Objective: Present the pharmacokinetic/pharmacodynamic (PK/PD) relationship and contribution to anti-tremor efficacy for suvecaltamide and its active metabolites (JZZ05000034=M01, JZZ05000035=M02) in a harmaline-induced rat model of essential tremor (ET).

Background: T-type calcium (Ca_V3) channels regulate neuronal excitability and are thought to play a key role in mediating pathological tremor-producing oscillations in conditions like ET. Suvecaltamide (JZP385), a potent, selective T-type calcium channel modulator, reduced the functional impact of tremor in a phase 2 trial (NCT03101241) in ET.

Method: Tremor was quantified using piezoelectric signals in rats receiving harmaline (15 mg/kg, intraperitoneal) 1 hour before single oral doses of suvecaltamide or its metabolites (analytes). Plasma and brain analyte concentrations were measured in satellite experiments following harmaline and analyte administration.

Results: Suvecaltamide dose-dependently suppressed existing tremor when administered post-harmaline, with significant effects at ≥1 mg/kg. Tremor reduction was rapid and sustained during 4-hour recordings. All analytes were measurable in plasma and brain. While suvecaltamide concentrations peaked early and then decreased, active metabolite concentrations were more sustained over the experimental period. When dosed directly, both metabolites reduced tremor at plasma concentrations consistent with those achieved after suvecaltamide administration. Plasma suvecaltamide, M01, and M02 concentrations after 1 mg/kg administration were consistent with those achieved at steady state in humans at projected therapeutic doses. We characterized the PK/PD relationship of the suvecaltamide total active moiety in rats and utilized Ca_V3 potency and unbound plasma concentrations to translate this relationship to humans.

Conclusion: These results illustrate contributions to efficacy by active suvecaltamide metabolites in rats, which must be considered clinically given they are predicted to translate to human efficacy. These data support the continued clinical development of suvecaltamide for adults with moderate-to-severe ET (NCT05122650) or residual Parkinson’s disease tremor (NCT05642442).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/contribution-to-efficacy-by-active-metabolites-of-suvecaltamide-in-a-preclinical-rat-model-of-essential-tremor/