[Pfizer]
[Folio]
Title
Multiple-dose clinical pharmacology of the
catechol-O-methyl-transferase inhibitor tolcapone in elderly sub=
jects.
Author
Dingemanse J; Jorga K; Z=FCrcher G; Fotteler B; Sedek G; Nielsen=
T; van
Brummelen P
Address
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, B=
asel,
Switzerland.
Source
Eur J Clin Pharmacol, 50:47-55, 1996
Abstract
OBJECTIVE: The purpose of this study was to assess the multiple-=
dose
clinical pharmacology of tolcapone, a novel
catechol-O-methyltransferase (COMT) inhibitor, in elderly subjec=
ts.
METHODS: The drug was administered orally t.i.d. for 7 days to f=
our
sequential groups of eight elderly subjects (gender ratio 1:1) a=
t doses
of 100, 200, 400 and 800 mg in a double-blind, randomised,
placebo-controlled, ascending-multiple-dose design. On days 2 an=
d 7, a
single dose of levodopa/benserazide 100/25 mg was given 1 h afte=
r the
first intake of tolcapone. Plasma concentrations of tolcapone; i=
ts
metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were
determined during the course of the study in conjunction with CO=
MT
activity in erythrocytes. RESULTS: Tolcapone was well tolerated =
at all
dose levels, with a slight increase in gastrointestinal adverse =
events
in females at higher doses. The drug was rapidly absorbed and
eliminated and showed no changes in pharmacokinetics with time d=
uring
multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 =
mg
t.i.d., tolcapone accumulated moderately as reflected in increas=
ed Cmax
and AUC values. Despite the long halflife of 3-O-methyltolcapone=
(39
h), only minor accumulation occurred due to suppression of its
formation by tolcapone. The pharmacodynamics of tolcapone did no=
t
change during the week of treatment as reflected in inhibition o=
f COMT
activity in erythrocytes, the derived parameters of the plasma
concentration-effect relationship (inhibitory Emax model with co=
nstant
EC50 values) and the effect on levodopa pharmacokinetics (1.6 to
2.5-fold increase in bioavailability). This suggests the absence=
of
tolerance development and the insignificance of the altered
pharmacokinetics at 400 and 800 mg t.i.d. with regard to the
pharmacodynamics. CONCLUSION: The results of this study offer pr=
omising
perspectives for the application of tolcapone as adjunct therapy=
to
levodopa in the treatment of Parkinson's disease.
Language
Eng
Unique Identifier
96311493
---------------------------------------------------------------------=
-------
MESH Headings
Aged; Benzophenones (AE/*PD/PK); Biotransformation; Catechol
Methyltransferase (*AI/BL); Dopamine Agents (PD); Dose-Response
Relationship, Drug; Double-Blind Method; Enzyme Inhibitors (AE/*=
PD/PK);
Erythrocytes (DE/EN); Female; Half-Life; Human; Levodopa (PD); M=
ale;
Middle Age
---------------------------------------------------------------------=
-------
Publication Type
CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
ISSN
0031-6970
Country of Publication
GERMANY
---------------------------------------------------------------------=
-------
http://www.medscape.com
Medscape is produced by Medscape, Inc.
All material on this server Copyright =A9 1994, 1995, 1996, 1997 =
by the
publishers involved.
[Click this icon to load the navigation map (0.9Kb)]
