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Estimation of the Absolute Bioavailability of Rivastigmine in Patients with Mild to Moderate Dementia of the Alzheimer’s Type

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Abstract

Objective

To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer’s type, at the highest approved single dose of 6mg.

Design and setting

Randomised, two-period crossover, single-centre, non-blinded, inpatient study.

Patients and participants

Eleven patients (five females and six males) with mean age 69.5 years.

Methods

The 6mg oral dose was compared with a 2mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method.

Results

Following oral administration of a single 6mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 µg/L. By a noncompartmental approach, the absolute bioavailability of the 6mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration.

Conclusion

A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics.

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Acknowledgements

The authors are grateful to Aaron Crawford, PhD, for his help in preparing this manuscript.

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Authors and Affiliations

  1. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

    Mohammad Hossain, Craig McDonald, Greg Sedek & Francoise Pommier

  2. California Clinical Trials, 8501 Wilshire Boulevard, Beverly Hills, California, 90211-3150, USA

    Stanford S. Jhee, Thomas Shiovitz & Neal R. Cutler

  3. Ingenix Pharmaceutical Services, Beverly Hills, California, USA

    Stanford S. Jhee, Thomas Shiovitz & Neal R. Cutler

Authors
  1. Mohammad Hossain
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  2. Stanford S. Jhee
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  3. Thomas Shiovitz
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  4. Craig McDonald
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  5. Greg Sedek
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  6. Francoise Pommier
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  7. Neal R. Cutler
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Corresponding author

Correspondence to Stanford S. Jhee.

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Hossain, M., Jhee, S.S., Shiovitz, T. et al. Estimation of the Absolute Bioavailability of Rivastigmine in Patients with Mild to Moderate Dementia of the Alzheimer’s Type. Clin Pharmacokinet 41, 225–234 (2002). https://doi.org/10.2165/00003088-200241030-00006

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  • DOI: https://doi.org/10.2165/00003088-200241030-00006

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