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Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease

College of Pharmacy and Allied Health (Drs. Nelson and Berchou), Wayne State University; Department of Pharmacy (Dr. Nelson), Harper Hospital; Department of Neurology and Neurochemical Pharmacology Research Unit (Drs. Berchou, LeWitt, Kareti, and Galloway), Lafayette Clinic; School of Medicine (Drs. Berchou, LeWitt, and Galloway), Wayne State University; and Clinical Neurosciences Program and Center for Cell Biology (Dr. LeWitt), Sinai Hospital of Detroit Detroit, MI.

Eight parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, E_max, and sigmoid E_max pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 µg/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 µg/ml. LD plasma concentrations fluctuating around 0.9 µg/ml may result in the "on/off" effects seen in Parkinson's disease.

Address correspondence and reprint requests to Dr. Merlin V. Nelson, Department of Pharmacy Practice, Wayne State University, Detroit, MI 48202.

Supported by a contract from Merck Sharp and Dohme Research Laboratories and by research support from the State of Michigan, Department of Mental Health (Lafayette Clinic).

Presented in part at the 41st annual meeting of the American Academy of Neurology, Chicago, IL, April 1989.

Received March 28, 1989. Accepted for publication in final form June 19, 1989.

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