title: Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors.
abstract: OBJECTIVE
  Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects.
  
  
  METHODS
  PK data from five phase 1 or 2 studies (N = 436) in the dose range from 100 to 3000 mg were analyzed using NONMEM. A two-compartment base model with first-order absorption, lag time, linear elimination, and bioavailability that decreased with dose was updated to describe the PK of sonidegib. Covariate analyses were performed and were incorporated into the population PK full model.
  
  
  RESULTS
  The base and full models were robust with a good fit to the study data. Population-predicted geometric means (inter-individual variability, CV%) of apparent oral clearance, apparent volume of distribution at steady state, accumulation ratio, and elimination half-life were 9.5 L/h (71.4 %), 9163 L (74.9 %), 21 (131 %) and 29.6 days (109 %). Clinically relevant covariate effects were: A high-fat meal increased sonidegib bioavailability fivefold, healthy volunteers had threefold higher clearance, sonidegib bioavailability decreased with increasing dose levels, and PPI coadministration reduced sonidegib bioavailability by 30 %. Sonidegib PK was not significantly impacted by baseline age, weight, total bilirubin, alanine aminotransferase, albumin, creatinine clearance, gender, and ethnicity (Western countries versus Japanese).
  
  
  CONCLUSIONS
  No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Goel
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.|Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stein
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Nedelman
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Chiparus
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Pai-Hsi
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Gogov
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA. dalila.sellami@novartis.com.
authors.forename: Dalila
authors.initials: D
authors.lastname: Sellami
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011725:Pyridines / Q000493:pharmacokinetics*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib
keywords: Basal cell carcinoma; Bioavailability; Food effect; Modeling; Pharmacokinetics; Solid tumors; Sonidegib