Effects of Renal Impairment on Steady-State Plasma Concentrations of Rivastigmine: A Population Pharmacokinetic Analysis of Capsule and Patch Formulations in Patients with Alzheimer's Disease.
The glomerular filtration rate (GFR), a measure of renal function, decreases by approximately 10 mL/min every 10 years after the age of 40 years, which could lead to the accumulation of drugs and/or renal toxicity. Pharmacokinetic studies of drugs excreted both renally and non-renally are desirable in patients with impaired renal function, defined by parameters including estimated GFR (eGFR) and creatinine clearance (CLCR).



We describe here a population pharmacokinetic analysis of the possible effects of renal impairment on steady-state plasma concentrations of rivastigmine and its metabolite NAP226-90 after rivastigmine patch (5 cm2[4.6 mg/24 h], 10 cm2[9.5 mg/24 h], 15 cm2[13.3 mg/24 h], and 20 cm2[17.4 mg/24 h]) and capsule (1.5, 3, 4.5, and 6 mg/12 h) treatment in patients with Alzheimer's disease.



The data used to conduct the current pharmacokinetic analysis were obtained from the pivotal phase III, 24-week, multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group study (IDEAL). One blood sample was collected from each patient at steady-state to measure plasma concentrations of rivastigmine and NAP226-90 using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The steady-state plasma concentrations of rivastigmine and NAP226-90 were plotted against CLCRand eGFR data, and boxplots were constructed after stratification by renal function.



The two groups (mild/no renal impairment vs. moderate/severe/end-stage renal impairment) showed comparable demographic covariates for all patch sizes and capsule doses. No correlation was observed between CLCRor eGFR and plasma concentrations of rivastigmine or NAP226-90. Boxplots of concentrations of rivastigmine or NAP226-90 for each dose largely overlapped for patch and capsule. Additionally, model-based estimates of plasma concentrations adjusted for body weight yielded similar results.



The results of this study show that renal function does not affect rivastigmine or NAP226-90 steady-state plasma concentrations, and no dose adjustment in patients with renal impairment is required. CLINICALTRIALS.GOV: NCT00099242.
WSJ-386.12.48.10, Novartis Institutes for Biomedical Research, Translational Medicine, Clinical PK/PD, 4002, Basel, Switzerland. gilbert.lefevre@novartis.com.
Gilbert
G
Lefèvre
Novartis Pharma AG, 4002, Basel, Switzerland.
Francesca
F
Callegari
Novartis Pharma AG, 4002, Basel, Switzerland.
Sandro
S
Gsteiger
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
Yuan
Y
Xiong
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D002214:Capsules; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D010627:Phenethylamines / Q000097:blood; D010636:Phenols / Q000097:blood; D051437:Renal Insufficiency / Q000097:blood* / Q000150:complications; D000068836:Rivastigmine / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D057968:Transdermal Patch
C494046:3-(1-dimethylaminoethyl)phenol; D002214:Capsules; D018696:Neuroprotective Agents; D010627:Phenethylamines; D010636:Phenols; D000068836:Rivastigmine
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