Population Pharmacokinetics of Obinutuzumab (GA101) in Chronic Lymphocytic Leukemia (CLL) and Non‐Hodgkin's Lymphoma and Exposure–Response in CLL

Abstract

Treatment regimens involving obinutuzumab (GA101) demonstrated increased efficacy to rituximab in clinical trials for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). However, the pharmacokinetic (PK) properties and the exposure–response relationships of obinutuzumab still need to be fully described. Data from four clinical trials of obinutuzumab were analyzed to describe the PK properties in patients with NHL or CLL and the pharmacodynamic (PD) properties in patients with CLL. A population PK model with linear time-dependent clearance described the obinutuzumab concentration–time course. Diagnosis, baseline tumor size (BSIZ), body weight, and gender were the main covariates affecting obinutuzumab exposure. In patients with CLL, exposure was not associated with safety but showed positive trends of correlation with efficacy. Although efficacy correlated positively with exposure, since both efficacy and exposure correlated negatively with BSIZ, it was not possible to determine with certainty whether it would be beneficial to adjust the dose according to BSIZ.

Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma

“…In a separate detailed PK analysis, bodyweight was shown to not have a clinically significant effect on the PK of obinutuzumab. 31 The observation that women with NHL had higher obinutuzumab exposure than men is similar to previous observations with rituximab PK in elderly DLBCL patients. 32,33 Elderly females with DLBCL who received rituximab plus CHOP therapy had slower rituximab clearance and improved PFS versus elderly males; however, these trends were not seen for younger patients.…”

“…This observation is supported by findings from the recent PK analysis, where sex did not have a clinically significant effect on the PK of obinutuzumab. 31 Our data revealed a relationship between serum concentrations of obinutuzumab and base-line tumor burden: in patients with high base-line tumor burden who received low-dose obinutuzumab (400/400 mg), antibody PK was highly variable. In contrast, the PK of the higher obinutuzumab dose was more homogeneous and independent of base-line tumor burden.…”

“…24,25 These findings are supported by recent detailed obinutuzumab PK analyses where MCL patients were shown to have higher clearance rates than CLL patients, while those with DLBCL or BCL had the lowest clearance rates. 31 These observations are likely due to differences in the levels of circulating target B cells in these diseases, and the relative expression of CD20 receptors on circulating B cells. [38][39][40] Although nearly all of the patients in GAUDI and GAUGUIN had previously received rituximab treatment, this would have had little or no influence on obinutuzumab PK.…”

Obinutuzumab: what is there to learn from clinical trials?

“…50,54,55 In CLL patients, a phase 1/2 study suggested a dose-response relationship and an influence of tumor burden. 56 This was further confirmed by retrospective analysis of PK data 53 and also suggested by a prospective randomized phase 2 trial. 57 Finally, the same dosing regimen as for NHL patients was applied for CLL.…”

“…51 In OBZ PK studies including CLL and NHL patients, the influence of BSA/weight on exposure remains controversial. 52,53 Using higher doses at the beginning of treatment in order to quickly improve exposure and saturate targets was also suggested. 50,54,55 Indeed, higher doses infused at days 1 and 8 (1600 mg) followed by infusions of 800 mg improved exposure and overall response rates (ORRs) in NHL, compared with lower doses (400 mg).…”