Spreadsheet-Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients.

Abstract

There is a growing interest in the use of physiologically based pharmacokinetic (PBPK) models as clinical pharmacology drug development tools. In PBPK modeling, not every organ or physiological parameter is required, leading to the development of a minimal PBPK (mPBPK) model, which is simple and efficient. The objective of this study was to streamline mPBPK modeling approaches and enable straightforward prediction of clearance of protein-based products in children. Four mPBPK models for scaling clearance from adult to children were developed and evaluated on Excel spreadsheets using (1) liver and kidneys; (2) liver, kidneys, and skin; (3) liver, kidneys, skin, and lymph; and (4) interstitial, lymph, and plasma volume. There were 35 therapeutic proteins with a total of 113 observations across different age groups (premature neonates to adolescents). For monoclonal and polyclonal antibodies, more than 90% of observations were within a 0.5- to 2-fold prediction error for all 4 methods. For nonantibodies, 79% to 100% of observations were within the 0.5- to 2-fold prediction error for the 4 different methods. Methods 1 and 4 provided the best results, >90% of the total observations were within the 0.5- to 2-fold prediction error for all 3 classes of protein-based products across a wide age range. The precision of clearance prediction was comparatively lower in children ≤2 years of age vs older children (>2 years of age) with methods 1 and 4 predicting 80% to 100% and 75% to 90% of observations within the 0.5- to 2-fold prediction error, respectively. The results of the study indicated that mPBPK models can be developed on spreadsheets, with acceptable performance for prediction of clearance.