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Memantine Pharmacotherapy

A Naturalistic Study Using a Population Pharmacokinetic Approach

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Abstract

Background and objective

Memantine plasma concentrations show considerable interindividual variability. High memantine plasma concentrations are associated with the occurrence of neuropsychiatric adverse effects such as confusion. The objective of the present study was, therefore, to investigate the reasons for the observed variability of the pharmacokinetics of memantine in a representative patient population and to explore patient covariates on drug disposition.

Subjects

Fifty-six ambulatory Western European patients aged 50–91 years.

Methods

This prospective study used a full population pharmacokinetic sampling design. After at least 11 days of continuous memantine intake, the patients provided pharmacokinetic profiles, with six measurements each over a 12-hour period, with a total of 335 serum memantine concentrations. Covariates considered for inclusion in the models were: subject demographic factors (age, total body weight, gender), laboratory tests (urinary pH), total daily dose of memantine, memantine formulation type, comedication eliminated via tubular secretion and smoking history. The model development was conducted in three sequential steps. First, an adequate basic structural model was chosen (e.g. a one-, two- or three-compartment pharmacokinetic model). The data were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed-effects model computer program NONMEM. Second, the effects of covariates were investigated on post hoc estimates using multivariate statistics. Third, the covariates with significant effects in the second step were used to build a final covariate pharmacokinetic model, again using NONMEM.

Results

A two-compartment model with first-order absorption satisfactorily described memantine pharmacokinetics. In the final regression model, total bodyweight, memantine formulation type (solution vs tablets) and concomitant medication eliminated via tubular secretion were all important determinants of the apparent clearance (CL/F). The final regression model was: CL/F (L/h) = (1.92 + 0.048 · BW [kg]) · 0.53QFRM · 0.769CMD where FRM = 1 for patients receiving memantine solution, otherwise FRM = 0; CMD = 1 for patients receiving a comedication eliminated via tubular secretion, otherwise CMD = 0; and BW is bodyweight. Compared with the basic model, the final population pharmacokinetic model explained 61% of the interindividual variance of the apparent clearance.

Conclusions

The population pharmacokinetic model that was developed identified a set of sources of variability in the apparent clearance of memantine, which can be used as a reference in order to optimise memantine therapy in Western European patients.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

We wish to thank all of the patients who have participated in the trial, the personnel of the participating outpatient clinics and Bernd Eilbacher (Merz + Co., Frankfurt/Main, Germany) for measurement of memantine plasma concentrations. The GAM analysis was performed by Christina Rabe and Annette Pfahlberg, PhD (Department of Medical Informatics, Biometry and Epidemiology, University of Erlangen, Erlangen, Germany). No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Erlangen, Schwabachanlage 6, D-91054, Erlangen, Germany

    Johannes Kornhuber, Evelin M. Kennepohl, Stefan Bleich, Jens Wiltfang, Thomas Kraus & Udo Reulbach

  2. Department of Clinical Pharmacology, University of Göttingen, Göttingen, Germany

    Ingolf Meineke

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  1. Johannes Kornhuber
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  2. Evelin M. Kennepohl
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  3. Stefan Bleich
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  4. Jens Wiltfang
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  7. Ingolf Meineke
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Correspondence to Johannes Kornhuber.

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Kornhuber, J., Kennepohl, E.M., Bleich, S. et al. Memantine Pharmacotherapy. Clin Pharmacokinet 46, 599–612 (2007). https://doi.org/10.2165/00003088-200746070-00005

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