A drug–drug interaction study of everolimus (an mTOR inhibitor) and JI-101, an orally active inhibitor of VEGF 2, PDGF, and EphB4 receptors, in patients with advanced urologic tumors.

Abstract

e15077 Background: The effects of JI-101 on the pharmacokinetics (PK) of everolimus and vice versa were investigated in an open-label single sequence cross over study. This was the first clinical study done with JI-101 and another agent. Methods: Four Caucasian men ( prostate cancer=3, renal cell carcinoma=1) were enrolled with a median age of 70 yrs (range 65-80). Each received single-agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8 and single-agent 200 mg of JI-101 on day 15. All patients had adequate organ function and ECOG performance status <2. Serial plasma samples were collected for PK evaluations on Days 1, 8, and 15 (pre dose and at 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after dosing each day). Plasma everolimus and JI-101 concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: No serious adverse events were observed. A single dose of JI-101 increased exposure (AUC0-inf in ng*hr/mL), of everolimus by approximately 22% in 3 patients However, in the 4th patient (aged 80 yrs) exposure increased by 3-fold with a concomitant 2-fold increase in half life (t ½ ) of everolimus. Examination of historic PK data of JI-101 suggested that age may be a factor to explain the interaction in this patient. No consistent trend was observed for the JI-101 exposure with everolimus (-41 to +38%). Conclusions: 1) Limited data suggests that dose reduction of JI-101 might be necessary when combining with everolimus. 2) A decrease in hepatic metabolism that occurs with age may have influenced the observed interaction. 3) A phase I combination study should be performed to further understand the PK and clinical safety of JI-101 with 10 mg everolimus. Change in PK parameters on coadministration of everolimus and JI-101. Change in PK parameters of everolimus Subject Age Everolimus AUC 0 to inf (ng.h/mL) Everolimus T ½ (h) 1 70 370 402 9 19.4 18 2 65 210 300 43 19.7 21.5 3 71 468 529 13 17.1 17.6 4 80 304 906 198 17.8 37.0 Change in PK parameters of JI-101 Subject Age JI-101 AUC 0 to inf (ng.h/mL) JI-101 T ½ (h) 1 70 4,462 6,109 37 8.4 22.2 2 65 4,785 2,847 -41 10.2 10.2 3 71 2,030 2,322 14 6.4 8.1 4 80 24,565 33,781 38 67.7 128.3