title: Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.
abstract: BACKGROUND
  Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of μ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed μ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus.
  
  
  METHODS
  In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry.
  
  
  RESULTS
  In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg.
  
  
  CONCLUSIONS
  Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.
authors.affiliation: A Hawi Consulting, Ridgefield, CT, USA. Ahawi@ahawi.com.
authors.forename: Amale
authors.initials: A
authors.lastname: Hawi
authors.affiliation: DaVita Clinical Research, Minneapolis, MN, USA. Harry.alcorn@davita.com.
authors.forename: Harry
authors.initials: H
authors.lastname: Alcorn
authors.affiliation: DaVita Clinical Research, Minneapolis, MN, USA. Jolene.berg@davita.com.
authors.forename: Jolene
authors.initials: J
authors.lastname: Berg
authors.affiliation: PPD, Richmond, VA, USA. Carey.hines@ppdi.com.
authors.forename: Carey
authors.initials: C
authors.lastname: Hines
authors.affiliation: Edenridge Associates LLC, Wilmington, DE, USA. howardhait@edenridgeassociates.com.
authors.forename: Howard
authors.initials: H
authors.lastname: Hait
authors.affiliation: Trevi Therapeutics, 195 Church Street, 14th Floor, New Haven, CT, 06510, USA. Thomas.sciascia@trevitherapeutics.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sciascia
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D016022:Case-Control Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009266:Nalbuphine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061214:Patient Safety; D011537:Pruritus / Q000188:drug therapy* / Q000209:etiology; D012016:Reference Values; D006435:Renal Dialysis / Q000009:adverse effects* / Q000379:methods; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D064232:Visual Analog Scale
chemical_list: D003692:Delayed-Action Preparations; D009266:Nalbuphine