Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial.

Introduction: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.

Methods: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure.

Population Pharmacokinetics and Exposure-Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma.

Introduction: Outcomes remain poor in patients with diffuse large B cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure-response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase 1b/2 CAVALLI study, to confirm dose selection for future studies.

Methods: Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400-800 mg venetoclax (cycle 1: days 4-10; cycles 2-8: days 1-10) in combination with R for eight cycles and CHOP for 6-8 cycles.

Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant.

The limited effectiveness of rituximab plus intravenous immunoglobulin (IVIG) in desensitization may be due to incomplete B cell depletion. Obinutuzumab is a type 2 anti-CD20 antibody that induces increased B cell depletion relative to rituximab and may therefore be more effective for desensitization. This open-label phase 1b study assessed the safety, pharmacokinetics, and pharmacodynamics of obinutuzumab in highly sensitized patients with end-stage renal disease.

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data.

Objectives: Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited.

Methods: We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501).