title: Pharmacokinetics of dalfampridine extended release 7.5-mg tablets in healthy subjects and individuals with mild and moderate renal impairment: an open-label study.
abstract: Dalfampridine extended release tablets (D-ER; prolonged-release fampridine in Europe) are available to improve walking in patients with multiple sclerosis (MS). D-ER is mainly renally eliminated; the approved 10-mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. This study evaluated single-dose and steady-state pharmacokinetics of a 7.5-mg dose of D-ER in healthy subjects (n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. D-ER plasma concentrations were consistently higher in subjects with renal impairment relative to healthy individuals with a significant (P < .0001) inverse linear relationship between creatinine clearance and drug exposure. Steady-state AUC0-12 among healthy subjects, 167.0 ± 55.3 ng h/mL, increased 74% and 151% with mild and moderate renal impairment, respectively. The overall incidence of adverse events was 61.5%, 47.1%, and 33.3% in healthy subjects, and subjects with mild and moderate renal impairment, respectively, and for treatment-related adverse events the rates were 0%, 17.6%, and 8.3%, respectively. The most common adverse events were headache, dizziness, and arthralgia. The pharmacokinetics of D-ER 7.5-mg twice daily in subjects with mild renal impairment was comparable to 10-mg twice daily in patients with MS who had normal renal function. Exposure was significantly higher in moderate renal impairment.
authors.affiliation: PharmaPolaris International, Davis, CA, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Samara
authors.forename: Peter
authors.initials: P
authors.lastname: Winkle
authors.forename: Patricia
authors.initials: P
authors.lastname: Pardo
authors.forename: Herbert R
authors.initials: HR
authors.lastname: Henney
authors.forename: Susan L
authors.initials: SL
authors.lastname: Way
authors.forename: Eppie
authors.initials: E
authors.lastname: Brown
authors.forename: Angela
authors.initials: A
authors.lastname: Lee
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Blight
mesh_terms: D015761:4-Aminopyridine / Q000009:adverse effects / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D005006:Ethnicity; D005260:Female; D006207:Half-Life; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics*; D021241:Spectrometry, Mass, Electrospray Ionization; D013607:Tablets; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D026902:Potassium Channel Blockers; D013607:Tablets; D015761:4-Aminopyridine
keywords: dalfampridine; moderate renal impairment; multiple sclerosis; pharmacokinetics; severe renal impairment