Pharmacology: Mechanism of Action:
APO-PRAMIPEXOLE (pramipexole dihydrochloride monohydrate) is a non-ergot dopamine agonist with high in vitro specificity at the D2
subfamily of dopamine receptors. Pramipexole is a full agonist and exhibits higher affinity to the D3
receptor subtypes (which are in prominent distribution within the mesolimbic area) than to D2
receptor subtypes. While APO-PRAMIPEXOLE exhibits high affinity for the dopamine D2
receptor subfamily, it has low affinity for α2
adrenergic receptors and negligible or undetectable affinity for other dopaminergic, adrenergic, histaminergic, adenosine and benzodiazepine receptors.
The ability of pramipexole to alleviate the signs and symptoms of Parkinson's disease is believed to be related to its ability to stimulate dopamine receptors in the striatum. This assumption is supported by a dose-dependent antagonism of Parkinsonian symptoms in rhesus monkeys pre-treated with the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which destroys dopamine cell bodies in the substantia nigra.
In human volunteers, a dose-dependent decrease in prolactin was observed.
Comparative Bioavailability: A comparative bioavailability study was conducted in December 2005, under fasting conditions, using APO-PRAMIPEXOLE, and the reference product, MIRAPEX tablets (manufactured by Boehringer Ingelheim (Canada) Ltd.). The study consisted of a randomized, single dose (1 x 0.25 mg pramipexole dihydrochloride), crossover design, with two treatments and two periods. Seventeen (17) healthy male/female volunteers completed the study in its entirety. (See Table 4.)
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Study demographics and trial design: Up to February 29, 1996, 1715 patients have been exposed to pramipexole dihydrochloride, with 669 patients being exposed for over one year and 222 patients being exposed for over two years.
The effectiveness of pramipexole dihydrochloride monohydrate in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three Phase 3 studies provide the most persuasive evidence of pramipexole dihydrochloride monohydrate's effectiveness in the management of patients with Parkinson's disease who were or were not receiving concomitant levodopa. Two of the trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.
Study results: In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subscales, served as the primary outcome assessment measure.
Studies in patients with early Parkinson's disease: Patients in the two studies with early Parkinson's disease had mean disease duration of 2 years, limited or no prior exposure to levodopa, and were not experiencing the "on-off" phenomenon and dyskinesia characteristics of later stages of the disease.
One of the trials was a double-blind, placebo-controlled, parallel study in which patients were randomized to pramipexole dihydrochloride monohydrate (N = 164) or placebo (N = 171). The trial consisted of a 7-week dose escalation period and a 6-month maintenance period. Patients could be on selegiline and/or anticholinergics but not on levodopa products. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day, administered in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS Part II (activities of daily living [ADL] subscale) score was 1.9 in the pramipexole dihydrochloride monohydrate group and -0.4 in the placebo group. The mean improvement from baseline on the UPDRS part III (motor subscale) was 5.0 in the pramipexole dihydrochloride monohydrate group and -0.8 in the placebo group. Both differences were statistically significant. The mean daily dose of pramipexole dihydrochloride monohydrate during the maintenance period was 3.8 mg/day.
The difference in mean daily dose between males and females was less than 10%. Patients >75 years (N = 26) received the same mean daily dose as younger patients.
The second early Parkinson's disease study was a double-blind, placebo-controlled parallel trial which evaluated dose-response relationships. It consisted of a 6-week dose escalation period and a 4-week maintenance period. A total of 264 patients were enrolled. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but not on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride monohydrate (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo. No dose-response relationship was demonstrated. The between treatment differences on both parts of the UPDRS were statistically significant in favour of pramipexole dihydrochloride monohydrate at all doses.
In both studies in early Parkinson's disease patients, no differences in effectiveness were detected based upon age or gender. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.
To date, results comparing pramipexole dihydrochloride monohydrate to levodopa are not available.
Studies in patients with advanced Parkinson's disease: In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" times.
Patients (N = 181 on pramipexole dihydrochloride monohydrate, N = 179 on placebo) had a mean disease duration of 9 years, had been exposed to levodopa for a mean of 8 years, received concomitant levodopa during the trial and had "on-off" periods. Patients could additionally be on selegiline, anticholinergics, amantadine, or any combination of these. The study consisted of a 7-week dose-escalation period and a 6-month maintenance period. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose but no higher than 4.5 mg/day, administered in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) score was 2.7 in the pramipexole dihydrochloride monohydrate group and 0.5 in the placebo group. The mean improvement from baseline on the UPDRS part III (motor) score was 5.6 in the pramipexole dihydrochloride group and 2.8 in the placebo group. Both differences were statistically significant. The mean daily dose of pramipexole dihydrochloride during the maintenance period was 3.5 mg/day. The dose of levodopa could be reduced if dyskinesia or hallucinations developed. Levodopa dose reduction occurred in 76% and 54% of pramipexole dihydrochloride monohydrate and placebo-treated patients, respectively. On average, the percent decrease was 27% in the pramipexole dihydrochloride monohydrate group and 5% in the placebo group.
In females the mean daily dose was approximately 10% lower than in male patients. Patients aged over 75 years (N = 24) had approximately a 10% lower dose than younger patients.
The mean number of "off" hours per day during baseline was approximately 6 hours for both groups. Throughout the trial, patients treated with pramipexole dihydrochloride monohydrate had a mean "off" period of approximately 4 hours, while the duration of "off" periods remained essentially unchanged in the placebo-treated subjects.
No differences in effectiveness were detected based upon age or gender.
Receptor binding studies: Preclinical studies, which compared the relative pharmacological activities and receptor binding affinities (displacement of [3H] spiroperidol) of the pramipexole racemate and its optical isomers, showed the levorotational (-) enantiomer to be more potent.
Studies with cloned human receptors, expressed in cultured Chinese hamster ovary (CHO) cells, indicate that, within the recently discovered D2 receptor subfamily, pramipexole binds with highest affinity to the D3 subtype (Ki=0.5 nM). Pramipexole has approximately a 5- to 10-fold preferential affinity for the D3 receptor when compared to its affinities for the high affinity forms of the D2S, D2L and D4 subtypes (Ki values: 3.3, 3.9 and 5.1 nM, respectively). As is true for other dopamine agonists, exposure of the receptor to a non-hydrolyzable analog of GTP decreases the affinity of pramipexole for the cloned D3 receptor much less than it does for the cloned D2 or D4 subtypes. The small GTP-shift for agonists of the D3 receptor site is an indication of the weak coupling of this receptor to the G-protein second messenger system in CHO cells.
Besides binding to the dopamine-D2 receptor subfamily, pramipexole has a low affinity for α2-adrenoreceptors and a very low affinity for histamine H2 and serotonin 5-HT1A receptors. Its affinity for other dopaminergic, adrenergic, histaminergic, serotonergic, cholinergic, glutamatergic, adenosine and benzodiazepine receptors is negligible or undetectable.
Receptor binding autoradiography with [3H] pramipexole (5 nM, 62 Ci/mmole) was used to evaluate the distribution of pramipexole binding sites within the rat brain. The highest concentrations of [3H] pramipexole binding sites were found in the Islets of Calleja, previously reported to contain D3, but not D2 or D4 mRNA. [3H] Pramipexole binding was also high in other mesolimbic areas, such as the nucleus accumbens, olfactory tubercle, and amygdala. [3H] Pramipexole binding was also high in caudate, although slightly less than in mesolimbic areas. Striatal areas have higher D2:D3 mRNA ratios than do mesolimbic regions. Fewer [3H] pramipexole binding sites were found in VTA and substantia nigra, areas rich in cell bodies for dopamine neurons. Although it is likely that much of this [3H] pramipexole binding reflects D2 receptors, the relatively high mesolimbic binding could reflect the preferential affinity pramipexole has for the D3 receptor subtype.
Animal Studies: Antagonism of Reserpine-Induced Akinesia: Reserpine treatment leads to depletion of monoamines, including dopamine. Animals so treated are essentially akinetic, but can be activated by dopamine agonists.
Pramipexole (30 μmole/kg = 9 mg/kg IP) stimulated locomotor activity in reserpinized mice. These data are consistent with a pramipexole-induced stimulation of postsynaptic dopamine receptors in the basal ganglia.
Antagonism of Haloperidol-Induced Catalepsy: The dopamine receptor antagonist haloperidol induces hypomotility, rigidity, and catalepsy in the rat. The cataleptic behaviour is regarded to be highly predictive of neuroleptic-induced Parkinson-like extrapyramidal side effects.
In one study, rats were injected with haloperidol 1 mg/kg. Rats were considered cataleptic if they maintained a position with their forepaws elevated on a 6 to 8 cm high rod for at least 30 seconds two hours after haloperidol. Pramipexole dose-dependently suppressed catalepsy, with an ED50 of 4.4 mg/kg SC.
In a second study, catalepsy, produced by 5 μmole/kg SC (= 2 mg/kg) of haloperidol, was scored by measuring the time rats remained with their forepaws on a squared wooden cube. Pramipexole (50 μmole/kg = 15.1 mg/kg) readily blocked the catalepsy.
Rotational Behavior in 6-Hydroxydopamine (6-OHDA) Lesioned Rats: When 6-OHDA is injected unilaterally into the medial forebrain bundle of rats, a selective degeneration of presynaptic dopaminergic neurons occurs; rendering the animals essentially hemi-Parkinsonian. The postsynaptic neurons at the site of the lesion become hypersensitive to dopamine agonists. When dopamine agonists are administered to lesioned rats, a contralateral rotational behaviour can be observed. The number of rotations is evaluated in a rotameter.
In an initial study, pramipexole and, for comparison, apomorphine was tested in doses of 0.01 to 0.1 mg/kg. The D1- and D2-selective dopamine antagonists, SCH 23390 and haloperidol, respectively, were used to determine the subfamily of receptors involved. All compounds were administered SC.
Both pramipexole (ED50 0.026 mg/kg, maximum effect 80 to 140 minutes after administration) and apomorphine (ED50 0.030 mg/kg, maximum effect 5 to 65 minutes after administration) induced contralateral turning behaviour in 6-OHDA-lesioned rats. Whereas the effect of apomorphine ceased after 80 minutes, pramipexole was effective throughout the recording period of 2 hours.
Pretreatment with 0.05 mg/kg of haloperidol markedly attenuated the effect of pramipexole (0.05 mg/kg). The very high dose of 2 mg/kg of SCH 23390 also inhibited the effect, albeit to a smaller extent.
A second study confirmed the potent and long-lasting effects of pramipexole in this animal model of Parkinson's disease; maximal effects occurred with a dose of 0.3 μmole/kg (= 0.09 mg/kg) SC. Higher doses produced less effect.
MPTP-Induced Parkinsonian Symptoms in Rhesus Monkeys: MPTP (n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a highly selective neurotoxin which destroys the dopamine cell bodies in the zona compacta of the substantia nigra. The chronic dopamine depletion in the substantia nigra, results in a syndrome which resembles severe Parkinsonism, observed in patients. The effect of MPTP is irreversible. Due to chronic denervation, the postsynaptic dopamine D2 receptors become hypersensitive. A presynaptic action of a compound in the substantia nigra is excluded in this model because the presynaptic neurons have been destroyed.
Pramipexole (0.03 to 0.1 mg/kg IM) dose-dependently reversed the Parkinson-like symptoms in MPTP-treated rhesus monkeys. The dose which antagonized the symptoms in 50% of the animals (ED50) was 0.045 mg/kg IM. A dose of 0.06 mg/kg was effective in all animals. The animals' locomotor activity, recorded with an electronic device mounted on their arm, returned to normal and did not exceed that of monkeys not pretreated with MPTP. Stereotyped movements, abnormal excitation, salivation, or sedation were not observed in the dose range tested. A dose of 0.1 mg/kg IM was effective for more than 5h.
In another study, oral doses of 0.05 to 0.1 mg/kg of pramipexole were evaluated in MPTP-treated rhesus monkeys. At a dose of 0.075 mg/kg, the compound completely reversed the Parkinsonian symptoms. The duration of action varied between 5 and 24 hours.
Following oral administration, pramipexole is rapidly absorbed reaching peak concentrations between 1 and 3 hours. The absolute bioavailability of pramipexole is greater than 90%. Pramipexole can be administered with or without food. A high-fat meal did not affect the extent of pramipexole absorption (AUC and Cmax) in healthy volunteers, although the time to maximal plasma concentration (Tmax) was increased by about 1 hour.
Pramipexole displays linear pharmacokinetics over the range of doses that are recommended for patients with Parkinson's disease.
Pramipexole is extensively distributed, having a volume of distribution of about 500 L. Protein binding is less than 20% in plasma; with albumin accounting for most of the protein binding in human serum. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately 2.0 and a blood to plasma ratio of approximately 1.5. Consistent with the large volume of distribution in humans, whole body autoradiography and brain tissue levels in rats indicated that pramipexole was widely distributed throughout the body, including the brain.
Metabolism and Excretion:
Urinary excretion is the major route of pramipexole elimination. Approximately 88% of a 14C-labelled dose was recovered in the urine and less than 2% in the faeces following single intravenous and oral doses in healthy volunteers. The terminal elimination half-life was about 8.5 hours in young volunteers (mean age 30 years) and about 12 hours in elderly volunteers (mean age 70 years). Approximately 90% of the recovered 14C-labelled dose was unchanged drug; with no specific metabolites having been identified in the remaining 10% of the recovered radio-labelled dose. Pramipexole is the levorotational (-) enantiomer, and no measurable chiral inversion or racemization occurs in vivo.
The renal clearance of pramipexole is approximately 400 mL/min, approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.
Special Populations and Conditions:
Because therapy with pramipexole is initiated at a subtherapeutic dose and gradually titrated according to clinical tolerability to obtain optimal therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment.
Early vs. advanced Parkinson's disease patients: The pharmacokinetics of pramipexole was comparable between early and advanced Parkinson's disease patients.
Pediatrics: The pharmacokinetics of pramipexole in the pediatric population has not been evaluated.
Geriatrics: Renal function declines with age. Since pramipexole clearance is correlated with renal function, the drug's total oral clearance was approximately 25% to 30% lower in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). The decline in clearance resulted in an increase in elimination half-life from approximately 8.5 hours in young volunteers (mean age 30 years) to 12 hours in elderly volunteers (mean age 70 years).
Gender: Pramipexole renal clearance is about 30% lower in women than in men, most of this difference can be accounted for by differences in body weight. The reduced clearance resulted in a 16 to 42% increase in AUC and a 2 to 10% increase in Cmax. The differences remained constant over the age range of 20 to 80 years. The difference in pramipexole half-life between males and females was less than 10%.
Race: The potential influence of race on pramipexole pharmacokinetics has not been evaluated.
Hepatic Insufficiency: The potential influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated; however, it is considered to be small. Since approximately 90% of the recovered 14C-labelled dose was excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.
Renal Insufficiency: The clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. A lower starting and maintenance dose is recommended in patients with renal impairment (see Dosage & Administration). In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. As pramipexole clearance is reduced even more in dialysis patients (N = 7) than in patients with severe renal impairment, the administration of pramipexole to patients with end stage renal disease is not recommended.
Anticholinergics: As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole are rather unlikely.
Antiparkinsonian drugs: In volunteers (N = 11), selegiline did not influence the pharmacokinetics of pramipexole. Population pharmacokinetic analysis suggests that amantadine may alter the oral clearance of pramipexole (N = 54). Levodopa/carbidopa did not influence the pharmacokinetics of pramipexole in volunteers (N = 10). Pramipexole did not alter the extent of absorption (AUC) or elimination of levodopa/carbidopa, although it increased levodopa Cmax by about 40%, and decreased Tmax from 2.5 to 0.5 hours. While increasing the dose of pramipexole dihydrochloride monohydrate in Parkinson's disease patients it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication is kept constant.
Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, increased pramipexole dihydrochloride monohydrate AUC by 50% and increased its half-life by 40% in volunteers (N = 12).
Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transport system, did not influence the pharmacokinetics of pramipexole dihydrochloride monohydrate in volunteers (N = 12).
Other drugs eliminated via renal secretion: Concomitant therapy with drugs secreted by the renal cationic transport system (e.g., amantadine, cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine), may decrease the oral clearance of APO-PRAMIPEXOLE and thus, may necessitate an adjustment in the dosage of APO-PRAMIPEXOLE. In case of concomitant treatment with these kinds of drugs (incl. amantadine) attention should be paid to signs of dopamine overstimulation, such as dyskinesias, agitation or hallucinations. In such cases a dose reduction is necessary. Concomitant therapy with drugs secreted by the renal anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide and chlorpropamide) are not likely to have any effect on the oral clearance of APO-PRAMIPEXOLE.
CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect APO-PRAMIPEXOLE elimination because pramipexole dihydrochloride monohydrate is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole dihydrochloride monohydrate does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, suggesting that pramipexole dihydrochloride will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid).
Dopamine antagonists: Since APO-PRAMIPEXOLE is a dopamine agonist, dopamine antagonists such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide may diminish the effectiveness of APO-PRAMIPEXOLE and should ordinarily not be administered concurrently.
Miscellaneous: Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with APO-PRAMIPEXOLE and when taking concomitant medication that increase plasma levels of pramipexole (e.g. cimetidine).
Toxicology: Acute toxicity:
The acute toxicity of pramipexole was studied in mice, rats, and dogs following oral and intravenous single doses. Administration of the pramipexole dose was followed by a 14-day observation period. Comparative lethality data are presented in the following table. (See Table 5.)
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Clinical symptoms following acute dosing in rats and mice included ataxia, convulsions, dyspnea, tachypnea, reduced motility, increased nervousness or hyperactivity. In dogs, oral and intravenous dosing resulted in frequent and prolonged vomiting.
The effects of long-term administration of pramipexole were evaluated in the rat, minipig, and monkey. Definitive studies have been summarized in Table 6. (See Table 6.)
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Mouse: Pramipexole was administered to Chbb: NMRI mice, 50/sex/group for two years at drug-in-diet doses of 0.3, 2, or 10 mg/kg/day. Two control groups received only powdered feed.
Plasma concentrations of pramipexole rose with increasing doses in an almost linear, or more steeply than linear, manner. On average, females had higher plasma levels than males.
No distinct, drug-related clinical effects were noted at 0.3 mg/kg/day, although this group had a tendency to consume less feed than the control groups. In the 2 and 10 mg/kg groups, lower body weights and a tendency for increased food and water consumption were noted. Increased spontaneous activity was noted in females at 2 mg/kg, and in both sexes at 10 mg/kg.
The following non-neoplastic changes were noted: increased incidence of fibro-osseous proliferative lesions in the femurs of treated females, decreased incidence of tubular atrophy in the testes of treated males. Increased haemopoietic activity was noted in the femoral bone marrow of females at 2 and 10 mg/kg.
With the exception of a nonsignificant decrease in hepatocellular adenomas in males in all treated groups, and statistically significant decreases in adrenal cortical adenomas in males at 10 mg/kg and malignant lymphomas in females at 2 and 10 mg/kg, the incidence of neoplastic changes was similar in treated and control animals.
Therefore, under the conditions of the study, no carcinogenic effect of the test compound could be established.
Rat: Pramipexole was administered to Chbb: THOM rats, 50/sex/group, for two years by drug-in-diet, at doses of 0.3, 2, or 8 mg/kg/day. Two control groups received only vehicle (powdered feed).
Plasma concentrations of pramipexole increased almost proportionally with increasing dose.
The incidence of mortality (unscheduled deaths and sacrifices) was similar in the treated and two control groups.
Increased spontaneous activity was observed in females at 8 mg/kg. A dose-related, slight to marked decrease in body weight gain was observed in all treated groups, particularly in females. Food consumption was slightly decreased in males from all treated groups, but was moderately increased in females at 2 and 8 mg/kg.
An increased incidence of the following non-neoplastic changes was noted: Leydig cell hyperplasia in males at 2 and 8 mg/kg; large, prominent corpora lutea in females at 8 mg/kg; chronic suppurative inflammatory lesions and haemorrhages in the uteri of females at 2 and 8 mg/kg; change in normal glandular pattern in the mammary gland parenchyma in females at 2 and 8 mg/kg; retinal degeneration in males and females at 2 and 8 mg/kg; minimal to slight diffuse hepatocellular fatty change in females at 2 and 8 mg/kg. A treatment-related decrease in the incidence of focal/multifocal medullary hyperplasia of the adrenal gland and cystic changes of the mammary gland were observed in females at 2 and 8 mg/kg.
A statistically significant increase in the incidence of Leydig cell adenomas was noted in males at 2 and 8 mg/kg. The following neoplasms were significantly decreased in rats at 2 and 8 mg/kg: mammary gland neoplasia in females, pituitary adenomas in both sexes, total number of primary neoplasms in females. Additionally, a decrease in the incidence of benign adrenal medullary neoplasms was observed in female rats at 0.3, 2, and 8 mg/kg/day.
Although retinal degeneration was observed in albino rats given 2 or 8 mg/kg/day, no retinal degeneration was noted at the low dose of 0.3 mg/kg/day. No retinal degeneration was seen in the two-year carcinogenicity study in mice at doses of 0.3, 2, or 10 mg/kg/day, in the one-year drug-in-diet rat study at doses of 0.5, 3, or 15 mg/kg/day, or in any other study in any species. In investigative studies, the treatment of albino rats with pramipexole clearly reduced the rate of disk shedding from photoreceptor cells, suggesting a perturbation of the steady-state necessary for maintenance of membrane integrity. This change was associated with increased sensitivity of the retina of albino rats to the damaging effects of light. In contrast, pigmented rats exposed to the same levels of pramipexole and even higher intensities of light had absolutely no degeneration of any portion of the retina.
In conclusion, under the conditions of this study, apart from slight decreases in body weight gain, no drug-related adverse effects, including hyperplastic/neoplastic lesions, were recorded at the lowest dose of 0.3 mg/kg/day. Therefore, the NOAEL was 0.3 mg/kg/day.
Mutagenicity studies: In a standard battery of in vitro and in vivo studies, pramipexole was found to be non-mutagenic and non-clastogenic.
Reproduction and Teratology:
Reproduction and general fertility: Groups of 24 male and 24 female Chbb: THOM rats were administered pramipexole in distilled water at doses of 0 (vehicle), 0.1, 0.5, or 2.5 mg/kg/day. Males were treated for 10 weeks prior to mating and throughout copulation; females were treated 2 weeks prior to mating during the mating period, and during the gestation and lactation periods.
No treatment-related effects were observed in adults in the 0.1 mg/kg/day group. Additionally, no treatment-related effects were observed in the offspring in this group.
Rats in the 0.5 mg/kg/day group (particularly females) showed clinical signs of CNS excitation (agitation and constant running lasting 6 to 7 hours). Food consumption, body weight, mating, and pregnancy parameters were not affected. A dose of 2.5 mg/kg/day caused moderate to severe agitation in adults, associated with temporary retardation of body weight and food consumption. Treatment-related irregularities in the estrous cycle and/or the severe agitation observed over the treatment period in the 2.5 mg/kg/day group may have been connected to the longer mating performance and the high percentage (61%) of females which failed to become pregnant in this group. The high percentage of non-pregnant females may also have been due to an inhibition of prolactin secretion by pramipexole since the maintenance of functional corpora lutea and successful implantation are dependent upon prolactin.
In the 0.5 mg/kg group, litter parameters of the Caesarean-section group were unchanged, but in the spontaneous delivery group pup body weight development was delayed. While it was not possible to evaluate litter parameters for the Caesarean-section group at 2.5 mg/kg (only one dam produced living progeny), the few pups from the 2.5 mg/kg spontaneous delivery group weighed less at birth and had an even smaller weight increase during the rearing than the 0.5 mg/kg group. In both groups, a slight delay in opening of the eyes was observed. Effects observed in pups in the 0.5 and 2.5 mg/kg/day groups were believed to result from maternal toxicity.
Under the conditions of this study, pramipexole produced maternal toxicity at doses of 0.5 mg/kg/day and greater. There was no indication of impaired male fertility. No teratogenic effects were seen. Apart from retarded weight gain and a retardation in the maturation parameter 'opening of the eyes' in the mid- and high-dose pups, the fertility test on the F1 generation showed no impairments. The maximum no-effect dose was 0.1 mg/kg/day.
Due to the lower conception rate in rats administered 2.5 mg/kg/day in the previously mentioned study; a second Segment I study was conducted. Pramipexole in distilled water was administered to rats at oral doses of 0 (vehicle) or 2.5 mg/kg/day to groups of 24 males at least 9 weeks before mating and during the mating period, and to groups of 24 females at least 2 weeks before mating and during the mating and gestation period as follows: Group 0 (vehicle control): males and females treated with distilled water; Group 1 (positive control): males and females treated with 2.5 mg/kg/day pramipexole; Group 2: males treated with 2.5 mg/kg/day pramipexole, females with distilled water; and Group 3: males treated with distilled water, females with 2.5 mg/kg/day of pramipexole.
Slight toxic effects were noted in treated animals (temporary reduction in body weight gain in males, body weight loss in females at study initiation accompanied by decreased feed intake followed by overcompensation). Both sexes reacted with moderate to severe agitation, which lasted 8 hours or more after administration.
Although treated and untreated couples mated as expected, the number and percentage of pregnant dams were significantly reduced in treated females regardless of whether or not the male partners had been treated. The estrous cycle of about 50% of treated females was prolonged. Light microscopical examination of ovaries from treatment groups 1 and 3 showed an increase in the number of corpora lutea by 75% and 62.5%, respectively. A slight decrease in number of ovarian follicles (showing all stages of folliculogenesis) was noted. A significant (p<0.001) decrease in prolactin levels in all treated males and in eight out of 10 treated females after the administration of 2.5 mg/kg per day was found. The prolonged estrous cycle, the inhibition of nidation, and the increased number of corpora lutea were regarded as a consequence of the marked reduction in prolactin levels. No evidence of embryo/fetotoxicity or teratogenicity was noted.
Plasma levels taken two hours after the last administration showed concentrations of pramipexole in the range of 93 to 236 ng/mL (females) and 134 ng/mL (males).
In conclusion, under the conditions of this study, the effect of lowered fertility in females was clearly shown to be a consequence of female rather than male treatment with pramipexole.
Teratogenicity: Groups of 36 female Chbb: THOM rats were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 0.5 or 1.5 mg/kg/day from days 7 to 16 of gestation.
Treatment-related CNS stimulation and a dose-dependent decrease in food intake was observed at 0.5 and 1.5 mg/kg/day. In the majority of high-dose (1.5 mg/kg/day) dams (approximately 78%), there were early resorptions of the entire litter. All surviving pups developed normally. The embryotoxicity (resorptions) seen in the high-dose group were associated with predominantly pharmacodynamically-induced CNS effects (agitation and increased spontaneous activity) in the dams. Although a dose of 0.5 mg/kg/day also produced CNS symptoms in the dams, it did not cause embryotoxic or fetotoxic effects in the offspring. No teratogenicity was observed up to and including the high dose of 1.5 mg/kg/day.
Under the conditions of this study, the NOAEL for maternal toxicity was 0.1 mg/kg/day, the NOAEL for embryo-fetal toxicity was 0.5 mg/kg/day, and the teratogenic NOAEL was 1.5 mg/kg/day.
Groups of 18 mated female Chbb: HM rabbits were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 1, or 10 mg/kg/day from day 6 to 18 of gestation. Fetuses were delivered by C-section on day 29.
Reversible excitation and restlessness after 3 to 4 days of treatment were observed at 10 mg/kg/day. Maternal toxicity was observed at 10 mg/kg per day (temporary dose-dependent weight loss or retarded weight gains, one intercurrent death after the third dose of 10 mg/kg probably due to shock-like cardiovascular collapse). Embryo/fetotoxicity or teratogenicity was not observed.
Under the conditions of this study, the NOAEL for maternal toxicity was 1 mg/kg/day and the embryo/fetotoxic and teratogenic NOAEL was 10 mg/kg/day.
Peri-postnatal toxicity: Groups of 24 pregnant Chbb: THOM rats were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 0.5, or 1.5 mg/kg/day from day 16 of gestation through day 21 of parturition.
The low dose of 0.1 mg/kg/day was well tolerated. Doses of 0.5 and 1.5 mg/kg/day caused considerable agitation and hyperactivity, particularly in lactating rats. Slight maternal toxicity (decreased food consumption) was observed in the 1.5 mg/kg/day dose group. No effects on the duration of pregnancy were observed at any dose.
In the 3-week rearing phase, during which dams in the 0.5 and 1.5 mg/kg/day groups showed signs of great agitation, the body weight increase of pups in those groups was less than that of the controls, perhaps due to insufficient opportunity to suckle. There was no increase in pup mortality, and no fetotoxicity was observed.
The physiological behaviour of the pups during the rearing period and the marginal differences between a few behavioural and developmental parameters in the 0.5 and 1.5 mg/kg/day dose groups, show that despite the great state of excitement in the dams, the vast majority of pups developed normally. Only body weight, which was less (to a dose-dependent degree) than that of control animals, had not recuperated by the time the offspring reached sexual maturity. While the F1 females were lighter, there was no biologically relevant effect on mating and gestational parameters.
Under the conditions of this study the NOEL for maternal toxicity and fetal development was 0.1 mg/kg/day.
Local tolerance: Pramipexole at a single dose of 100 mg or repeated doses of 0.05% to 0.5% for three days was not irritating to rabbit eyes. Doses of 0.00625% to 0.5% administered to rabbits for four weeks caused mild to moderate increased conjunctival secretion and isolated mild reddening. There was no concentration-effect relationship and findings were fully reversible. No treatment-related histopathological changes of dose-related systemic reactions were observed.
Pramipexole at a single dose of 0.5 g applied occlusively and semi-occlusively to the intact skin of male rabbits was not irritating. Repeated doses of 0.1 g applied to the skin of male rabbits under occlusion for 24-hour periods for five consecutive days was not irritating to intact skin but caused mild, reversible irritation to abraded skin.
A 0.1% injectable solution of pramipexole injected paravenously into the jugular vein was conditionally tolerated by rats. Single intravenous injections of pramipexole 0.1% solution into the marginal vein of the ear were tolerated by rabbits. Single intraarterial injections of pramipexole into the central artery of the ear were tolerated by rabbits.
A skin sensitization (Maximization Test) study in guinea pigs with pramipexole base resulted in a mild sensitizing potential based on sensitization rates of 25% (first challenge) and 20% (rechallenge). A skin sensitization (Modification of Beuhler Test) study in guinea pigs with pramipexole base as a CPA-patch formulation did not reveal any sensitizing potential.
A 0.1% pramipexole solution for injection added to freshly drawn citrated human blood had no haemolytic effect.
RETINOPATHY IN ALBINO RATS: See Precautions.