Haini Wen (1), Muhammad Waqas Sadiq (2), Lena E. Friberg (1), Elin M. Svensson (1,3)
(1) Department of Pharmacy, Uppsala University, Uppsala, Sweden (2) Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden (3) Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
Objectives:
Oral inhalation is an attractive approach for drug delivery, especially when targeting respiratory diseases. Inhalation provides a rapid onset of action and high concentrations in specific lung regions.1 Moreover, localized delivery minimizes systemic side effects associated with oral or intravenous administration, and often requires lower doses to achieve therapeutic effects.1,2 However, accurately assessing and predicting the exposure of orally inhaled drugs in the human lung poses a significant challenge in drug development. The translational ability to bridge between animals and humans has generally not been well addressed in previous modelling approaches, limited by the availability of pulmonary concentrations in human subjects due to sampling difficulties.3–5 Thus, we aim to develop a comprehensive physiologically based pharmacokinetic (PBPK) framework tailored for the pulmonary pharmacokinetic (PK) behavior in both humans and rats, in order to bridge the translational gap.
Methods:
A mechanistic pulmonary PBPK model for rats was developed to integrate the pulmonary disposition processes including drug deposition, dissolution, mucociliary clearance, and mass transfer in lung tissues. The lung airways were divided into 24 generations, with generation 1 to 16 representing the tracheobronchial region, and generation 17 to 24 the alveolar region. The mechanistic lung model was implemented within a lung compartment, which was connected to a systemic compartmental PK model. Drug parameters including physiochemical properties, lung specific parameters, deposition specific parameters, and systemic PK parameters were collected from literature. Apparent permeabilities were translated to effective permeabilities with in vivo-in vitro correlation methods. Pulmonary drug input process relied on permeability and partition coefficients estimated in the PBPK model. Based on sensitivity analysis, key parameters were estimated with plasma and lung PK profiles of salbutamol and fluticasone propionate in rats. The PBPK model was translated by keeping the estimated parameters and switching physiological and anatomical parameters from rats to humans. The translational performance of the model was evaluated by comparing model predictions with observations of pulmonary and plasma PK as well as lung-to-plasma ratio in humans. All PBPK model development and simulations were performed using open-source software MoBi® and PKSIM® Version 11.2 (Open Systems Pharmacology, https://www.open-systems-pharmacology.org/). The current model adopts a similar lung spatial structure to the model by Boger et al,4 and the implementation was based on the inhalation model provided by Pellowe.6
Results:
Based on PK observations in rats, the estimated effective permeability and unbound tissue-plasma partition coefficient of the lung for salbutamol and fluticasone propionate were 1.08×10-5 (95% confidence interval (CI), 9.04 ×10-6 -1.26×10-5) cm/s and 7.29 (95% CI, 5.68 – 8.9), and 8.62×10-5 (95% CI, 5.7-11.5 ×10-5) cm/s and 715 (95% CI, 449 – 980), respectively. After inter-species translation, the model accurately captured the time concentration profiles of salbutamol and fluticasone propionate in both plasma and epithelial lining fluid of bronchoalveolar lavage (BAL) samples from human subjects after oral inhalation. Model-predicted lung-to-plasma ratios were within 2-fold errors of the reported ratios based on observations of BAL-obtained PK profiles. However, with parameters estimated on the entire lung, the translated models have consistently overestimated drug concentrations in the bronchial epithelial lining fluid compared to the actual concentrations observed through bronchosorption in human subjects.
Conclusions:
A general pulmonary PBPK framework was established to facilitate interspecies translation to predict the pulmonary kinetics of oral inhalations. The general PBPK framework would help integrate and interpret preclinical studies and facilitate pulmonary drug delivery.
References:
[1]Patton, J. S. & Byron, P. R. Inhaling medicines: delivering drugs to the body through the lungs. Nat. Rev. Drug Discov. 6, 67–74 (2007).
[2] Newman, S. P. Chapter 9 – Therapeutic aerosols. In Aerosols Lung (Clarke, S. W. & Pavia, D.) 197–224 (Butterworth-Heinemann, 1984). doi:10.1016/B978-0-407-00265-4.50014-3
[3]Boger, E. et al. Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs. CPT Pharmacomet. Syst. Pharmacol. 5, 201–210 (2016).
[4]Boger, E. & Fridén, M. Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms. J. Aerosol Med. Pulm. Drug Deliv. 32, 1–12 (2019).
[5]Himstedt, A., Braun, C., Wicha, S. G. & Borghardt, J. M. Understanding the suitability of established antibiotics for oral inhalation from a pharmacokinetic perspective: an integrated model-based investigation based on rifampicin, ciprofloxacin and tigecycline in vivo data. J. Antimicrob. Chemother. 77, 2922–2932 (2022).
[6]Pellowe, M. Inhalation-model/configure_inhalation_parameters.R at main · Open-Systems-Pharmacology/Inhalation-model. at <https://github.com/Open-Systems-Pharmacology/Inhalation-model/blob/main/configure_inhalation_parameters.R>
Reference: PAGE 32 (2024) Abstr 11051 [www.page-meeting.org/?abstract=11051]
Poster: Drug/Disease Modelling - Absorption & PBPK