Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Bortezomib (B) in Patients (pts) with Relapsed Multiple Myeloma (MM): A Phase I/II Study in Japan.
Authors: Tobinai Kensei , Watanabe Takashi , Ogawa Yoshiaki , Ogura Michinori , Morishima Yasuo , Minami Hironobu , Itoh Kuniaki , Hotta Tomomitsu 
Published: April 2020

Abstract
The preceding US studies of B showed remarkable efficacy with acceptable toxicities in pretreated pts with MM; however, its PK profiles in pts with MM have not been fully elucidated. The study objectives were to characterize PK/PD profiles, dose-limiting toxicities (DLTs) and recommended dose for Japanese pts of B (phase I part), and investigate anti-tumor activity and safety (phase II part). B was given as IV bolus at 0.7, 1.0 and 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days for up to 6 cycles. 34 pts with relapsed MM were enrolled, and 33 of them were assessable for response. The plasma concentrations of B were assessed on days 1 and 11 in 16 pts at 0.7, 1.0 and 1.3 mg/m2/day (cycle1 of phase I part). 65% of pts were male and the median age was 60 (34–72). The median numbers of treatment cycles of B was 4 (1–6). DLT (in cycle 1) of grade 3 febrile neutropenia in 1 of 6 pts at 1.3 mg/m2 led to this dose level as the phase II dose. Grade 3 or greater adverse events (AEs) were rare; however, 15% of pts discontinued bortezomib due to AEs. Grade 3 or greater hematologic AEs included lymphopenia (56%), neutropenia (44%), anemia and thrombocytopenia (32%). One pt suffered from fatal pulmonary disorder, and the autopsy revealed diffuse alveolar damage. Pleural/pericardial effusion, bronchial wall thickening and lumen narrowing were also observed. Other non-hematologic AEs were mild. According to the modified EBMT criteria, objective responses were observed in 10 of 33 pts (30%; 95% CI, 16–49%), including 5 immunofixation-positive CRs (15%) and 5 PRs (15%). The plasma concentration-time profile of B was not dependent on the dose administered. A biexponential decline was observed after administration of the bolus dose, characterized by a rapid distribution phase and subsequent prolonged elimination phase. The elimination of unchanged drug from plasma on day 11 was slower than that on day 1. The volume of distribution (Vz) value was indicative of extensive distribution into tissues. At all dose levels, elimination half-life (t1/2) was prolonged and total clearance (CL) was decreased on day 11. Accordingly, estimated plasma concentration at the end of administration (C0) and area under the curve (AUC) were increased on day 11. AUC increased dose-dependently despite noticeable inter-patient variations, while C0 did not show apparent dose-dependency. These results, together with the tissue distribution data in animal studies, suggest that B is rapidly distributed into the extravascular tissues. There were no major differences in the mean observed maximum inhibition of the 20S proteasome activity inhibition rates (E20smax) in whole blood on days 1 and 11, and their times (t20smax) were taken from the effect versus time profiles. Importantly, no major differences in the relationship between plasma concentration of B and inhibition of the 20S proteasome were observed between Japanese pts and non-Japanese pts. This was evident by the comparable maximum effect (Emax) and plasma concentrations of B required to achieve 50% of Emax (EC50) calculated using the simple Emax model. In conclusion, B showed remarkable efficacy with acceptable toxicities in Japanese pts with relapsed MM. The unique PK/PD profiles of B revealed by this study warrant further investigations, including more relevant administration schedules.