title: Identification and characterisation of a salt form of Danirixin with reduced pharmacokinetic variability in patient populations.
abstract: The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD). The hydrobromide salt of DNX was identified as having superior biopharmaceutical properties compared to the free base (FB) form in clinical development and the impact of switching to the hydrobromide salt (HBr) was predicted by integrating the nonclinical data in a PBPK model (using GastroPlus™) to enable simulation of clinical drug exposure with FB and HBr salts in the absence and presence of a gastric acid reducing comedication (omeprazole, a proton pump inhibitor (PPI)). Subsequent investigation of DNX pharmacokinetics in a Phase 1 clinical study comparing FB with HBr salt forms confirmed that DNX HBr had reduced the variability of drug exposure and that exposure was not affected by PPI co-administration with DNX HBr. This case study therefore adds to the surprisingly few examples of a more soluble salt of a weak base translating to an improvement in human pharmacokinetics and illustrates a clear clinical benefit of salt selection during drug development.
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK. Electronic address: Jackie.C.Bloomer@gsk.com.
authors.forename: Jackie C
authors.initials: JC
authors.lastname: Bloomer
authors.affiliation: Clinical Pharmacology Modelling and Simulation Department, GlaxoSmithKline R&D, Iron Bridge Road, Uxbridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Ambery
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Connolly
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Garden
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Henley
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Hodnett
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Keel
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kreindler
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lloyd
authors.affiliation: Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, UK.
authors.forename: Wayne
authors.initials: W
authors.lastname: Matthews
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Yonchuk
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018054:Hydrobromic Acid / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry*; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry*
chemical_list: D010880:Piperidines; D013450:Sulfones; D018054:Hydrobromic Acid; C581951:danirixin
keywords: Danirixin; GSK1325756; GastroPlus™; Hydrobromide salt; PK variability; Physiologically-based pharmacokinetic model (PBPK); Proton pump inhibitor; TNO TIM-1; Weak base