Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Bortezomib (B) in Patients (pts) with Relapsed Multiple Myeloma (MM): A Phase I/II Study in Japan.

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 (V_z) value was indicative of extensive distribution into tissues. At all dose levels, elimination half-life (t_1/2) 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 (E_20smax) in whole blood on days 1 and 11, and their times (t_20smax) 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 (E_max) and plasma concentrations of B required to achieve 50% of E_max (EC₅₀) calculated using the simple E_max 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.