Population pharmacokinetic modelling of CHF6001 following dry powder inhalation in healthy volunteers.
Koen Jolling (1), Massimo Cella (2), Mirco Govoni (2), Anna Nandeuil (3), Andreas Lindauer (1)
(1) SGS Exprimo, Mechelen, Belgium, (2) Chiesi Farmaceutici, Parma, Italy, (3) Chiesi Farmaceutici, Paris, France.
Objectives: CHF6001 is a potent and selective phosphodiesterase-4 (PDE-4) inhibitor to treat chronic obstructive pulmonary disease (COPD) and asthma. CHF6001 is being developed for inhalation to help overcome the well-known gastrointestinal side effects associated with this therapeutic class when given orally [1]. Data from 2 phase I studies were used to evaluate the population pharmacokinetics of CHF6001 and to investigate the influence of selected covariates on CHF6001 PK parameters. While initially available in Hard Gelatine Capsules delivered by the Aerolizer® device, CHF6001 is now developed via the novel multi-dose NEXThaler inhaler®. The goal of the analysis was to simulate CHF6001 plasma profiles of relevant clinical doses to be administered via the NEXThaler® inhaler.
Methods: CHF6001 plasma concentrations (2931 samples from 100 subjects) after inhalation in healthy volunteers were obtained from 2 phase I dose escalation (SAD & MAD) studies: study FIH and study Extension. Both studies were double-blind, randomized, placebo-controlled. In the MAD part of FIH study, doses were administered once daily via the Aerolizer® inhaler, while in the Extension study administration was twice daily via the NEXThaler® inhaler. CHF6001 concentrations were modelled with non-linear mixed-effect approaches using NONMEM V7.3.0. The explored covariates were inhaler device (FORM), body weight (WT), body mass index (BMI), age and sex. Simulations were done for a total daily dose of 2400µg to compare once and twice daily dose regimens with the NEXThaler device.
Results: The final model describing CHF6001 PK was a two-compartment disposition model with 3 parallel absorption pathways (slow, intermediate and fast) and first-order elimination, similarly as the one developed by Borghardt et al. [2]. The residual error model was a combination of a proportional and an additive component for the non-transformed data. For both devices the majority of the available dose was absorbed via the slow pathway (D2, KA2). This fraction was estimated to be 62.8% and 41.3% of the bioavailable dose for NEXThaler® and Aerolizer®, respectively. The smallest available fraction, 10% for NEXThaler® and 12% for Aerolizer®, was absorbed via an early very fast pathway (D3). The remaining fraction, 27.2% for NEXThaler® and 26% for Aerolizer®, was absorbed via the early intermediate pathway (KA1). The absorption rate constant for the latter pathway (KA1) was estimated to be 39.9% higher for Aerolizer® as compared to NEXThaler®. When using the Aerolizer® device, the median Cmax was found to be 8% higher, for a dose of 2.4 mg, as compared to the NEXThaler® device, while the AUC was found to be 20.7% lower. Tmax with the Aerolizer® device was found to be 1 hour faster as compared to the NEXThaler® device (2 hours versus 3 hours after dose). Simulating the same total daily dose but with different regimens (i.e. QD vs. BID) via the Nexthaler® device, a similar 24h exposure was obtained, but with BID dosing resulting in 35% lower fluctuation (calculated as Cmax-Cmin/Cav) and 11% lower Cmax.
Conclusions:
The PK of CHF6001 could be described by a two-compartment disposition model with 3 parallel absorption pathways and first-order elimination. Physiologically, being the gastrointestinal drug availability of CHF6001 very low, the 3 absorption pathways may represent 3 different compartments of the lung; a fast absorption pathway (D3) associated to the distal small airways and an intermediate (KA1) and slow pathway (D2) associated to upper airway regions. The slow absorption (D2) could account for a long drug retention into the lung, potentially leading to tight engagement at the target receptors.
The Nexthaler® device was characterised by a higher drug availability in comparison to the Aerolizer®. In addition, simulations with the Nexthaler® device supported twice-daily administration, with lower Cmax and lower fluctuation than once daily dosing. This could be associated to reduced risk of systemic adverse effects and better engagement at the target receptors.
References:
[1] Pinner, NA et al. Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Clin Ther. 2012 Jan;34(1):56-66.
[2] Borghardt et al. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Br J Clin Pharmacol. 2016 Mar; 81(3): 538–552
