disease (GOLD), Global Strategy For the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2014.
[2] Global Initiative for Asthma (GINA), Global strategy for asthma management and prevention. 2014.
[3] Weber, B. and G. Hochhaus, A pharmacokinetic simulation tool for inhaled corticosteroids. AAPS J, 2013. 15(1): p. 159-71.
[4] Bäckman, P. and B. Olsson. Predictive modeling of deposition, dissolution, absorption and systemic exposure. in Orlando Inhalation Conference. 2014. Orlando, FL.
[5] Chaudhuri, S.R. and V. Lukacova, Simulating Delivery of Pulmonary (and intranasel) aerosolised Drugs, in Orally inhaled & nasal drug products. 2010: www.ondrugdelivery.com. p. 26-30.
[6] Collingwood, S.P., et al., Respiratory drug discovery, current developments and future challenges: Highlights from the Society of Medicines Research Symposium, held on June 14 th, 2012 – Horsham, UK. Drugs of the Future, 2012. 37(8): p. 619-625.
[7]Bartels, C., et al., Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach. Br J Clin Pharmacol, 2013. 76(6): p. 868-79.
[8] Borghardt, J.M., et al. Expanding the Mechanistic Knowledge about Pulmonary Absorption processes using a Population Pharmacokinetic Model for Inhaled Olodaterol. in Respiratory Drug Delivery. 2014. Fajardo, Puerto Rico: Davis Healthcare International Publishing, LLC.
[9] Parra-Guillen, Z., et al., Population Pharmacokinetic Analysis of Tiotropium in Healthy Volunteers after Intravenous Administration and Inhalation. J Pharmacokinet Pharmacodyn, 2014. 41(1): p. S54.
[10] Borghardt, J.M., et al. The physiological interpretation of population pharmacokinetic modelling results for inhaled olodaterol. in PAGE. Annual Meeting of the Population Approach Group in Europe. . 2014. Alicante, Spain.
[11] Patton, J.S., C.S. Fishburn, and J.G. Weers, The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc, 2004. 1(4): p. 338-44. c
Reference: PAGE 24 () Abstr 3327 [www.page-meeting.org/?abstract=3327]
Poster: Drug/Disease modeling - Absorption & PBPK