Dataset Information

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, r_s : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (r_s : 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

ClinicalTrials.gov NCT02168842.

SUBMITTER: Venuto CS

PROVIDER: S-EPMC7951102 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStudies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD).ObjectiveTo assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD.DesignMulticenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842).Setting57 Parkinson Study Group sites in North America.ParticipantsPatients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment.Intervention5 mg of immediate-release isradipine twice daily or placebo for 36 months.MeasurementsThe primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures.Results336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness.LimitationThe isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects.ConclusionLong-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD.Primary funding sourceNational Institute of Neurological Disorders and Stroke.

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