The effect of pramipexole extended release on the levodopa equivalent daily dose in Lebanese Parkinson diseased patients

Lama Faddoul jodi-mack@hotmail.com

Lebanese International University, Lebanon

Bahia Chahine bahia.chahine@liu.edu.lb

Lebanese International University, Lebanon

Sahar Haydar jodi-mack@hotmail.com

Lebanese International University, Lebanon

Sahar Abourida sahar.haydar@liu.edu.lb

Lebanese International University, Lebanon

Souheil Hallit souheilhallit@hotmail.com

Holy Spirit University of Kaslik, Lebanon

Etwal Bou Raad etwal.bouraad@liu.edu.lb

Lebanese International University, Lebanon

Parkinson’s disease (PD) is a chronic, irreversible neurodegenerative disorder, induced by massive dopamine loss and it is recognized by motor and non-motor symptoms. 1 PD available treatment is symptomatic with no proven efficacy to slow or reverse the disease progression. 2 The estimated prevalence of PD, in 2004, among Lebanese population is 0.36%. 3 Lebanese PD annual mortality rate is 0.2 per 100,000 people due to disease progression, and or medication related adverse events. 4

Levodopa and dopamine agonists are considered essential options in early and advanced PD treatment guidelines. 5, 6 Among all multiple antiparkinsonian therapies that are now available, the standardized levodopa equivalent dose (LED) is set to provide a useful tool to compare dose intensities of different medications in clinical trials. It is the dose that produces the same antiparkinsonian effect as 100 mg of immediate release levodopa. 7

Pramipexole is a non-ergot dopamine agonist approved for the treatment of early PD. It is indicated either to delay the use of Levodopa, or as an add-on to Levodopa for patients with advanced PD experiencing Levodopa induced dyskinesia, and off periods. 8, 9 Various in vivo and in vitro studies have showed that pramipexole has promising neuroprotective effects 10, 11, while clinical human studies did not. 12 Pramipexole was expected to hold a significant potential in PD treatment since it is associated with lower motor complication risks, and higher reduction in Unified Parkinson Disease Rating Score (UPDRS). 13, 14 UPRDS is used to follow the longitudinal course of PD and is divided into 6 sections, where section III includes a clinician-scored motor evaluation that can be used as a measure of Pramipexole efficacy on motor functioning. 14

Pramipexole is available in two formulations; an immediate release (IR), and a once-daily extended release (ER) formula. The ER was verified to be bioequivalent to the IR formulation. 15 Furthermore the ER formulation was associated with better patient adherence to therapy, constant plasma concentration drug level, improved clinical response, and safety profile. 15, 16 Several studies investigated the effect of pramipexole addition to PD patients’ regimens on levodopa daily dose. 17, 18 According to our knowledge there are no studies comparing the addition of pramipexole ER into the same patient’s regimen before and after Pramipexole ER introduction.

Moreover, there is not enough information regarding the PD treatment, complication, and prognosis among the Lebanese population. Therefore, this study was undertaken to quantify the potential benefit of pramipexole ER on total LED and UPDRS-III score. The primary objective was to compare the total LED before and after introduction of pramipexole ER into the regimen for each individual PD patient.

Out of 176 patients 54.5% were males and 45.5% were females. The mean age of the patients ranged from 27-88 was 60 years old (SD=8.1), 56.8% were less than or equal to 65 years. Regarding the disease duration, the mean was 2.5 years (SD=2.4). The mean baseline LED was 451.5 mg and the mean baseline UPDRS-III score was 18.99 points (SD=12.7) with 86.3% of patients less or equal to 30. ( Table 2)

Table 2
Baseline patient characteristics

Pramipexole ER showed a significant difference on the mean changes in LED and UPDRS-III score. After 13 weeks of initiating Pramipexole ER, the mean decrease in LED was for all patients -49.42 mg (p<0.001, 95%CI [35.28-63.55]) and the mean decrease in UPDRS-III score for all patients was -6 points (p<0.001).

Subgroup analyses

In patients aged 65 years and below, the change in mean total LED from baseline (350.80 mg) was a decrease of 63.19 mg with a p<0.001, 95%CI [42.07-84.31]. In patients aged more than 65 years, the change in mean total LED from baseline (559.25 mg) was a decrease of 34.67 mg with a p<0.001 CI 95% [16.16-53.18].

In patients having an UPDRS-III score of less than or equal to 33, the change in mean total LED from baseline (436.73 mg) was a decrease of 56.76 mg (p<0.001; 95%CI [41.32-72.20]). However, in patients having an UPDRS-III score of more than 33 the change in mean total LED from baseline (545.06 mg) was a decrease of 2.96 mg with a p value<0.844 95%CI [27.32-33.15] ( Figure 1).

Figure 1
Change in levodopa equivalent dose.

According to our knowledge there are no studies evaluating the change in total LED in the same patient before and after introduction of pramipexole ER in Lebanon. In this study, it was observed that the total LED can be significantly reduced. Either due to symptom’s improvement or patient’s adherence using the Pramipexole ER, PD medication’s dose or agents were reduced or removed from the regimen. This result was consistent with other related studies. 23, 24

Our study showed an 8 points decrease in UPDRS-III score at 13 weeks with pramipexole ER, greater than the suggested cutoff point for efficacy. A similar study demonstrated a decrease of 6.1 points in pramipexole ER treated group. 25

When taking age into consideration, pramipexole ER use was associated with lower LED in both groups (≤65 and >65 years), this indicates that pramipexole ER is an effective option in elderly patients. This correlates well with previous studies done to evaluate the efficacy of pramipexole in older patients. 26- 29 A research that was conducted Pellicano et al. showed that pramipexole ER has levodopa sparing effect in patients older than 65 years 16. This theory is aligned with the standards of care in levodopa therapy among older adults with functional impairments due to the potential of worsening of the quality of life as well as greater risk of psychiatric side effects with dopamine agonists versus levodopa. However, in terms of doses, pramipexole ER decrease LED in older patients therefore further studies are required to proven the effect of dose reduction to be either beneficial or clinically insignificant and unnecessary.

With respect to the UPDRS-III score pramipexole ER was significantly correlated with lower LED total doses in patients with mild motor symptoms.

(UPDRS-III ≤33). In contrast, pramipexole ER levodopa sparing effect in patients having moderate to severe motor symptoms (UPDRS-III >33) was not significantly different. This result correlates well with other studies showing that the use of pramipexole ER was associated with lower LED in patients having mild-moderate PD 30, 31 and not with severe PD, which can be explained by the need of combination therapies and higher doses to control advanced PD symptoms.

Although PD is a progressive degenerative disorder, pramipexole ER showed its ability to spare or delay the use of high levodopa doses and the absolute dependency to Levodopa, thus sparing the patient from complications that may arise from levodopa multiple daily dosing.

The total LED is significantly lowered when pramipexole ER is introduced to the same patient. The dose reduction is mostly prominent in patients aged less than 65 years with an UPDRS score less than 33. Furthermore, patients aged more than 65 years can also benefit from the LED reduction. This study opens new horizons on the potential role of health care professionals in maintaining the patient on the lowest effective levodopa equivalent daily dose and optimize the treatment therapy, thus decreasing the side effects that might arise from overdosing of antiparkinsonian drugs.