Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer.

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the "wearing-off" phenomenon). The drug indication is for Parkinson's disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature.

Narrow Therapeutic Index drugs: clinical pharmacology perspective.

OBJECTIVES: Historically, the identification of drugs with the Narrow Therapeutic Index (NTI) has been empirically based on the clinical practice. In general terms, NTI drugs can be defined based on the steepness of the dose-response relationship and the degree of overlap between the effective and the toxic concentrations. KEY FINDINGS: The current definition in the Code of Federal Regulations is based on animal data and as such lacks direct clinical relevance. By basing these criteria on those factors that affect the degree of separation of the concentrations that elicit the therapeutic and the adverse effects, it was attempted to avoid the vagaries inherent in preparing a list of individual drugs themselves. SUMMARY: The overall conclusions are: (1) The issue of NTI drugs is still highly controversial, (2) The lists of NTI drugs are arbitrary and (3) Variability may contribute to the safety and efficacy. The objectives are to (1) To facilitate consensus on the definition of a NTI, (2) To identify characteristics of NTI and (3) To develop criteria for identifying NTI. The FDA should consider not only the pharmacokinetics (PK) studies, but also comparative efficacy and safety studies, for the NTI drugs to further to try 'convince or educate' the prescribers.