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Toxicology & Clinical Pharmacology

Toxicology & Clinical Pharmacology. James Keirns, Ph.D. Senior Director, Biopharmaceutical Sciences Astellas Pharma US, Inc. Non-Clinical Safety Assessment. Dose limiting toxicities Transient, spontaneously reversible No histopathologic findings Consistent with ion channel blockade

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Toxicology & Clinical Pharmacology

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  1. Toxicology & Clinical Pharmacology James Keirns, Ph.D. Senior Director, Biopharmaceutical SciencesAstellas Pharma US, Inc.

  2. Non-Clinical Safety Assessment Dose limiting toxicities Transient, spontaneously reversible No histopathologic findings Consistent with ion channel blockade Salivation, tremor, ataxia, convulsions Therapeutic Index in dogs 10-fold Source: Pages 21-23

  3. PK & Metabolismin Dogs and Humans Rapid distribution, short elimination t½ Primarily metabolized by CYP2D6 Systemic exposure of parent compound and metabolites up to 3-fold higher in dogs vs. humans Source: Table 2, page 22

  4. Key Clinical PK Features Dose proportional and linear PK Rapid distribution high Vd (2 L/kg) Short t1/2 (3h); 5.5h in PM Not highly protein bound (37-47%)　 Metabolic pathways well characterized Source: Pages 30-32

  5. Cmax and AUC90 Similar in CYP2D6 Poor and Normal (Extensive) Metabolizers , N=290 , N=16

  6. Clinical Pharmacokinetics/Special Population • Cmax and systemic exposure in the first 90 minutes were not significantly influenced by: • Age – CYP2D6 expression • Sex –CYP2D6 Inhibitors • Renal function –Beta Blockers • Phase 3 studies indicated that there were no safety implications with co-administration of CYP2D6 inhibitors or substrates Source: Pages 33-38

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