title: Pharmacokinetic profile of defibrotide in patients with renal impairment.
abstract: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (Cmax); 108.39 (CI: 97.85, 120.07) for area under the concentration-time curve to the time of the last quantifiable plasma concentration (AUC0-t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0-∞). These ranges were within 80%-125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC0-t, 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; Cmax, 53.8 µg/mL) were within 5%-8% of parameters after the first dose (AUC0-t, 117 µg·h/mL; AUC0-∞, 118 µg·h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%-37% and 50%-60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD.
authors: Gentium.
authors: Paola
authors: P
authors: Tocchetti
authors: Clinical Operations, Gentium, Villa Guardia, Como, Italy.
authors: Elena
authors: E
authors: Tudone
authors: Reporting and Analysis Services, Pharsight, a Certara Company, Montreal, Quebec, Canada.
authors: Jean-Francois
authors: JF
authors: Marier
authors: Orlando Clinical Research Center, Orlando, FL.
authors: Thomas C
authors: TC
authors: Marbury
authors: Early Development and Clinical Pharmacology, Jazz Pharmaceuticals.
authors: Katie
authors: K
authors: Zomorodi
authors: Early Drug Development, Jazz Pharmaceuticals, Palo Alto, CA, USA.
authors: Mark
authors: M
authors: Eller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D011089:Polydeoxyribonucleotides; C036901:defibrotide
keywords: dialysis; end-stage renal disease; hepatic veno-occlusive disease; sinusoidal obstruction syndrome