A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Requip Pharmacology, Pharmacokinetics, Studies, Metabolism - Ropinirole
Requip Pharmacology, Pharmacokinetics, Studies, Metabolism - Ropinirole
CLINICAL PHARMACOLOGY
Mechanism of Action
Requip is a non-ergoline dopamine agonist with high relative in vitro
specificity and full intrinsic activity at the D 2 and D 3
dopamine receptor subtypes, binding with higher affinity to D 3 than
to D 2 or D 4 receptor subtypes. The relevance of D 3
receptor binding in Parkinson's disease is unknown.
Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole
and its metabolites have negligible in vitro affinity for dopamine D
1 , 5-HT 1 , 5-HT 2 , benzodiazepine, GABA,
muscarinic, alpha 1 -, alpha 2 -, and beta-adrenoreceptors.
The precise mechanism of action of Requip as a treatment for Parkinson's
disease is unknown, although it is believed to be due to stimulation of post-synaptic
dopamine D 2 -type receptors within the caudate-putamen in the brain.
This conclusion is supported by studies that show that ropinirole improves motor
function in various animal models of Parkinson's disease. In particular, ropinirole
attenuates the motor deficits induced by lesioning the ascending nigrostriatal
dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) in primates.
Clinical Pharmacology Studies
In healthy normotensive subjects, single oral doses of Requip in the
range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse
rates. Upon standing, Requip caused decreases in systolic and diastolic
blood pressure at doses above 0.25 mg. In some subjects, these changes were
associated with the emergence of orthostatic symptoms, bradycardia and, in one
case, transient sinus arrest with syncope. The effect of repeat dosing and slow
titration of Requip was not studied in healthy volunteers.
The mechanism of Requip -induced postural hypotension is presumed to
be due to a D 2 -mediated blunting of the noradrenergic response
to standing and subsequent decrease in peripheral vascular resistance. Nausea
is a common concomitant of orthostatic signs and symptoms.
At oral doses as low as 0.2 mg, Requip suppressed serum prolactin concentrations
in healthy male volunteers.
Requip had no dose-related effect on ECG wave form and rhythm in young
healthy male volunteers in the range of 0.01 to 2.5 mg.
Pharmacokinetics
Absorption, Distribution, Metabolism and Elimination
Ropinirole is rapidly absorbed after oral administration, reaching peak concentration
in approximately 1-2 hours. In clinical studies, over 88% of a radiolabeled
dose was recovered in urine and the absolute bioavailability was 55%, indicating
a first pass effect. Relative bioavailability from a tablet compared to an oral
solution is 85%. Food does not affect the extent of absorption of ropinirole,
although its T max is increased by 2.5 hours when the drug is taken
with a meal. The clearance of ropinirole after oral administration to patients
is 47 L/hr (cv=45%) and its elimination half-life is approximately 6 hours.
Ropinirole is extensively metabolized by the liver to inactive metabolites and
displays linear kinetics over the therapeutic dosing range of 1 mg to 8 mg t.i.d.
Steady-state concentrations are expected to be achieved within 2 days of dosing.
Accumulation upon multiple dosing is predictive from single dosing.
Ropinirole is widely distributed throughout the body, with an apparent volume
of distribution of 7.5 L/kg (cv=32%). It is up to 40% bound to plasma proteins
and has a blood-to-plasma ratio of 1:1.
The major metabolic pathways are N-despropylation and hydroxylation to form
the inactive N-despropyl and hydroxy metabolites. In vitro studies indicate
that the major cytochrome P 450 isozyme involved in the metabolism
of ropinirole is CYP1A2, an enzyme known to be stimulated by smoking and omeprazole,
and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones,
such as ciprofloxacin and norfloxacin. The N-despropyl metabolite is converted
to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites.
The hydroxy metabolite of ropinirole is rapidly glucuronidated. Less than 10%
of the administered dose is excreted as unchanged drug in urine. N-despropyl
ropinirole is the predominant metabolite found in urine (40%), followed by the
carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite
(10%).
P 450 Interaction: In vitro metabolism
studies showed that CYP1A2 was the major enzyme responsible for the metabolism
of ropinirole. There is thus the potential for inhibitors or substrates of this
enzyme to alter its clearance when coadministered with ropinirole. Therefore,
if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or
started during treatment with Requip , adjustment of the Requip dose
may be required.
Population Subgroups
Because therapy with Requip is initiated at a subtherapeutic dosage
and gradually titrated upward according to clinical tolerability to obtain the
optimum therapeutic effect, adjustment of the initial dose based on gender,
weight or age is not necessary.
Age: Oral clearance of ropinirole is reduced by 30% in patients
above 65 years of age compared to younger patients. Dosage adjustment is not
necessary in the elderly (above 65 years) as the dose of ropinirole is to be
individually titrated to clinical response.
Gender: Female and male patients showed similar oral clearance.
Race: The influence of race on the pharmacokinetics of ropinirole
has not been evaluated.
Cigarette Smoking: The effect of smoking on the oral clearance
of ropinirole has not been evaluated. Smoking is expected to increase the clearance
of ropinirole since CYP1A2 is known to be induced by smoking.
Renal Impairment: Based on population pharmacokinetic analysis,
no difference was observed in the pharmacokinetics of ropinirole in patients
with moderate renal impairment (creatinine clearance between 30 to 50 mL/min.)
compared to an age-matched population with creatinine clearance above 50 mL/min.
Therefore, no dosage adjustment is necessary in moderately renally impaired
patients. The use of Requip (ropinirole hydrochloride) in patients with severe
renal impairment has not been studied.
The effect of hemodialysis on drug removal is not known, but because of the
relatively high apparent volume of distribution of ropinirole (525 L), the removal
of the drug by hemodialysis is unlikely.
Hepatic Impairment: The pharmacokinetics of ropinirole have
not been studied in hepatically impaired patients. These patients may have higher
plasma levels and lower clearance of the drug than patients with normal hepatic
function. The drug should be titrated with caution in this population.
Other Diseases: Population pharmacokinetic analysis revealed
no change in the oral clearance of ropinirole in patients with concomitant diseases,
such as hypertension, depression, osteoporosis/arthritis, and insomnia, compared
to patients with Parkinson's disease only.
Clinical Trials
The effectiveness of Requip in the treatment of Parkinson's disease
was evaluated in a multi-national drug development program consisting of 11
randomized, controlled trials. Four were conducted in patients with early Parkinson's
disease and no concomitant L-dopa and 7 were conducted in patients with advanced
Parkinson's disease with concomitant L-dopa.
Among these 11 studies, three placebo-controlled studies provide the most persuasive
evidence of ropinirole's effectiveness in the management of patients with Parkinson's
disease who were and were not receiving concomitant L-dopa. Two of these three
trials enrolled patients with early Parkinson's disease (without L-dopa) and
one enrolled patients receiving L-dopa.
In these studies a variety of measures were used to assess the effects of treatment
(e.g., the Unified Parkinson's Disease Rating Scale [UPDRS], Clinical Global
Impression scores, patient diaries recording time "on" and "off," and tolerability
of L-dopa dose reductions).
In both studies of early Parkinson's disease (without L-dopa) patients, the
motor component (Part III) of the UPDRS was the primary outcome assessment.
The UPDRS is a four-part multi-item rating scale intended to evaluate mentation
(Part I), activities of daily living (Part II), motor performance (Part III),
and complications of therapy (Part IV). Part III of the UPDRS contains 14 items
designed to assess the severity of the cardinal motor findings in patients with
Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability,
etc.) scored for different body regions and has a maximum (worst) score of 108.
Responders were defined as patients with at least a 30% reduction in the Part
III score.
In the study of advanced Parkinson's disease (with L-dopa) patients, both reduction
in percent awake time spent "off" and the ability to reduce the daily use of
L-dopa were assessed as a combined endpoint and individually.
Studies in Patients with Early Parkinson's Disease (without L-dopa)
One early therapy study was a 12-week multicenter study in which 63 patients
(41 on Requip ) with idiopathic Parkinson's disease receiving concomitant
anti-Parkinson medication (but not L-dopa) were randomized to either Requip
or placebo. Patients had a mean disease duration of approximately 2 years.
Patients were eligible for enrollment if they presented with bradykinesia and
at least tremor, rigidity, or postural instability. In addition, they must have
been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I=unilateral
involvement with minimal impairment to V=confined to wheelchair or bed, is a
standard instrument used for staging patients with Parkinson's disease. The
primary outcome measure in this trial was the proportion of patients experiencing
a decrease (compared to baseline) of at least 30% in the UPDRS motor score.
Patients were titrated for up to 10 weeks, starting at 0.5 mg b.i.d., with
weekly increments of 0.5 mg b.i.d. to a maximum of 5 mg b.i.d. Once patients
reached their maximally tolerated dose (or 5 mg b.i.d.), they were maintained
on that dose through 12 weeks. The mean dose achieved by patients at study endpoint
was 7.4 mg/day. At the end of 12 weeks, 71% of Requip -treated patients
were responders, compared with 41% of patients in the placebo group (p=0.021).
Statistically significant differences between the percentage of responders
on Requip compared to placebo were seen after 8 weeks of treatment.
In addition, the mean percentage improvement from baseline in the Total Motor
Score was 43% in Requip -treated patients compared with 21% in placebo-treated
patients (p=0.018).
Statistically significant differences in UPDRS motor score between Requip
and placebo were seen after 2 weeks of treatment.
The median daily dose at which a 30% reduction in UPDRS motor score was sustained
was 4 mg.
The second trial in early Parkinson's disease (without L-dopa) patients was
a double-blind, randomized, placebo-controlled 6-month study. Patients were
essentially similar to those in the study described above; concomitant use of
selegiline was allowed, but patients were not permitted to use anticholinergics
or amantadine during the study. Patients had a mean disease duration of 2 years
and limited (not more than a 6-week period) or no prior exposure to L-dopa.
The starting dose of Requip in this trial was 0.25 mg t.i.d. The dose
was titrated at weekly intervals by increments of 0.25 mg t.i.d. to a dose of
1.0 mg t.i.d. Further titrations at weekly intervals were at increments of 0.5
mg t.i.d. up to a dose of 3.0 mg t.i.d and then weekly at increments of 1.0
mg t.i.d. Patients were to be titrated to a dose of at least 1.5 mg t.i.d. and
then to their maximally tolerated dose, up to a maximum of 8.0 mg t.i.d. The
mean dose attained in patients at study endpoint was 15.7 mg/day.
The primary measure of effectiveness was the mean percent reduction (improvement)
from baseline in the UPDRS Motor Score. In this study 241 patients were enrolled.
At the end of the 6-month study, Requip -treated patients had 22% improvement
in motor score, compared with a 4% worsening in the placebo group (p<0.001).
Statistically significant differences in UPDRS motor score improvement between
Requip and placebo were seen after 12 weeks of treatment.
Study in Patients with Advanced Parkinson's Disease (with L-dopa)
This double-blind, randomized, placebo-controlled 6-month trial evaluated 148
patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa.
Patients in this study had a mean disease duration of approximately 9 years,
had been exposed to L-dopa for approximately 7 years, and had experienced "on-off"
periods with L-dopa therapy. Patients previously receiving stable doses of selegiline,
amantadine and/or anticholinergic agents could continue on these agents during
the study. Patients were started at a Requip dose of 0.25 mg t.i.d. and
titrated upward by weekly intervals until an optimal therapeutic response was
achieved. The maximum dose of study medication was 8 mg t.i.d. All patients
had to be titrated to at least a dose of 2.5 mg t.i.d. Patients could then be
maintained on this dose level or higher for the remainder of the study. Once
a dose of 2.5 mg t.i.d. was achieved, patients underwent a mandatory reduction
in their L-dopa dose, to be followed by additional mandatory reductions with
continued escalation of the Requip dose. Reductions in the dosage of
L-dopa were also allowed if patients experienced adverse events that the investigator
considered related to dopaminergic therapy. The mean dose attained at study
endpoint was 16.3 mg/day. The primary outcome was the proportion of responders,
defined as patients who were able both to achieve a decrease (compared to baseline)
of at least 20% in their L-dopa dose and a decrease of at least 20% in the proportion
of the time awake in the "off" condition (a period of time during the day when
patients are particularly immobile), as determined by patient diary. In addition,
the mean percent change from baseline in daily L-dopa dose was examined.
At the end of 6 months, 28% of Requip -treated patients were classified
as responders (based on combined endpoint) while 11% of placebo-treated patients
were responders (p=0.02). Based on the protocol-mandated reductions in L-dopa
dosage with escalating Requip doses, Requip -treated patients
had a 19.4% mean reduction in L-dopa dose while placebo-treated patients had
a 3% reduction (p<0.001). L-dopa dosage reduction was also allowed during
the study if dyskinesias or other dopaminergic effects occurred. Overall, reduction
of L-dopa dose was sustained in 87% of Requip -treated patients and in
57% of patients on placebo. On average, the L-dopa dose was reduced by 31% in
Requip -treated patients.
The mean number of "off" hours per day during baseline was 6.4 hours for Requip
-treated patients and 7.3 hours for patients treated with placebo. At the
end of the 6-month study, patients treated with Requip had a mean of
4.9 hours per day of "off" time, while placebo-treated patients had a mean of
6.4 hours per day of "off" time.
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