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

Abstract

Objectives Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration‐dependent neuroprotective effects in animal models of Parkinson’s disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression. Methods Plasma samples from nearly all study participants randomized to immediate‐release isradipine 5‐mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration‐time curve. Isradipine exposure parameters were tested for correlations with 36‐month changes in disease severity clinical assessment scores, and time‐to‐event analyses for initiation of antiparkinson therapy. Results Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy‐adjusted Unified Parkinson’s Disease Rating Scale parts I–III score over 36 months (Spearman rank correlation coefficient, rs: 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (rs: 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78–0.98, P = 0.02). Interpretation In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation. Trial Registration http://ClinicalTrials.gov NCT02168842.

Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives

“…Thus, the results of the clinical trial did not support the hypothesis that isradipine, at this dosage, can slow the progression of PD [143]. One possible explanation for this result is that the bioavailability of isradipine at the used dosage was not sufficient to target the Ca V 1.3 channels in neurons, but a direct empiric measure of effective local drug engagement is not feasible [143,144]. This explanation has been further supported by modeling the pharmacokinetics of isradipine based on the trial data, indicating that the critical threshold for therapeutic efficacy might have been reached only transiently and for a short time [144].…”

“…One possible explanation for this result is that the bioavailability of isradipine at the used dosage was not sufficient to target the Ca V 1.3 channels in neurons, but a direct empiric measure of effective local drug engagement is not feasible [143,144]. This explanation has been further supported by modeling the pharmacokinetics of isradipine based on the trial data, indicating that the critical threshold for therapeutic efficacy might have been reached only transiently and for a short time [144]. The administration of higher doses is discouraged because of the secondary cardiovascular effects that isradipine may induce.…”

Post-Translational Modification of Cav1.2 and its Role in Neurodegenerative Diseases

“…In humans, the ongoing phase III clinical study STEADY-PD is investigating the potential of the LTCC blocker isradipine for treatment of PD. Although the study showed that long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD, it did modestly decrease cumulative levodopa equivalent dose and the time needed for antiparkinsonian treatment (McFarthing and Simuni, 2019;Parkinson Study Group STEADY-PD III Investigators, 2020;Venuto et al, 2021). According to epidemiological studies (Becker et al, 2008;Ritz et al, 2010;Pasternak et al, 2012;Lee et al, 2014) and meta-analyses (Gudala et al, 2015;Lang et al, 2015;Mullapudi et al, 2016), patients treated with DHPs have a reduced risk of PD.…”

Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2021 Update

“…Another more recent example is the calcium channel blocker isradipine. The phase 3 STEADY-PD clinical trial results indicated that this treatment had no impact on the progression of PD in newly diagnosed individuals [20], but recent post-hoc analysis of the phase 3 clinical trial data has provided some evidence to support a re-examination of this agent [21]. Accordingly, a similar reanalysis is now being conducted on the earlier Phase II clinical data.…”