A model-based comparison of absorption pharmacokinetics for a selective glucocorticoid receptor modulator administered with different inhalation devices
Muhammad Waqas Sadiq(1), Yingxue Chen(2), Åsa Kragh(1), Susanne Prothon(1), Ajay Aggarwal(3), Ulf G Eriksson(1), Ulrika Wählby Hamrén(1)
(1)Quantitative Clinical Pharmacology RIA, Early Clinical Development, AstraZeneca R&D, Gothenburg, Sweden. (2)Quantitative Clinical Pharmacology RIA, Early Clinical Development, AstraZeneca R&D, Waltham, United States. (3)RIA TMU, Early Clinical Development, AstraZeneca R&D, Waltham, United States.
Objectives: AZD7594 is non-steroidal selective inhaled glucocorticoid receptor modulator (iSGRM) currently in development for the treatment of asthma. This work presents population pharmacokinetic (PK) modelling performed to quantify the absorption PK after inhaled administration of AZD7594 with different devices.
Methods: PK data from a phase 1 clinical study, in healthy subjects, evaluating inhalation of single doses of AZD7594 via two dry powder inhaler devices (DPI), called the Monodose and SD2FL device, and an intravenous (IV) reference dose was used for model development. A second study in Japanese healthy subjects evaluating single and multiple doses administered via the SD2FL device was used for model validation.
A population modelling approach was used to build a PK model, using NONMEM version 7.3 with first order conditional estimation. The IV model was evaluated first. The IV parameters were subsequently fixed, and the pulmonary absorption model of AZD7594 was developed to compare the absorption pharmacokinetics with different devices.
Results: The IV model was determined to be a three-compartment distribution model with systemic clearance estimate of 72.4 L/h. The absorption of AZD7594 after oral inhalation was best described with three first order (slow, medium, fast) and one zero order rate of absorption. The parameter estimates for the two DPIs were similar, except that the fast absorption rate was unidentifiable for the SD2FL device. For the Monodose device estimates of the fast, medium and slow absorption half-life were 0.1, 1.1 and 71 (h). For the SD2FL, the medium and slow absorption half-lives were 1.4 and 80 (h). The duration of the zero order absorption was estimated to 32 and 24 (h) for the Monodose and SD2FL devices, respectively. The absolute bioavailability after inhalation was estimated to 46% relative to the IV reference dose. The model for the SD2FL device (based on data from healthy non-Asian subjects) successfully describes the trends, but is slightly over-predicting, the concentrations after repeated dosing in healthy Japanese subjects suggesting a lower bioavailability, after inhalation in the Japanese study population.
Conclusions: The developed population PK model successfully describes the trends and variability in the observed data from different inhalation devices. The absorption kinetics of AZD7594 were very similar for the two DPI devices.