Parent and Metabolite Concentration-QT Modeling to Evaluate QT-Interval Prolongation at Savolitinib Therapeutic Doses.

Abstract

Savolitinib is an oral, potent, and highly selective MET-tyrosine kinase inhibitor under investigation in various tumor types. A thorough QT study evaluated effects on QT interval after a 600-mg single savolitinib dose in healthy subjects. We report exposure-response (E-R) modeling from this study to characterize the effects of savolitinib and its metabolites, M2 and M3, on QTc changes. In a novel application, in vitro potencies against hERG current provided mechanistic support to model the metabolites' effects. The hERG IC50 estimates (95% CI) were 25.8 (22.2-29.9) and 22.6 (14.7-34.6) μM for parent and M2, respectively. The E-R was described by both linear and Emax models, with exposure captured by an active moiety that consisted of savolitinib and M2 concentrations, weighted by the hERG IC50 ratio (1.14). The maximal increase in ΔΔQTcF and EC50 estimates (95% CI) was 18.5 (9.2-27.7) ms and 5709 (2889-8529) nM, respectively. Ignoring M2 contribution resulted in under prediction of QTcF prolongation in the hypothetical case of inhibited M2 clearance; at 300 mg Cmax, the mean (90% CI) of ∆∆QTcF was 9.0 (5.7-12.6) and 5.9 (2.9-8.9) ms using the hERG-informed and parent-only linear models, respectively. Simulations in normal setting confirmed modest QTcF prolongation with 600 mg, but not 300 mg. Using the linear model, the mean (90% CI) maximum ΔΔQTcF were 12.3 (8.6-16.2) and 5.5 (2.6-8.5) ms for 600 and 300 mg, respectively. Further clinical studies will monitor cardiac safety to assess the clinical significance of QT-interval prolongation with savolitinib.

• Authors: Stein Schalkwijk, Tarjinder Sahota, Remy B Verheijen, Alexander R Harmer, Ghada F Ahmed
• Journal: The AAPS journal (AAPS J) Vol. 23 Issue 3 Pg. 46 (03 17 2021) ISSN: 1550-7416 [Electronic] United States
• PMID: 33733338 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrazines
• Triazines
• 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine

Topics

• Double-Blind Method
• Electrocardiography
• Healthy Volunteers
• Heart Rate (drug effects)
• Humans
• Inhibitory Concentration 50
• Long QT Syndrome (chemically induced, diagnosis)
• Male
• Middle Aged
• Models, Biological
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Triazines (administration & dosage, adverse effects, pharmacokinetics)