Åsa M Kragh (1), Johanna Melin (1), Ulrika Wählby Hamrén (1), Michael Gillen (2)
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca: (1) Gothenburg, Sweden; (2) Gaithersburg, US
Introduction: PT010 is a triple fixed-dose combination, with budesonide (B/BD), glycopyrronium (G/GP) and formoterol (FF), formulated using co-suspension delivery technology in a pressurized metered dose inhaler (MDI) [1], developed for the inhaled treatment of chronic obstructive pulmonary disease (COPD).
Objectives: To evaluate the population pharmacokinetic (popPK) properties of PT010, and the impact of covariates on each of its components, in patients with COPD.
Methods: Pharmacokinetic (PK) data from 9 clinical studies, in subjects with mild to very severe COPD, were included in the analysis. Each study contained data on one or more of the following triple-, dual- and mono products (i) PT010, (ii) BFF MDI, (iii) GFF MDI (Bevespi Aerosphere® [2]), (iv) BD MDI, (v) GP MDI, and (vi) FF MDI. In total, 3930 samples from 220 subjects were included in the analysis of BD, 7612 samples from 481 subjects were included in the analysis of GP, and 10277 samples from 652 subjects were included in the analysis of FF.
Different structural base models were investigated, and the following covariates were considered: age, body weight, absolute estimated glomerular filtration rate (eGFR), sex, smoking status, COPD severity, and formulation effects of products (ii)-(vi) versus (i) on relative bioavailability (Frel).
Simulations were conducted to assess the impact of identified covariates on AUC, Cmax, and Cmin, during BID dosing of the planned market dosage form of PT010 (BD/GP/FF: 320[160]/18/9.6 μg) at steady state.
Results:
Budesonide
The final popPK model for BD was a 3-compartment model with first-order absorption, including body weight as covariate on the inter-compartmental clearance parameters (Qp1/F and Qp2/F), and age as covariate on clearance (CL/F).
All evaluated covariates had a minor impact on Cmax, Cmin, and/or AUC of BD. The “worst case” combination of covariates (selected to obtain the highest Cmax/AUC) are low body weight and high age. Considering the 10th percentiles of body weight and age in the BD data set (57.6 kg; 74 years), the change in median Cmax, Cmin, and AUC at steady state, relative to the typical individual, was predicted to be approximately 7%, -5%, and 7%, respectively. These differences were not considered clinically relevant.
Glycopyrronium
The final popPK model for GP was a 2-compartment model with first-order absorption. Covariates included in the final model were absolute eGFR on CL/F, body weight on the volumes of distribution (Vc/F and Vp/F) and Q/F, and smoking status on the absorption rate constant (ka) and Frel.
Absolute eGFR was the covariate that had the greatest impact on Cmax, Cmin, and AUC of GP. The “worst case” combination of covariates are low body weight, low absolute eGFR, and former smoker. Considering the 10th percentiles of body weight and absolute eGFR in the GP data set (57.6 kg; 63.7 mL/min), the increase in median Cmax, Cmin, and AUC at steady state, relative to the typical individual, was predicted to be approximately 21%, 30%, and 29%, respectively. These differences were expected since GP is renally cleared to a large extent, and they were not considered clinically relevant.
Formoterol
The final popPK model for FF was a 2-compartment model with first-order absorption. Important covariates included in the final model were body weight on CL/F and Vc/F, smoking status on ka and CL/F, and COPD severity on ka. Other covariates included in the final model were formulation effects for BFF MDI, GFF MDI, and FF MDI on Frel (higher relative to PT010). The formulation effects were relatively small (<16% increase) and not considered clinically relevant.
Body weight was the covariate that increased Cmax, Cmin, and AUC the most. The “worst case” combination of covariates are low body weight, mild or moderate COPD, and former smoker. Considering the 10th percentile of body weight in the FF data set (58.0 kg), the increase in median Cmax, Cmin, and AUC at steady state, relative the typical individual, was predicted to be approximately 24%, 26%, and 23%, respectively. These differences were not considered clinically relevant.
Conclusions: The popPK properties of PT010, in patients with COPD, were thoroughly evaluated and none of the identified covariate effects were deemed clinically relevant.
References:
[1] Ferguson GT, et al. Respiratory Medicine 134 (2018) 16-23
[2] Bevespi Aerosphere is a trademark of the AstraZeneca group of companies
Reference: PAGE 28 (2019) Abstr 8842 [www.page-meeting.org/?abstract=8842]
Poster: Drug/Disease Modelling - Other Topics