title: Effects of advanced age and renal dysfunction on the single- and repeated-dose pharmacokinetics of modified-release flupirtine.
abstract: BACKGROUND
  Flupirtine is a nonopioid, central analgesic without antipyretic or antiphlogistic properties. Flupirtine-MR is an oral modified-release formulation with a 100 mg fast-input and a 300 mg portion with slow protracted release.
  
  
  METHODS
  Single- (D01) and repeated-dose (D03-D09) pharmacokinetics of 400 mg flupirtine-MR were investigated in patients with severe renal dysfunction (REN: N: 12; 21 50 years of age; creatinine clearance (CLCr)≤30 mL/min per 1.73 m2 body surface area (BSA)) and healthy older subjects (EN1: N: 8; 60-69 years; CLCr≥80 mL/min and EN2: N: 8; ≥70 years, CLCr≥60 mL/min) vs. young healthy control subjects (YN: N: 12; 21-40 years; CLCr≥90 mL/min).
  
  
  RESULTS
  Renal dysfunction led to a relatively small average increase in systemic exposure to flupirtine: on D09, the REN : YN-ratios were 1.37 (95% confidence interval (CI): 1.03-1.82), 1.21 (CI: 1.01-1.45), and 1.34 (CI: 1.09-1.64) for Css,0, Css,max, and Css,av, respectively. A similar increase in exposure was observed in older subjects: the respective EN1:YN-ratios were 1.30 (CI: 0.95-1.79), 1.23 (CI: 1.01-1.49), and 1.23 (CI: 0.98-1.54); the EN2:YN-ratios were 1.50 (CI: 1.10-2.04), 1.16 (CI: 0.85-1.41), and 1.41 (CI: 1.12-1.79), respectively. Neither age nor renal function was a predominant factor of pharmacokinetic variability. Single and repeated doses of flupirtine-MR were very well tolerated.
  
  
  CONCLUSIONS
  The average renal and age effects were small, but the use of a lower starting dose (1/2 tablet) is recommended since some of these subjects might have relatively high exposure levels.
authors.forename: Christian
authors.initials: C
authors.lastname: de Mey
authors.forename: Emil
authors.initials: E
authors.lastname: Gatchev
authors.forename: Boriana
authors.initials: B
authors.lastname: Deliyska
authors.forename: Bernd
authors.initials: B
authors.lastname: Terhaag
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000097:blood / Q000652:urine; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D000700:Analgesics; D015415:Biomarkers; D003692:Delayed-Action Preparations; D003404:Creatinine; C034161:flupirtine