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

Abstract

Introduction: 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 (CL_CR).

Objective: 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.

Methods: 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 CL_CR and eGFR data, and boxplots were constructed after stratification by renal function.

Results: 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 CL_CR or 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.

Conclusion: 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.

Fig. 1

Rivastigmine and NAP226-90 steady-state plasma concentrations stratified by baseline renal impairment as measured by creatinine clearance (CL_CR) and estimated glomerular filtration rate (eGFR) following patch application

Fig. 2

Rivastigmine and NAP226-90 steady-state plasma concentrations stratified by baseline renal impairment as measured by creatinine clearance (CL_CR) and estimated glomerular filtration rate (eGFR) following capsule administration

Fig. 3

Rivastigmine and NAP226-90 steady-state plasma concentrations versus baseline creatinine clearance and estimated glomerular filtration rate following patch application

Fig. 4

Rivastigmine and NAP226-90 steady-state plasma concentrations versus baseline creatinine clearance and estimated glomerular filtration rate following capsule administration