Population pharmacokinetics and pharmacodynamics of dalfampridine-ER in healthy volunteers and in patients with multiple sclerosis

Abstract

Objective:

Using data pooled from several studies of dalfampridine extended release (ER), a population pharmacokinetic model was developed for the purposes of characterizing the population pharmacokinetics and pharmacodynamics of dalfampridine-ER with respect to variability in pharmacokinetics, covariates affecting the pharmacokinetics, and whether the current therapeutic dosage represents an optimal dosage. Studies were conducted in healthy volunteers and multiple sclerosis (MS) patients over the course of development and registration of dalfampridine extended release tablets (dalfampridine-ER [Ampyra]; prolonged-, modified- or sustained-release fampridine [Fampyra] in some countries).

Methods:

The model used to best describe the population pharmacokinetics of dalfampridine-ER was an open, one-compartment model with first-order absorption, first-order elimination and an absorption lag time.

Results:

The population median estimated oral clearance was 36 L/h for a 50-year-old woman with a creatinine clearance of 105 mL/min and 42 L/h for a comparable man. The typical volume of distribution was 304 L for women and 403 L for men. The estimated absorption rate constant was 1.22 hours⁻¹ in the fasted state and 2.22 hours⁻¹ when given with food. The covariates identified as having a significant effect (p < 0.01) on model fit were food and gender on absorption rate, and gender, age and creatinine clearance on oral clearance. Only creatinine clearance and age are of clinical relevance. Concomitant medications did not affect any of the parameters in the model. Exposure–response relationships for both efficacy and safety were consistent with what has been observed in clinical trials. Limitations of this study include some reliance on unpublished data, and the limited effectiveness of the model for determining the likelihood of the efficacy and safety of dalfampridine-ER in clinical practice.

Conclusions:

The approved therapeutic dosage regimen of dalfampridine-ER 10 mg twice daily was identified as the optimum dosing regimen based on model-predicted exposure response relationships for efficacy and adverse events. A limitation of this study is the limited effectiveness of the models used to predict long-term efficacy and safety of dalfampridine-ER in clinical use.

Keywords::

• Dalfampridine
• Fampridine
• Pharmacodynamics
• Pharmacokinetics
• Multiple sclerosis

Transparency

Declaration of funding

The study and editorial support for this manuscript were funded by Acorda Therapeutics Inc., Ardsley, NY, USA.

Declaration of financial/other relationships

S.W. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article. Y.G. has disclosed that he is an employee of Quantitative Solutions, which was contracted by Acorda Therapeutics Inc. to conduct this study; and H.R.H.III is an employee and stockholder of Acorda Therapeutics Inc.

CMRO peer reviewers on this manuscript have received honoraria for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

The authors thank E. Jay Bienen PhD of The Curry Rockefeller Group, LLC, Tarrytown, NY, USA, for editorial assistance.

Previous presentation: Gao Y, Marinucci L, Way S, Henney HR III, Wada R. A population pharmacokinetic analysis of dalfampridine extended release tablets in healthy volunteers and multiple sclerosis patients. Poster presented at: American Conference on Pharmacometrics (ACoP), 3–6 April 2011, San Diego, CA, USA.

Notes

*Ampyra is a registered trademark of Acorda Therapeutics Inc., Ardsley, NY, USA.

†Fampyra is a registered trademark of Biogen Idec Australia Pty Ltd, North Ryde, NSW, Australia.

*Ampyra is a registered trademark of Acorda Therapeutics Inc., Ardsley, NY, USA.

†Fampyra is a registered trademark of Biogen Idec Australia Pty Ltd, North Ryde, NSW, Australia.