title: Exposure-response modeling of average daily pain score, and dizziness and somnolence, for mirogabalin (DS-5565) in patients with diabetic peripheral neuropathic pain.
abstract: Mirogabalin (DS-5565) is an α2δ-1 ligand being developed for pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. Nonlinear mixed-effects analyses were performed on average daily pain and on the incidence of the adverse events dizziness and somnolence. These models were used to predict the dose of mirogabalin equivalent to pregabalin and the probability of meaningful reduction in pain compared with placebo and pregabalin. In addition, regimen effects were evaluated for reductions of adverse events. Mirogabalin was estimated to be 17-fold more potent than pregabalin. The effectiveness of 150 mg pregabalin, dosed twice daily, attenuated by week 5. Therefore, the estimated mechanism-based equivalent dose (ED) of 17.7 mg mirogabalin was higher than that predicted to achieve comparable pain reduction. If attenuation of the pregabalin effect is real, mirogabalin doses lower than the ED could yield comparable pain reduction, albeit with less differentiation in pain from placebo. The incidence rate of dizziness and somnolence decreased over time. Twice-daily dosing of mirogabalin was predicted to yield a lower incidence rate of dizziness than once-daily dosing; thus, titration of dosages should reduce adverse event rates. These model results were used to influence phase 3 dosing selection.
authors.affiliation: Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hutmacher
authors.affiliation: Wolverine Pharmacometrics Corporation, Ann Arbor, MI, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Frame
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo, Inc., Edison, NJ, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Miller
authors.affiliation: Translational Medicine & Clinical Pharmacology, Daiichi Sankyo, Inc., Edison, NJ, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Truitt
authors.affiliation: Daiichi Sankyo Development Ltd., Chiltern Place, Chalfont Park, Buckinghamshire, UK.
authors.forename: Domenico
authors.initials: D
authors.lastname: Merante
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use; D001643:Bridged Bicyclo Compounds / Q000009:adverse effects / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy*; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement
chemical_list: D000700:Analgesics; D001643:Bridged Bicyclo Compounds; C000598618:mirogabalin
keywords: bounded outcome scores; nonlinear mixed-effects modeling; pharmacodynamics; time-to-event analysis