Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson's disease.
OBJECTIVE
To identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson’s disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis.


METHODS
Patients included were first-time users of the non-ergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180 days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment.


RESULTS
The study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85–21.2]. Daily levodopa dosages between 500 and 1000 mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08–4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07–0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship.


CONCLUSIONS
This study identified apomorphine use and levodopa dosages between 500 and 1000 mg as non-genetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings.
Arbouw
Maurits E L
ME
Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
Movig
Kris L L
KL
Egberts
Toine C G
TC
Poels
Petra J E
PJ
van Vugt
Jeroen P P
JP
Wessels
Judith A M
JA
van der Straaten
R J H M
RJ
Neef
Cees
C
Guchelaar
Henk-Jan
HJ
D000368:Aged; D000483:Alleles; D052160:Benzothiazoles / Q000009:adverse effects / Q000627:therapeutic use; D015331:Cohort Studies; D000075202:Contraindications; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D000077487:Pramipexole; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics
D052160:Benzothiazoles; D018491:Dopamine Agonists; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole; D000077487:Pramipexole