Pharmacology

Pramipexole is an amino-benzothiazole–type dopamine agonist.

It binds to presynaptic and postsynaptic dopamine D2 and D3 receptors, but does not have affinity for the dopamine D1 receptor site.

Pharmacodynamics. Pramipexole stimulates presynaptic and postsynaptic dopamine D2 receptors in a dose-dependent manner and reduces extracellular concentrations of dopamine by inhibiting dopamine synthesis and release. Pramipexole is highly specific to D3 and D2 receptors, with affinity to D3 being about 8 times higher than that of D2. Although not proven, the motor benefits of pramipexole in Parkinson disease are likely due to dopamine D2 stimulation, whereas its effects on mood and apathy may be related to its D3 agonist properties. Pramipexole has a relatively high affinity for a2 adrenoreceptors but has little effect on other neurotransmitter systems. In addition to an antiparkinsonian effect, it is considered to have a neuroprotective effect demonstrated by prevention of levodopa-induced toxicity in vitro. The possible mechanisms are as follows:

A review of various studies shows that neuroprotection requires treatment prior to neurologic insult and high concentrations of pramipexole are required

Pharmacokinetics. Pramipexole exhibits linear pharmacokinetics over the dose range of 0.125 to 1.5 mg administered every 8 hours in healthy volunteers. Plasma concentrations of pramipexole are proportional to dose. The plasma elimination half-life is approximately 7 to 9 hours, sufficiently long to make it a practical drug for oral administration in Parkinson disease patients with short-duration levodopa responses. Pramipexole is excreted by the renal organic transport system and renal clearance accounts for about 80% of the total clearance of an oral dose.

Therapeutic drug monitoring. A simple and validated ultra-high-pressure liquid chromatography–tandem mass spectrometry method was developed for the simultaneous determination of the dopaminergic agents pramipexole and ropinirole in the plasma of patients with Parkinson disease (28). This method was successfully applied to measure plasma concentrations of pramipexole and ropinirole in a series of patients with Parkinson disease on chronic treatment.

Formulations. An extended-release formulation of pramipexole is available for use as a once-daily oral treatment for Parkinson disease, and the effects are equal to that of 3-times-daily immediate release pramipexole. Potential benefits of prolonged release of pramipexole include improved compliance and a potential for better symptomatic control, particularly in patients with early disease who can be managed with monotherapy. Introduction of extended-release pramipexole in Taiwan resulted in higher levodopa equivalent dose per day in prescriptions with pramipexole than those who were prescribed immediate release pramipexole because of better compliance to the medication (08).

Near-infrared light-responsive pramipexole and hollow gold nanospheres-loaded biodegradable poly (D, L-lactide-co-glycolide) microspheres have been fabricated using solid-in-oil-in-water and water-in-oil-in-water emulsion-solvent evaporation techniques to achieve remotely triggerable modulated drug release (22).

Dexpramipexole, the (R)-(+) enantiomer of pramipexole, is a pharmacologically distinct entity regarding dopamine receptor affinity and is in clinical trials as a neuroprotective for the treatment of neurodegenerative diseases. Because dexpramipexole is excreted exclusively by the kidneys, it should not be used in patients with severe renal impairment (15).

Methods of delivery. An experimental study has investigated iontophoretic delivery of pramipexole and determined that therapeutic amounts of the drug could be delivered transdermally (18). A prolonged-release pramipexole transdermal patch is in development. Studies in rats have shown that the patch produces a significantly longer half-life and improved bioavailability compared to oral tablets (32). It has the potential to serve as an alternative to conventional oral tablets and improve patient compliance.

Pharmacogenetics. DRD3 Ser9Gly gene polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with Parkinson disease (25).

Clinical trials

Efficacy of this drug is indicated by studies shown in Table 1. Although clinical trials started in 1997, only those conducted within the last decade are listed in Table 1.

Table 1. Clinical Trials of Pramipexole in Parkinson Disease

Most of the early clinical trials were limited to a period of 31 weeks, but they showed that pramipexole is effective as monotherapy in early Parkinson disease and may delay the need for levodopa. Pramipexole is also effective in patients with advanced Parkinson disease as an adjunctive therapy to levodopa, particularly in those who have experienced undesirable motor effects due to levodopa therapy. Pramipexole reduces the motor fluctuations and enables reduction of levodopa dose. In patients with advanced disease and "on-off" phenomena, pramipexole also reduced the mean number of "off" hours per day from 6 to 4; the number of "off" hours did not change with placebo.

Presently available evidence indicates the following advantages of pramipexole:

Extended-release (ER) and immediate-release (IR) formulations of pramipexole have been compared in clinical trials, and the results are as follows (12):

A metaanalysis of randomized clinical trials shows that pramipexole is effective in improving the symptoms of patients with primary moderate-to-severe restless legs syndrome, although the quality of evidence is rather low (24). Further clinical trials should use objective measures for the evaluation of restless legs syndrome and closely observe any augmentation during treatment.

Indications

Pramipexole is approved for the treatment of early Parkinson disease as monotherapy and as an adjunct to levodopa in advanced stages of the disease. It is also approved for the treatment of restless legs syndrome.

Off-label uses

Contraindications

Patients with advanced Parkinson disease who have blood pressure problems should use pramipexole with care. Because elderly patients are likely to be on drugs that affect the nervous system, they are more at risk for developing hallucinations. Pramipexole is excreted through the kidneys and patients with kidney disease may require dosage adjustment.

Goals and duration of treatment

In addition to ameliorating the core symptoms of akinesia and rigidity in Parkinson disease, pramipexole improves tremor and depressive symptoms in routine clinical practice.

Long-term (mean of 8 years) analysis of patients with reported studies of shorter duration shows that efficacy of pramipexole decreases with time, with increase in dose, and with addition of other agents (23). There is some concern that long-term treatment with pramipexole may aggravate restless legs syndrome. The patient’s response and the need for further treatment should be evaluated after 3 months.

Dosing

For Parkinson disease, pramipexole is administered orally 3 times daily and the recommended starting dose is 0.375 mg per day for 1 week. The dose is increased gradually, but not more often than once in 5 to 7 days, until a maximum therapeutic effect is reached. The maximum dose is 4.5 mg per day given in 3 divided doses. The daily maintenance dose is 1.5 mg. It is recommended that levodopa dose be reduced during the pramipexole dose escalation period. If treatment is to be discontinued, pramipexole should be tapered off over a 1-week period.

A 3-times daily immediate-release formulation and a once-daily extended-release formulation of pramipexole are bioequivalent, and most patients can be switched overnight from 1 to the other without the need for dosage adjustment.

For restless legs syndrome, immediate-release tablets of pramipexole should be taken once a day, 2 to 3 hours before going to bed. The recommended starting dose is 0.088 mg of active drug, but this can be increased every 4 to 7 days to reduce symptoms further, to a maximum of 0.54 mg. The prolonged-release tablets are not suitable for restless legs syndrome.

Special considerations

Geriatrics. Elderly patients are more susceptible to the adverse effects of pramipexole-it should only be used when there are motor fluctuations with levodopa-carbidopa therapy. Use of pramipexole enables levodopa-carbidopa dose reduction, thus helping to overcome the “off” periods. Elderly patients with renal disease require dose adjustment. The half-life of the drug is 12 hours in elderly subjects. Compared with healthy elderly persons, patients with Parkinson disease have reduced drug clearance (about 30% lower), presumably because of decreased renal function.

Pregnancy. No information is available about the use of pramipexole in pregnancy. This is unlikely in patients with Parkinson disease but may coexist with off-label indications. Animal studies have shown that pramipexole could be teratogenic at high doses, but the evidence is insufficient. Nevertheless, use of pramipexole should be avoided during pregnancy.

As a dopaminergic agonist, pramipexole is contraindicated in lactating mothers because it suppresses lactation. Concentration in milk is much higher than in plasma, increasing the risk of transmission to the baby.

Anesthesia. There are no special interactions of anesthetics with drugs used for Parkinson disease. Pramipexole should be discontinued for at least 6 hours before anesthesia and can be resumed in the postanesthetic period after the patient has recovered from nausea. These are general precautions with dopamine agonists, as they tend to induce nausea and vomiting as side effects.

Interactions

Inhibitors of cytochrome P450 enzymes do not affect pramipexole elimination because it is not significantly metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4.

Because pramipexole is a dopamine agonist, dopamine antagonists such as neuroleptics (eg, phenothiazines) or metoclopramide may diminish its efficacy.

Cimetidine can increase the area under the curve of pramipexole by 50%. Coadministration with other drugs that are eliminated through the cationic transport system (eg, ranitidine, diltiazem, verapamil, and digoxin) can decrease the total clearance of an oral dose by 20%, and pramipexole can decrease their clearance. For a detailed list see Physicians’ Desk Reference.

Adverse effects

All patients enrolled in the advanced-disease trials for pramipexole were treated concurrently with levodopa, and some received amantadine, selegiline, and anticholinergics in various combinations. More than half (53%) of the patients treated had postural hypotension during pramipexole therapy, 47% had dyskinesia, 28% had extrapyramidal syndrome, 27% insomnia, 26% dizziness, and 17% hallucinations. Except for the hallucinations, all these events occurred in a substantial percentage of placebo recipients as well. Age appeared to increase the risk of hallucinations. Adverse events tended to be less frequent in patients with early disease. The most frequently reported events were nausea (28% of patients), dizziness (25%), drowsiness (22%), and insomnia (17%). Antecollis developed during treatment with pramipexole in a patient, and withdrawal of the drugs led to reversal of symptoms (19). For further details see Physicians’ Desk Reference.

Augmentation is the main complication of long-term treatment with pramipexole and is characterized by an overall increase in severity of restless legs syndrome symptoms. Other causes of augmentation such as iron deficiency and use of serotonergic drugs should be considered, and if appropriate measures do not improve the situation, pramipexole may be substituted by another dopaminergic drug. However, all dopaminergic drugs can cause augmentation of restless legs syndrome, and in this case, a nondopaminergic drug such as pregabalin may be used. Drug-induced dystonia and complex regional pain syndrome have been reported following introduction of pramipexole and increasing its dose to alleviate the symptoms of Parkinson disease in patients on chronic L-dopa treatment (29). This is due to overexpression of dopamine-3-like (D3) receptor, as the effect of a high dose of pramipexole and recovery follows discontinuation of the drug. Therefore, caution is required with observation of side effects when starting therapy with pramipexole and increasing the dose.

Patients on pramipexole therapy may have attacks of sleep without warning even while driving. The patients should be warned of this possibility and advised not to drive while on pramipexole therapy. Sleepiness with use of pramipexole may be treated with modafinil. Irresistible daytime sleepiness is a frequent problem in patients with Parkinson disease treated with dopamine agonists and is reported in almost half of patients treated with pramipexole in some series. It is managed by adjusting the amount of drug and dosage schedule or discontinuing the drug if the patient's lifestyle cannot adopt it.

Pramipexole, like other dopamine agonists, has been associated with compulsive behavior, and cases of pramipexole-induced pathological gambling that resolved following discontinuation of the drug have been reported (20). Punding, an impulse control disorder that is characterized by repetitive behavior, has been reported due to treatment with pramipexole, and it improved after discontinuation of the medication (21).

Peripheral edema is associated with pramipexole therapy and appears to be dose dependent but may also be idiosyncratic. No predisposing features have been identified, and edema responds poorly to diuretic therapy.