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28.09.2016 | Original Research Article | Ausgabe 10/2016 Open Access

Drugs & Aging 10/2016

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

Zeitschrift:
Drugs & Aging > Ausgabe 10/2016
Autoren:
Gilbert Lefèvre, Francesca Callegari, Sandro Gsteiger, Yuan Xiong

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 (CLCR).

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 CLCR 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 CLCR 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.

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