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Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease.

Authors
  • Bhattacharya, Indranil1
  • Manukyan, Zorayr2
  • Chan, Phylinda3
  • Heatherington, Anne1
  • Harnisch, Lutz3
  • 1 Prior employees of Pfizer Inc; Currently at Summit Therapeutics PLC, Cambridge, MA, USA.
  • 2 Pfizer Inc, Cambridge, MA, USA.
  • 3 Pfizer Inc, Sandwich, UK.
Type
Published Article
Journal
Journal of clinical pharmacology
Publication Date
Oct 12, 2017
Identifiers
DOI: 10.1002/jcph.1015
PMID: 29023829
Source
Medline
License
Unknown

Abstract

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10-4 L/[h·kg]; central volume of distribution 457 × 10-4 L/kg; maximum elimination rate 17.5 × 10-4 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10-4 h-1 ; complex removal rate 90 × 10-4 h-1 ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD.

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