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: ClinicalTrials.gov NCT02168842.