title: Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib.
abstract: Extended-release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E-R analyses were conducted using validated clinical endpoints from phase II dose-response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lamba
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hutmacher
authors.affiliation: University of California, Los Angeles, California, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Furst
authors.affiliation: San Diego Arthritis Medical Clinic, San Diego, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dikranian
authors.affiliation: Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Dowty
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: D
authors.initials: D
authors.lastname: Conrado
authors.affiliation: Pfizer Inc, Collegeville, Pennsylvania, USA.
authors.forename: T
authors.initials: T
authors.lastname: Stock
authors.affiliation: Pfizer Inc, Collegeville, Pennsylvania, USA.
authors.forename: C
authors.initials: C
authors.lastname: Nduaka
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cook
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: S
authors.initials: S
authors.lastname: Krishnaswami
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D017277:Drug Approval; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053612:Janus Kinases