title: Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.
abstract: IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2'-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA. xinru.panzhou@gmail.com.
authors.forename: Xin-Ru
authors.initials: XR
authors.lastname: Pan-Zhou
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Mayes
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Rashidzadeh
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Rahela
authors.initials: R
authors.lastname: Gasparac
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhadresa
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Kusum
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Marita Larsson
authors.initials: ML
authors.lastname: Cohen
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Bu
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Good
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Adel
authors.initials: A
authors.lastname: Moussa
authors.affiliation: Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Rush
mesh_terms: D000818:Animals; D002214:Capsules / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006151:Guanosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006157:Guanosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013607:Tablets / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D002214:Capsules; C557801:IDX184; D011355:Prodrugs; D013607:Tablets; D006151:Guanosine; C016578:7-methylguanosine; D006157:Guanosine Monophosphate
keywords: 2′-MeG; Ethylene sulfide; IDX184; Nucleotide prodrug; Portal and systemic pharmacokinetics