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Population Pharmacokinetic Modelling for Estimation of Remifentanil Metabolic-Ratio Using Non-steady-State Concentrations under Rapidly Adaptive Dosing

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Abstract

Purpose

To predict steady-state metabolite-to-drug concentration ratio (metabolic ratio) for analgesic drug remifentanil, using sparse non-steady-state data from patients with normal or impaired renal function during individualised, highly variable and rapidly adaptive intravenous infusion.

Methods

A three-compartment joint parent-metabolite population pharmacokinetic model was developed using concentrations of remifentanil and its metabolite remifentanil acid from two trials. Renal function was included as an important mechanistic covariate. To address the large covariate effect and highly individualised and rapidly adaptive dosing, standardised visual predictive check was conducted on the observations and individualised visual predictive check was conducted on metabolic ratio estimates. The model was used to simulate metabolic ratio distribution in patients with various renal functions.

Results

The model, including its covariate structure, adequately described the data. The predictive checks allowed informative model evaluation. The predicted median (10th - 90th percentile) of remifentanil metabolic ratio was 12.5 (2.4–58.2) for patients with normal or mildly impaired renal function, or 54.3 (12.8–218.4) for patients with moderately or severely impaired renal function.

Conclusions

The methodologies applied here allowed robust estimation of steady-state parameters using non-steady-state sparse data under highly variable adaptive dosing.

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Abbreviations

B:

Exponent for Metabolic Ratio

CI:

Confidence Interval

CL:

Remifentanil Clearance

CLM:

Elimination Clearance of the Metabolite Remifentanil Acid

CRCL0:

Baseline Creatinine Clearance

iVPC:

Individualised Visual Predictive Check

k0 :

Infusion Rate

M2 :

Amount of Remifentanil Acid in Its Blood Compartment

M3 :

Amount of Remifentanil Acid in Its Tissue Compartment

MR:

Metabolic Ratio

MRmax :

Maximal Metabolic Ratio

pcVPC:

Prediction-corrected Visual Predictive Check

Q:

Remifentanil Acid Distribution Clearance

R1 :

Amount of Remifentanil in Its Blood Compartment

sVPC:

Standardised Visual Predictive Check

V1 :

Remifentanil Blood Compartment Volume

V2 :

Remifentanil Acid Blood Compartment Volume

V3 :

Remifentanil Acid Tissue Compartment Volume

VPC:

Visual Predictive Check

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Acknowledgments and Disclosures

We thank Jonathan Bullman and remifentanil project team for their support, and Dr. Martin Bergstrand for discussion on prediction-corrected visual predictive check. Funding for this analysis was provided by GlaxoSmithKline. All authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors are employed by GlaxoSmithKline and declare no conflict of interest.

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  1. Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1 Ironbridge Road, Uxbridge, UB11 1BT, UK

    Monica Simeoni & Chao Chen

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  1. Monica Simeoni
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  2. Chao Chen
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Correspondence to Chao Chen.

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Simeoni, M., Chen, C. Population Pharmacokinetic Modelling for Estimation of Remifentanil Metabolic-Ratio Using Non-steady-State Concentrations under Rapidly Adaptive Dosing. Pharm Res 35, 216 (2018). https://doi.org/10.1007/s11095-018-2508-0

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  • DOI: https://doi.org/10.1007/s11095-018-2508-0

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