Isradipine plasma pharmacokinetics and exposure–response in early Parkinson’s

[Farooqji]

The findings suggest that "clinically attainable brain exposure to isradipine may slow early-stage Parkinsons progression"

ncbi.nlm.nih.gov/pmc/articl...

[Bolt_Upright]

Thanks for sharing Farooqji. I read through it. Not too positive but maybe a piece of the puzzle.

The phase 3 STEADY‐PD III clinical trial provided definite evidence that treatment with 5‐mg twice‐daily IR isradipine in early PD did not significantly alter progression of UPDRS scores over 36 months compared with placebo. While disappointing, the trial allowed us to investigate the relationship between plasma exposure to a DHP Ca2+ channel inhibitor with PD progression outcomes. 10 , 12 , 13 , 14 Such analysis is specifically relevant as the dose of isradipine was selected based on the maximal tolerable dose observed in the preceding phase 2 study, which was primarily powered to assess tolerability and not disease‐modifying efficacy. 15 Thus, it is plausible that negative results might be related to insufficient target engagement. 16 While there is no way to validate target engagement of Cav1 (L‐type) channels, preclinical data suggested that with sustained systemic drug delivery, there was a threshold exposure necessary to achieve protection of SN dopaminergic neurons. 10 The pharmacokinetic modeling conducted in this study suggests that although plasma isradipine concentrations varied considerably between individuals, 17 , 18 , 19 that threshold may not have been achieved or was exceeded for only a relatively short period of the dosing interval.

In conclusion, isradipine plasma concentrations measured from STEADY‐PD III participants were not correlated with most changes in PD severity, function, disability, and quality of life. However, higher isradipine exposures were modestly but significantly associated with a delay in the need for symptomatic therapy and a lower cumulative LED over 36 months. While these results raise the possibility that the study failed because of insufficient drug exposures, dose‐limiting side effects deterred increasing isradipine dose with the IR formulation. Thus, more targeted and sustained delivery of L‐type calcium channel inhibitors 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.

[racerCP in reply to Bolt_Upright]

I have been taking 10mg of Isradipine for the last 3 or 4 years. No side effects; well tolerated but don't know whether it slowed progression. I am 8 year post-diagnosis and starting to feel some progression in movement but still hanging in there.

[Bolt_Upright in reply to racerCP]

Thanks for sharing racerCP. Keep hanging in there. Are you taking any supplements?