J. Borghardt (1, 2), B. Weber (2), A. Staab (2), C. Kunz (2), J. Schiewe (3), C. Kloft (1)
(1) Dept. Clinical Pharmacy & Biochemistry, Freie Universitaet Berlin, Germany; (2) Dept. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany; (3) Dept. Respiratory Drug Delivery, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Objectives: A previously developed population pharmacokinetic model identified a three compartment systemic disposition model with a lung dose absorbed by three parallel absorption processes for inhaled olodaterol (1). After inhalation with the Respimat®, more drug deposition in higher airway generations (small airways and alveoli), where drug absorption is assumed to be fast, and less central airway deposition, where drug absorption is assumed to be slow, has been discussed (2). However, the model identified most of the lung dose to be slowly absorbed (ca. 70%, t1/2: 48.1 h). Lysosomal trapping of olodaterol in lung cells was proposed as a plausible physiological explanation. However, lysosomal trapping is a systemic effect and, hence, should also be present after IV administration. The objective of this analysis was to investigate the hypothesis of lysosomal trapping after IV administration and inhalation of olodaterol.
Methods: Olodaterol data after IV dosing (n=48) and inhalation (n=84) was available from different trials in healthy volunteers and evaluated using a population PK approach. In contrast to the previous approach (1), urine data collected over 96 h after IV administration was included for possibly identifying an additional process that could be associated with lysosomal trapping. Analyses were performed in NONMEM 7.2 and R 2.14.2.
Results: A four compartment disposition model was identified by the re-analysis of the IV data. By including the urine data, a longer terminal half-life with 82.4 h compared with 14.0 h described by the previous IV model (without urine data) was identified, even though full plasma concentration-time profiles up to 24 hours were available in the previous analysis. Simulations indicated that the additionally identified process was masked due to the lower limit of quantification. Applying the new parameter estimates to the inhalation data did not impact the structure of the inhalation PK model. However, the slowest absorption process (t1/2: 27.4 h) was faster compared with that of the previous inhalation model (t1/2: 48.1 h). Consequently, flip-flop kinetics that was demonstrated for the previous model was not present in the updated model.
Conclusions: The obtained results support the hypothesis of lysosomal trapping of olodaterol after both IV administration and inhalation. Nevertheless, the large, slowly absorbed fraction of the lung dose (ca. 75%) indicates lysosomal trapping to a larger extent after inhalation of olodaterol.
References:
[1] Borghardt JM, Weber B, Staab A, Kunz C, Schiewe J, Kloft C. Expanding the Mechanistic Knowledge about Pulmonary Absorption Processes using a Population Pharmacokinetic Model for Inhaled Olodaterol. Proceedings of Respiratory Drug Delivery 2014 (In press 2014).
[2] Ciciliani AM, Wachtel H, Langguth P. Comparing Respimat® Soft Mist™ Inhaler and DPI Aerosol Deposition by Combined In Vitro Measurements and CFD Simulations. Proceedings of Respiratory Drug Delivery 2014 (In press 2014).
Reference: PAGE 23 (2014) Abstr 3245 [www.page-meeting.org/?abstract=3245]
Poster: Drug/Disease modeling - Absorption & PBPK