Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson's disease

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. 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. 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 15x 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. This study identified apomorphine use and levodopa dosages between 500 and 1000 mg as non-genetic and the 15x 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.