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Model-Based Interspecies Scaling for Predicting Human Pharmacokinetics of CB 4332, a Complement Factor I Protein.

Rami Ayoun Alsoud1, Natacha Le Moan2, Lars Holten-Andersen2

  • 1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Journal of Pharmaceutical Sciences
|June 30, 2024
PubMed
Summary

Pharmacokinetic modeling of CB 4332 informed human dose selection. Model simulations suggest a 5 mg/kg weekly subcutaneous dose to reach efficacy targets, accounting for species-specific clearance and anti-drug antibodies.

Keywords:
ImmunogenicityInterspecies (dose) scalingPharmacometricsProteinsTranslational pharmacokinetics

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Area of Science:

  • Pharmacology
  • Biotechnology
  • Drug Development

Background:

  • CB 4332 is a 150 kDa recombinant complement factor I protein.
  • Preclinical pharmacokinetic (PK) studies were conducted in mice, rats, and nonhuman primates (NHPs).
  • Understanding interspecies PK is crucial for selecting the first-in-human dose.

Purpose of the Study:

  • To perform interspecies scaling of CB 4332 pharmacokinetics.
  • To inform the selection of an appropriate first-in-human dose for CB 4332.
  • To compare traditional and model-based PK approaches.

Main Methods:

  • Simultaneous modeling of PK data from preclinical studies using allometric scaling.
  • Incorporation of species-specific clearance parameters, including rat-specific clearance.
  • Estimation of anti-drug antibody (ADA)-induced clearance, considering the time of onset.
  • Calculation of human-equivalent dose using the no observed adverse effect level (NOAEL) and dose-by-factor approach.

Main Results:

  • Species-specific differences in CB 4332 elimination were identified and modeled.
  • Anti-drug antibody (ADA) formation was observed in rats and some NHPs, impacting clearance.
  • Traditional dose-by-factor approach suggested a starting subcutaneous (SC) dose of 0.9 mg/kg weekly.
  • Model simulations indicated that a 5 mg/kg weekly SC dose is predicted to achieve the target human efficacy concentration.

Conclusions:

  • Model-based PK analysis provides a more refined approach for dose selection compared to traditional methods.
  • Accounting for ADA formation is critical for accurate PK modeling and dose prediction.
  • A 5 mg/kg weekly SC dose of CB 4332 is predicted to be effective in humans based on PK modeling.