Dataset Information

Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

ABSTRACT:

Aims

Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety.

Methods

This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals.

Results

Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal.

Conclusion

Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.

SUBMITTER: Taubel J

PROVIDER: S-EPMC9292718 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling, and a rational therapeutic target for autoimmune diseases. This first-in-human phase I, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics (PK), target occupancy, and effects on QT interval of evobrutinib, a highly selective, oral inhibitor of BTK, in healthy subjects. This dose escalation trial consisted of two parts. Part 1 included 48 subjects in 6 ascending dose cohorts (25, 50, 100, 200, 350, and 500 mg) randomized to a single dose of evobrutinib or placebo. Part 2 included 36 subjects in 3 ascending dose cohorts (25, 75, and 200 mg/day) randomized to evobrutinib or placebo once daily for 14 days. Safety and tolerability, as well as PK and target occupancy (total and free BTK in peripheral blood mononuclear cells), were assessed following single and multiple dosing. PK parameters were determined by noncompartmental methods. QT interval was obtained from 12-lead electrocardiogram recordings and corrected for heart rate by Fridericia's method (QTcF). Treatment-emergent adverse events (TEAEs) were mostly mild, occurring in 25% of subjects after single dosing, and 48.1% after multiple dosing. There was no apparent dose relationship regarding frequency or type of TEAE among evobrutinib-treated subjects. Absorption was rapid (time to reach maximum plasma concentration (Tmax ) ~ 0.5 hour), half-life short (~ 2 hours), and PK dose-proportional, with no accumulation or time dependency on repeat dosing. BTK occupancy was dose-dependent, reaching maximum occupancy of > 90% within ~ 4 hours after single doses ? 200 mg; the effect was long-lasting (> 50% occupancy at 96 hours with ? 100 mg). After multiple dosing, full BTK occupancy was achieved with 25 mg, indicating slow turnover of BTK protein in vivo. Concentration-QTcF analyses did not show any impact of evobrutinib concentration on corrected QT (QTc). In summary, evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was associated with no prolongation of QT/QTc interval in healthy subjects. Evobrutinib is, therefore, suitable for investigation in autoimmune diseases.