Advantages of Allometric Scaling Methods for Predicting Human Pharmacokinetics of Novel JAK Inhibitor -Baricitinib and Dose Extrapolation

Sadanand Mallurwar^1*, Kratika Daniel² and Mahesh Bhat³

¹faculty of pharmacy, Mandsaur University, Mandsaur, Madhya Pradesh, India 458001

²Faculty of pharmacy,(B. R. Nahata College of Pharmacy),Mandsaur University, Mandsaur, Madhya Pradesh, India 458001

³Nuper Therapeutics, A division of Jain Pharmaceuticals, Off. No. 106, Nyati Emporious, Near Balewadi Stadium, Baner, Pune-411045

Corresponding Author E-mail: mallurwarsd@rediffmail.com

Abstract: Purpose: The primary motive of this study was to examine advantages of allometry scaling strategies for correct prediction of pharmacokinetics of Baricitinib in human from preclinical species. Baricitinib is basically Janus kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis. Currently approved by FDA in combination with remdesivir for treatment of COVID-19 hospitalized patient. Methods: The literature published pharmacokinetic parameters (Cl and V_d) of preclinical species (Rat, Dog and monkey) were utilized for the allometry scaling of Baricitinib. The connection among the primary pharmacokinetic parameters [Volume of distribution (V_d) and clearance (Cl)] and body weight (BW) were studied across three preclinical species, we used the double logarithmic plots for prediction of the human pharmacokinetic parameters i.e. Cl and V_d with use of simple allometry and with additional correction factors for better prediction. The dose extrapolation of baricitinib was carried out by FDA guidelines. Results: By application of the allometric scaling methods and principles correlation was found to be satisfactory for the prediction of intravenous human Cl and V_d for baricitinib. The volume of distribution (V_d) predicted by simple allometry (65.3 L) was found to be in agreement with the reported value (75.5 L); clearance (Cl) prediction by simple allometry was found to be at least 1.06 -closer to the reported value (245 mL/min); CF were used to predict the clearance.  Both brain weight (B.W) and maximum life span potential (MLP) predicted the Cl with 0.52- and 0.61 -fold difference. The application of monkey liver blood flow predicted Cl with 0.81 fold which was also in close agreement with reported value. The Cl prediction was also extrapolated using LBF (Liver blood flow) method and observed that the higher species (Dog and Monkey) have predicted Cl with better accuracy than rat. Conclusions: Overall, the simple allometry (SA), monkey liver blood flow (MLBF) and application of liver blood flow (LBF) methods showed excellent correlation with human. The time vs. plasma concentration simulated graph also showed the similar closeness with human profile. The inclusion of plasma protein binding factor didn’t improve the prediction accuracy. The FIH dose extrapolation were showed that PK guided approach and exponent for BSA based approach was found closer to actual human dose of 4.0 mg/Kg.

Keywords: Clinical Pharmacokinetics; FIH; Interspecies Scaling; Preclinical Pharmacokinetics; Simulations

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