Current treatment of Parkinson's disease (PD) involves inhibiting peripheral decarboxylation of oral l-dopa by coadministering a dopa decarboxylase inhibitor (DDC inhibitor) in a fixed combination with l-dopa. With a DDC inhibitor, the decarboxylation of l-dopa decreases and the metabolism shifts to the catechol-O-methyltransferase (COMT) pathway. Consequently, concentration of the product 3-O-methyldopa (3-OMD) increases in peripheral tissues and the degradation to 3-OMD becomes the main metabolic pathway when l-dopa is coadministered with a DDC inhibitor [1–3].
Entacapone is a specific, potent and reversible COMT inhibitor, with an apparent half-life of elimination of 1.5–3.5 h after oral administration and 0.4 h after i.v. administration [4, 5]. As well as inhibiting the peripheral formation of 3-OMD, entacapone also affects the formation of the other metabolites of l-dopa, including that of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA) . The short half-life of elimination and the reversible nature of COMT inhibition enables the safe coadministration of entacapone with each daily dose of l-dopa to increase the benefits of l-dopa therapy for PD [7–10].
It has been shown in earlier single dose studies in healthy volunteers that simultaneous administration of entacapone with l-dopa/carbidopa increases the AUC of l-dopa in a dose-dependent fashion by decreasing its peripheral metabolism . It has been shown in PD patients that entacapone 200 mg significantly increases the availability of l-dopa in plasma when coadministered with varying doses of l-dopa and DDC inhibitor [7, 8, 11–13]. However, it has not been investigated whether the effects of this dose of entacapone on l-dopa pharmacokinetics and metabolism are dependent on the dose of l-dopa or DDC inhibitor. Standard-release tablets of l-dopa and carbidopa in fixed-dose combinations of 100/10 mg, 250/25 mg, 50/12.5 mg, and 100/25 mg are marketed for treatment of PD. In addition to these standard-release tablets, we included the higher 150/37.5 mg and 200/50 mg doses, also used in clinical practice, in the study design, and investigated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of l-dopa over this range of doses. The pharmacokinetics of carbidopa and entacapone were also determined.