Allometric Scaling for Efficacious First-in-Human Dose Prediction of Pharmacologically-Active Parent and Metabolite Based on Rat, Dog and Monkey PK data
K. Lindauer(1), K Pasikanti(2) , F Khalil(1), M Gautrois(1), S Engelen(1), B Manning(2)
(1)Grünenthal GmbH, Aachen, Germany, (2)GRT Therapeutics Inc, USA
Introduction:
The initiation and conduct of a First-in-Human (FIH) clinical trial requires a deep understanding of a efficacious dose range[1]. Information about the pharmacokinetic (PK) and pharmacodynamic (PD) behavior from multiple animal species forms the basis of the FIH dose estimates. In applying allometric scaling, population PK/PD modeling is a valuable translational approach for FIH dose estimate, if a program will have a validated disease biomarker, which allows monitoring the disease stage and progression both in animal species and humans. In the absence of a disease biomarker, the estimated target receptor engagement (TE) of the free and total drug in plasma could be an important alternative for the evaluation of the PD effect. Our Nociceptin/Orphanin peptide receptor (NOP) agonist, the parent compound, showed high binding affinity to the human NOP receptor as well as to preclinical species orthologs. In addition, one main metabolite showed high binding affinity to the NOP receptor (Ki similar to parent). Therefore, both the parent compound and metabolite were characterized and analyzed in various in-vitro and in-vivo studies.
Objectives:
- Pharmacologically efficacious (80% NOP TE in plasma for 24h at steady state) FIH dose prediction based on pharmacologically active parent and metabolite animal PK data
Methods:
Non-linear mixed effect modelling using NONMEM® was applied to establish population PK models to describe the PK profile of rats, dogs and monkeys treated with different doses (1, 5, 10, 30, 100, 300 & 600 mg/kg) of the parent compound after oral and IV administration. The PK profile consisted of both the parent compound and metabolite time-dependent plasma concentrations. The animal species differences were considered within the model by applying allometric scaling to the relevant PK model parameter such as clearance (CL) and volume of distribution (V) (reference body weight was set to 3.5kg). The quality of the model was evaluated by standard methods such as goodness of fit plots.
To estimate the human dose of the parent compound, the expected total TE was evaluated by taking into account the predicted human concentration-time profiles of both the parent compound and metabolite. The efficacious dose for humans with an average body weight of 70kg, was calculated on the basis of the dose of parent compound required to achieve total NOP TE of 80% in plasma for 24h (considering contribution of both parent and metabolite). Given that the binding constants of the parent compound and metabolite were similar, the total TE of the receptor was estimated as a cooperative effect of the parent and metabolite within an overall sigmoidal concentration-response relationship.
Results:
Our FIH dose prediction was based on an integrated population PK model for the parent compound and pharmacologically-active metabolite. The resulting structural model was a two compartment model describing the parent compound and a one compartment model for the metabolite. The absorption of the parent compound, after oral administration, was described as a first order process (Kaparent=0.2h-1) to the central compartment. The parent compound is metabolized in the gut and the central compartment. Therefore, the metabolite formation was mapped by a first order process from the absorption compartment (Kametabolite=0.29/h) and the central compartment (CLparent->metabolite=2.3 l/h). The elimination of metabolite was modelled by a first order process (CLmetabolite=11.1 l/h). The volume of distribution values were Vcentral=9.4l, Vdepot=2.8l & Vmetabolite=67.9l and the allometric scaling exponent γ were between 0.8 and 1.1. The diagnostic plots[2] did not indicate a structural misspecification. The resulting model was applied for estimating the pharmacologically efficacious dose of the parent compound. For the clinical trial simulation 1000 virtual patient were drawn randomly and orally dosed 8 times once daily with 5, 10, 12.5 & 15mg. The 10mg dose was estimated to achieve a total NOP TE of 80% in plasma for 24h at steady state.
Conclusions:
Our FIH dose prediction was based on an integrated population PK model for the parent compound and pharmacologically-active metabolite. In the absence of a disease modifying biomarker, the estimated TE of the parent compound and metabolite was used to evaluate the expected efficacy of the orally administered parent compound. The upcoming FIH clinical trial will provide evidence of the respective dose prediction
References:
[1] Mishra A et .al.. First-in-human dose: current status review for better future perspectives. Eur J Clin Pharmacol. (2020) 76(9):1237-1243.
[2] Nguyen TH et. al.; Model Evaluation Group of the International Society of Pharmacometrics (ISoP) Best Practice Committee. Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics. CPT Pharmacometrics Syst Pharmacol. 2017 Feb;6(2):87-109