List of Original Publications L-dopa

Parkinson’s disease (PD) is a progressive central nervous system (CNS) disorder, the cardinal symptoms of which are bradykinesia, resting tremor, muscular rigidity, and impaired postural balance. The lack of dopamine (DA) in the CNS basal ganglia is associated with these symptoms. L-dopa, an immediate precursor of DA, is used to treat PD. Unlike DA, L-dopa penetrates into the CNS where it is converted to DA. However, the capacity of CNS neurones to produce or store DA deteriorates during the course of the disease and the patient's clinical condition becomes closely dependent on the availability of external L-dopa from plasma. L-dopa is rapidly absorbed and eliminated with a short half-life and extensively metabolised, to a great extent by dopa decarboxylase (DDC) enzyme, already outside the CNS. Thus, the plasma concentrations of L-dopa fluctuate with its dosing, which has to be more and more frequent during the course of the disease. DDC inhibitors used as an adjunct to L-dopa improve the tolerability of the treatment and decrease the L-dopa dose needed for a clinical response. O-methylation of L-dopa by catechol-methyl transferase (COMT) enzyme then becomes the major metabolic pathway. Entacapone, a COMT inhibitor, was developed to further improve L-dopa therapy by decreasing its peripheral metabolism by COMT to 3-O-methyldopa (3OMD). These studies were performed to investigate the pharmacokinetic suitability of entacapone for continuous, frequently repeated co-administration with L-dopa and a DDC inhibitor, to investigate the dose-response effects of entacapone in PD patients after continuous treatment with L-dopa/carbidopa, and to investigate whether the effects of entacapone at the 200-mg dose are comparable with different doses of Ldopa and carbidopa. Further, new statistical approaches for testing of bioequivalence were implemented and evaluated for formulation development. The studies showed that entacapone is rapidly absorbed. Entacapone may be considered a highly variable drug regarding its Cmax, which favours the use of a fourway replicate cross-over design for bioequivalence studies. This design minimises the sample size and is most efficient in indicating the differences and interchangeability between different formulations. It also allows the use of various statistical approaches in the assessment of bioequivalence. A new, more sensitive assay method revealed three phases in the elimination curve of entacapone. The studies showed that entacapone is almost completely eliminated with a short half-life during the early phases of elimination. In PD patients, COMT inhibition by entacapone is maintained during continuous treatment. Different repeated doses of entacapone inhibit COMT activity in a dose-dependent manner and thereby reduce the peripheral loss of L-dopa to 3-OMD, increasing its AUC and improving patients' clinical response measured as functional time ('on' -time). The patients' clinical condition is not further improved by increasing the dose from 200 mg to 400 mg. The COMT inhibition afforded by the 200-mg dose of entacapone is sufficient with all investigated doses of L-dopa and carbidopa. The 200-mg dose of entacapone similarly increases the AUC of L-dopa with different doses of L-dopa and carbidopa by changing the metabolic balance of Ldopa. These properties of entacapone provide the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone as a 200-mg dose with different doses of L-dopa and carbidopa.