Role of integrative pharmacokinetic and pharmacodynamic optimization strategy in the management of Parkinson"s disease patients experiencing motor fluctuations with levodopa

Abstract

Parkinson's disease is a progressively debilitating motor neuron disease that affects the dopaminergic neurons within the nigral-striatal and surrounding pathways and which is characterized clinically by rigidity, resting tremor and bradykinesia with or without postural imbalance. Levodopa is the "gold standard" for the treatment and management of Parkinson's disease worldwide. However, following prolonged use of the drug, the "honey-moon" which was once enjoyed by patients on levodopa begins to wane. The clinical as well as the socio-economic costs associated with such failure in response to levodopa is enormous. Various approaches in the management of Parkinson's disease patients experiencing motor fluctuations with levodopa treatment have been suggested and include both pharmacologic and non-pharmacologic strategies involving invasive surgical intervention. Currently, the non-pharmacological approach, which is invasive, remains to be fully perfected and is associated with high morbidity and mortality. The use of the non-invasive, pharmacological approach is currently the most widely accepted approach but would require a review of all possible drug regimens used. This entails evaluating the pharmacokinetics and pharmacodynamic actions of the drug regimens used and possibly, dosage form and route of administration of the drugs. The use of levodopa formulated for transdermal or intranasal administration might help improve the ease of use and compliance. Controversy abounds as to the role of plasma pharmacokinetics of levodopa in the management of Parkinson's patients, vis a vis its dynamics at the central nerve terminal and its receptor site. However, it is worthy of mention that an integrated optimal pharmacological approach involving the peripheral, and central pharmacokinetics of levodopa as well as its central pharmacodynamics would ensure better treatment and management of this disease. In addition, the choice of alternate formulations and routes of administration will not only improve on the bioavailability and overall pharmacokinetics of levodopa, but also increase compliance. Furthermore, monitoring of both plasma and central concentrations of levodopa and its metabolites might play a major role in individualization of pharmacotherapy in special Parkinsonian patients experiencing motor fluctuations with levodopa.