Som Menakuru, Senior Clinical Research Physician at Quotient Sciences, recently contributed to an article published in the American College of Clinical Pharmacology® Clinical Pharmacology in Drug Development journal, "A Phase 1 Study to Evaluate Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Savolitinib in Healthy Male Volunteers."
This open-label, two-part, phase 1 clinical study used a radiolabeled micro-tracer approach to evaluate absolute bioavailability and a traditional approach to determine the ADME of savolitinib in healthy male adult volunteers.
Aberrant activation of MET (hepatocyte growth factor receptor) signaling is associated with tumorigenesis and in many cancers, such as that of the kidney, liver, stomach, lung, and breast, an aggressive phenotype with poor clinical outcomes. Rapid disease progression and shortened survival have been linked to MET dysregulation. MET dysregulation has also been linked to acquired resistance to targeted therapies, limiting their therapeutic efficacy and leading to treatment failure. Savolitinib is an oral MET tyrosine kinase inhibitor and is under global clinical development outside of China as a monotherapy or combination therapy in additional disease areas.
Previous pharmacokinetic (PK) assessments of savolitinib in patients with advanced solid tumors and drug–drug interaction (DDI) studies in healthy volunteers have shown that savolitinib is rapidly absorbed, with a relatively short time of maximum observed concentration (tmax) of approximately 2–4 hours. Apparent terminal half-life (t½) is also short (approximately 4–7 hours), resulting in no accumulation of savolitinib after once-daily or twice-daily dosing. Mean plasma exposure of a pharmacologically active metabolite (M2; N-desmethyl savolitinib, M2 is approximately 3–4-fold less potent than savolitinib) and a nonactive metabolite (M3; hydroxy savolitinib) are approximately 33% and 12% of the exposure of savolitinib, respectively, based on area under the plasma concentration–time curve (AUC) (from time 0 to infinity) after a single oral dose of savolitinib.
Savolitinib is an oral MET (hepatocyte growth factor receptor) tyrosine kinase inhibitor, with demonstrated preliminary efficacy in several cancer types. Previous pharmacokinetics assessments showed that savolitinib is rapidly absorbed but there are limited data on the absolute bioavailability and absorption, distribution, metabolism, and excretion (ADME) of savolitinib.