Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma

Background In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL. Objective This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients. Patients and Methods In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m 2 ) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3–6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1–2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness‐of‐fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection. Results Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified. Conclusions A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE. Clinical Trial Registration ClinicalTrials.gov identifier number NCT01959698.