Silvia Grandoni 1, Nicola Cesari 1, Annalisa Piccinno 1, Johan W Smit 2, Massimiliano Germani 1
1 Chiesi Farmaceutici S.p.A. (Parma, Italy), 2 Curare Consulting (Liempde, Netherlands)
Objectives: CHF6001 is a PDE4 inhibitor that was specifically designed to be delivered via inhalation [1]. In vitro data showed that the compound is primarily metabolized by CYP3A4, therefore, clinical studies with strong and moderate CYP3A4 inhibitors were conducted to assess its drug-drug interaction (DDI) potential. The objective of this work was to develop a physiologically-based pharmacokinetic (PBPK) model describing the pharmacokinetics (PK) of the orally inhaled compound CHF6001 including the DDI with strong and moderate CYP3A4 inhibitors and prospectively generate hypothesis on the DDI in case of co-administration of weak CYP3A4 inhibitors.
Methods: CHF6001 PBPK model building and DDI simulations were performed in PK-Sim® v.12.0 [2]. Model development was conducted in sequential steps. Initially, a PBPK model was built to describe the PK of CHF6001 after intravenous administration. CYP3A4-mediated clearance was set in the model, starting from the fraction of the drug metabolized by CYP3A4, that was estimated from in vitro data, and in vivo mass-balance clinical data [3]. Subsequently the PBPK model was characterised to describe the PK of CHF6001 after inhalation, leveraging mass-balance clinical data and information related to the formulation such as the fine particle mass, particle size distribution and solubility. In this model, a fraction of the emitted dose is inhaled and reaches the lungs before entering in the systemic circulation, while the remaining fraction is swallowed and absorbed through the gastrointestinal system. The ability of the model to correctly describe CHF6001 PK after inhalation was assessed versus the clinical data including single dose (SD) and multiple ascending dose (MAD) concentration data [4]. The final PBPK model was deemed successful when the predicted-to-observed ratios of mean AUC and Cmax was less than 2-fold. The model was further successfully validated using data from two DDI studies in which CHF6001 was co-administered with the strong inhibitor itraconazole and the moderate inhibitor erythromycin. This step was performed leveraging the developed PBPK model for CHF6001 and the publicly available PK-Sim® PBPK models of itraconazole and erythromycin [5] with their inhibition parameters for CYP3A4. The ability of the model to correctly describe the observed plasma concentration-time course was tested comparing simulated AUC, Cmax and the corresponding geometric mean ratios (exposure in presence/absence of the perpetrator) with that observed from the clinical data. Different potential clinical scenarios were simulated to test the interaction between CHF6001 and weak CYP3A4 inhibitors.
Results: the developed PBPK model was able to describe the PK of CHF6001 after intravenous administration and after inhalation with predicted-to-observed AUC and Cmax ratios within the 2-fold range. The DDI due to the co-administration of CHF6001 with itraconazole and erythromycin was correctly described with AUC, Cmax and their corresponding geometric mean ratios within 2-fold error of the observed values [6].
Conclusions: the developed PBPK model, leveraging formulation data, non-clinical data and clinical mass-balance data, allowed to correctly describe the extent of CYP3A4 based DDI (using strong and moderate inhibitors) of this inhaled compound. This example supports the use of PBPK modelling to inform decision making on DDI and represents a Model Informed Drug Discovery and Development (MI3D) approach useful for optimizing the clinical development plan and the regulatory interactions.
References:
[1] Facchinetti F, Civelli M, Singh D, Papi A, Emirova A, Govoni M. Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease. Front Pharmacol. 2021;12:740803. doi:10.3389/fphar.2021.740803
[2] https://www.open-systems-pharmacology.org/
[3] Bassi M, Puviani V, Santoro D, Biondaro S, Emirova A, Govoni M. Pharmacokinetics and absorption, distribution, metabolism and excretion profiling of tanimilast following an intravenous 14C-microtracer coadministered with an inhaled dose in healthy male individuals. Drug Metab Dispos. 2025;53(1):100009. doi:10.1124/dmd.124.001895
[4] Mariotti F, Govoni M, Lucci G, Santoro D, Nandeuil MA. Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers. Int J Chron Obstruct Pulmon Dis. 2018;13:3399-3410. doi:10.2147/COPD.S174156
[5] https://github.com/Open-Systems-Pharmacology/OSP-PBPK-Model-Library
[6] Wagner C, Pan Y, Hsu V, et al. Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration. Clin Pharmacokinet. 2015;54(1):117-127. doi:10.1007/s40262-014-0188-4
Reference: PAGE 34 (2026) Abstr 12261 [www.page-meeting.org/?abstract=12261]
Poster: Drug/Disease Modelling - Absorption & PBPK