A re-examination of blood samples from people with early Parkinson’s disease in a Phase 3 trial — in which Dynacirc, a blood pressure medication, failed to slow disease progression — found that those with higher blood levels of Dynacirc were slower to start an antiparkinson therapy and needed lower doses once they did begin treatment.
These findings suggest that the trial’s failure may have been due to insufficient therapy exposure among some participants, its scientists noted.
The analysis, “Isradipine plasma pharmacokinetics and exposure-response in early Parkinson’s disease,” was published in the Annals of Clinical and Translational Neurology.
Dynacirc (isradipine) is a calcium channel blocker approved to treat hypertension (high blood pressure) by relaxing blood vessels, which helps to lower blood pressure.
Large population studies suggest that people being treated with calcium channel blockers are at a lesser risk of Parkinson’s disease, and Dynacirc has demonstrated neuroprotective effects in Parkinson’s animal models.
The Phase 3 Steady-PD3 study (NCT02168842) evaluated if Dynacirc (5 mg capsules, twice daily) might slow Parkinson’s disease progression in 336 recently diagnosed patients relative to a placebo. Results, recorded after 36 months (three years) of treatment failed to show significant efficacy beyond placebo. Still, it did demonstrate a small non-significant benefit for long-term Dynacirc use.
Furthermore, an analysis of blood samples collected from study participants found a high degree of variability in the levels of circulating Dynacirc among individuals, suggesting some may not have been exposed to a high enough dose to show effects.
Its 10 mg total daily dose was selected in an earlier Phase 2 trial, in which a higher, 20 mg daily dose was poorly tolerated by patients.
Now, researchers at the University of Rochester re-examined blood samples from trial participants to test for potential relationships between blood levels of Dynacirc and long-term efficacy and safety outcomes. For this, pharmacokinetic analyses were conducted, which essentially look at how a medicine is absorbed into the bloodstream and cleared from the body by metabolism and excretion.
A parameter, called Bayesian estimates of apparent oral clearance, or CL/F, was used to determine a patient’s overall elimination of Dynacirc from the body. Based on blood tests, patients were divided into fast, middle, and slow elimination groups. An exposure parameter, called AUC24, was also calculated to estimate Dynacirc exposure levels, and allowed researchers to divide patients into low, middle, and high exposure groups.
Among the 166 patients with an estimated Dynacirc CL/F (mean age 62.3 years, 71% men), 162 had clinical outcome data before treatment (baseline) and at 36 months post-treatment.
No correlations were seen between CL/F or AUC24 and changes in motor and cognitive function, or patients’ ability to perform activities of daily living, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS). Similar results were found after adjusting for antiparkinsonian therapy.
A weak correlation was observed between UPDRS nonmotor effects on daily living (EDL) scores and AUC24: a worse score correlated with greater Dynacirc exposure. There was also a weak a correlation between UPDRS nonmotor EDL and CL/F among men, in which scores worsened as CL/F (elimination) decreased.
“The explanation for this correlation in a single measure is not clear and is of questionable clinical significance,” the researchers wrote.
Next, a modest statistically significant correlation between Dynacirc CL/F and cumulative levodopa equivalent dose (LED) — contribution by each antiparkinson medicine — was observed through the 36‐month visit, suggesting that patients who eliminated Dynacirc faster needed more Parkinson’s medications. This correlation was driven by the values obtained in men, but not among women.
A statistical model also revealed CL/F of Dynacirc was an independent predictor of cumulative LED over 36 months, with a LED increase of about 5 mg for every 10 liters per hour increase in Dynacirc’s elimination from the blood.
The time to starting antiparkinson therapy was evaluated in relation to Dynacirc exposure, with 166 samples collected from placebo group patients as a reference. People were divided into three groups depending on Dynacirc elimination (fast, middle, and slow) or exposure (low, middle, and high) parameters.
Compared to the placebo group, the risk of needing to start Parkinson’s treatment fell by 13% when testing for a trend among fast to middle to slow elimination or low to medium to high exposure.
Consistently, those with the highest Dynacirc exposure in their blood went for a greater time without a need for therapy compared to placebo. The results were similar after adjusting for age or sex.
Reasons for starting Parkinson’s treatment, which included non-tremor symptoms such as slow movements, rigidity, walking problems, and imbalance, were less commonly reported in the high exposure group (47%), compared to middle exposure (51%), low exposure (67%), as well as placebo (57%) groups.
There was a significant correlation between Dynacirc elimination parameters and antiparkinson therapy‐adjusted UPDRS non-tremor scores, which suggested that as Dynacirc elimination increased, non-tremor scores worsened. A similar trend was observed for exposure, but did not reach statistical significance.
Dizziness, a common side effect of Dynacirc, did not differ with exposure levels. No changes in blood pressure were found with different Dynacirc exposures.
“While these results raise the possibility that the study failed because of insufficient drug exposures, dose‐limiting side effects deterred increasing [Dynacirc] dose,” the researchers concluded. “Thus, more targeted and sustained delivery of [calcium channel blockers] to the brain would provide a better test of their disease-modifying potential.”
“Most importantly, better strategies for determining target engagement and biological efficacy need to be developed,” they added.
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