Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine.
The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment.
Global Biostatistics, UCB Pharma, Alfred-Nobel-Str. 10, 40789, Monheim am Rhein, Germany, willi.cawello@ucb.com.
Willi
W
Cawello
Andreas
A
Fichtner
Hilmar
H
Boekens
Marina
M
Braun
D000279:Administration, Cutaneous; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D006814:Hungary; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D018570:Risk Assessment; D012720:Severity of Illness Index; D018154:Slovakia; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D057968:Transdermal Patch
D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine