Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease

Abstract

In this review the effect of adjunct 5-nitrocatechol based COMT inhibitors, especially entacapone, on the pharmacokinetics and efficacy of levodopa is detailed. The safety and adverse events are considered based mainly on phase III trial data and extension studies. Entacapone used as an adjunct to regular or controlled-release levodopa preparations increased ON-time and reduced OFF-time by 1 to 2 h daily in Parkinson's disease patients with wearing-off. The daily levodopa dose could also be reduced. Entacapone was generally well tolerated. Dopaminergic adverse events, such as dyskinesia and nausea, could usually be handled by reducing the levodopa dose. Several studies indicated that entacapone improved the quality-of-life of the patients. Entacapone treatment was also cost-effective. Open trial data supporting the use of the triple combination tablet (levodopa/carbidopa/entacapone) Stalevo TM are presented. Finally, the rationale for early use of COMT inhibitors in Parkinson's disease is considered and the design of the STRIDE trial is discussed. This is a double-blind randomised placebo controlled study where entacapone is administered at the time when levodopa is first introduced. The follow-up time is at least 2 years and the primary endpoint is the time to onset of dyskinesias.