Open AccessPharmacometric Analyses to Support Early Development Decisions for LY2878735: A Novel Serotonin Norepinephrine Reuptake Inhibitor
Author(s) -
Raddad E,
Melhem MR,
SloanLancaster JS,
Miller JW,
Van Wart SA,
Rubino CM
Publication year - 2013
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1038/psp.2013.43
Subject(s) - cyp2d6 , pharmacology , serotonin reuptake inhibitor , reuptake inhibitor , duloxetine , medicine , norepinephrine , pharmacokinetics , volume of distribution , pharmacodynamics , dosing , serotonin , cytochrome p450 , dopamine , receptor , metabolism , alternative medicine , pathology
LY2878735 is a novel dual serotonin (5‐hydroxytryptamine (5‐HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual‐target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21‐ and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6‐based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model‐based approach effectively synthesizes PK‐pharmacodynamic (PD) relationships, enabling efficient early development decisions. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi: 10.1038/psp.2013.43 ; published online 21 August 2013