2. Academic Validation
  3. Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab

Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab

  • J Pharm Sci. 2022 Apr;111(4):1208-1218. doi: 10.1016/j.xphs.2021.12.019.
Nicolas Frances 1,  Marina Bacac 2,  Katharine Bray-French 1,  François Christen 1,  Heather Hinton 2,  Elisabeth Husar 1,  Elizabeth Quackenbush 3,  Martin Schäfer 4,  Eginhard Schick 1,  Arthur Van De Vyver 1,  Wolfgang F Richter 5
Affiliations

Affiliations

  • 1 Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • 2 Roche Innovation Center Zürich, Roche Pharmaceutical Research and Early Development, Zürich, Switzerland.
  • 3 Roche Innovation Center New York, Roche Pharmaceutical Research and Early Development, New York City, NY.
  • 4 Roche Innovation Center Munich, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
  • 5 Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland. Electronic address: wolfgang.richter@roche.com.
PMID: 34953862 DOI: 10.1016/j.xphs.2021.12.019
Abstract

We present a novel approach for first-in-human (FIH) dose selection of the CD20xCD3 bispecific antibody, glofitamab, based on pharmacokinetic/pharmacodynamic (PKPD) assessment in cynomolgus monkeys to select a high, safe starting dose, with cytokine release (CR) as the PD endpoint. Glofitamab pharmacokinetics were studied in mice and cynomolgus monkeys; PKPD of IL-6, TNF-α and interferon-γ release following glofitamab, with/without obinutuzumab pretreatment (Gpt) was studied in cynomolgus monkeys. Potency differences for CR between cynomolgus monkeys and humans were determined by glofitamab incubation in whole blood of both species. The PKPD model for CR was translated to humans to project a starting dose that did not induce CR exceeding a clinically-predefined threshold. In cynomolgus monkeys, glofitamab showed a species-specific atypical high clearance, with and without B-cell debulking by Gpt. CR was related to glofitamab serum levels and B-cell counts. B-cell reduction by Gpt led to a marked decrease in CR. FIH starting dose (5 µg) was selected based on IL-6 release considering the markedly higher glofitamab in vitro potency in human vs monkey blood. This is a novel PKPD-based approach for selection of FIH starting dose for a CD20xCD3 bispecific antibody in B-cell lymphoma, evidenced in the glofitamab study, NP30179 (NCT03075696).

Keywords

Antibody drug(s); Antibody(s); IgG antibody(s); Interspecies (dose) scaling; Monoclonal antibody(s); Pharmacodynamics; Pharmacokinetics.

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