Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response

Abstract

Aims: Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use.

Methods: Elderly patients (n = 48), 65-99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression.

Results: A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h(-1) (53.2%), 114 l (121%), 80.7 l h(-1) (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration.

Conclusions: We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.

Keywords: analgesia; elderly; logistic regression; nefopam; population pharmacokinetics; renal impairment.

Figure 1

Schematic representation of structural pharmacokinetic models for nefopam (A) and desmethyl-nefopam (B). Abbreviations are as follows: CL, clearance; Cmt, compartment; dnef, desmethyl-nefopam; K13, apparent clearance of metabolization of nefopam to desmethyl-nefopam; Q, intercompartmental clearance; nef, nefopam; V, volume of compartment

Figure 2

Goodness-of-fit plots. (A) Observed (Obs) nefopam concentrations vs. individual-predicted (Ind.pred) nefopam concentrations. (B) Observed (Obs) desmethyl-nefopam concentrations vs. individual-predicted (Ind.pred) desmethyl-nefopam concentrations. Prediction-corrected visual predictive check (PC-VPC) for nefopam concentrations (C) and desmethyl-nefopam concentrations (D). The green lines show the 5th, 50th and 95th percentiles of observed data; the areas represent the 90% confidence interval around the simulated percentiles

Figure 3

Diagnostic plots. Normalized prediction distribution error (NPDE) as a function of population-predicted (popPred) concentrations of nefopam (A) and desmethyl-nefopam (C), and as a function of time for nefopam (B) and for desmethyl-nefopam (D)

Figure 4

Diagnostic plots. Population (blue dot) or individual (black circle) weighted residuals (PWRES or IWRES) vs. time for nefopam (A) and desmethyl-nefopam (C), and PWRES or IWRES vs. respective predictions for nefopam (B) and desmethyl-nefopam (D)

Figure 5

Monte Carlo simulations of different durations in nefopam infusion. The figure shows the probabilities, as a function of duration of infusion, to observe nefopam plasma maximum concentration (C_maxnef) and rate of increase of nefopam plasma concentration (RC_maxnef) lower than values linked to develop tachycardia or postoperative nausea and vomiting as determined by logistic regression (Table 3) and the probabilities as a function of duration of infusion to observe Area Under Curve of time course of nefopam plasma concentration (AUC_nef0→∞) above 950 μg h l⁻¹. The probabilities to observe C_maxnef and RC_maxnef were the same for all durations of infusion. , C_maxnef <389 μg l⁻¹; , RC_maxnef <764 μg l⁻¹; , AUC_nef0→∞ >950 μg h l⁻¹