Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The transdermal dopamine agonist rotigotine has been shown to be an efficacious and well tolerated treatment for Parkinson's disease and restless legs syndrome in clinical trials.• The prevalence of Parkinson's disease and restless legs syndrome increases with age.• Renal function deteriorates with age and can influence drug treatment.• Many patients with end-stage renal disease experience restless legs syndrome. WHAT THIS STUDY ADDS• The pharmacokinetic profiles of the active substance, unconjugated rotigotine, were similar in healthy subjects and subjects with renal impairment.• The results suggest that no dose adjustments are required for transdermal rotigotine in subjects with different stages of chronic renal insufficiency including patients on haemodialysis. AIMTo evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODSAll subjects received a single transdermal 10 cm 2 patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h -1 ). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. RESULTSPoint estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,tlast) and Cmax for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for Cmax for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. CONCLUSIONSThe pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis.

Caregivers’ and physicians’ attitudes to rotigotine transdermal patch versus oral Parkinson’s disease medication: an observational study

“…in those with impaired renal function, as no adaptation of dose is necessary. This is in support of previous findings [23][24][25] . The physicians participating in this observational study reported prescribing rotigotine transdermal patch as treatment for their patients (460%) because it contained rotigotine as the active substance.…”

Novel UHPLC‐MS/MS method for the determination of rotigotine in the plasma of patients with Parkinson's disease

“…Our paper describes the first fully validated method for the determination of ROT in human plasma. Our assay employs a lower plasma volume (500 μL vs 1 mL) than that used in the scant description of an HPLC MS/MS procedure for ROT plasma analysis published as supplementary material (Cawello et al, ), which provided no details on the extraction method. Our previously developed UHPLC‐MS/MS method for the plasma assay of the oral DAs PRA and ROP (Mohamed et al, ) required two main modifications for ROT determination: the composition of the mobile phase, to solve a chromatographic interference, and the doubling of the plasma and related tert‐ butyl methyl ether extraction volumes owing to the higher sensitivity required to measure the lower plasma concentrations of ROT compared with PRA and ROP, achieved at therapeutic dosages.…”

“…Post‐marketing data on ROT clinical pharmacokinetics are lacking and the literature on analytical methods for drug quantitation in human plasma is extremely scanty: we found only a preliminary paper describing a gas chromatographic/mass spectrometric method (Zavitsanos, Siddiqui, & Curtis, ) applied during the preclinical drug development phase, and a more recent HPLC‐MS/MS procedure summarized as the supplementary material to a clinical paper (Cawello, Ahrweiler, Sulowicz, Szymczakiewicz‐Multanowska, & Braun, ). Therapeutic dosages of ROT result in very low plasma concentrations (Elshoff et al, ) and a highly sensitive method is required (Cawello et al, ).…”

Rotigotine Transdermal Patch: A Review in Restless Legs Syndrome

“…No relevant increases in rotigotine plasma concentration were observed in patients with moderate hepatic [5] or mild to severe renal impairment [5,20]; the effect of severe hepatic impairment on rotigotine pharmacokinetics has not been investigated [5]. Impaired renal function leads to increased concentrations of rotigotine metabolites (conjugates and desalkyl metabolites); however, this is unlikely to have a clinical effect [5].…”