PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 24 (2015) Abstr 3604 [www.page-meeting.org/?abstract=3604]
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Poster: Drug/Disease modeling - Oncology
Ekaterina Gibiansky (1), Michael Brewster (2), Clarisse Chavanne (3), Nicolas Frey (3), and Candice Jamois (3)
(1) QuantPharm LLC, North Potomac, MD, USA; (2) Clinical Pharmacology, Roche Pharma Research & Early Development (pRED), Roche Innovation Center Welwyn, UK, F. Hoffmann-La Roche Ltd; (3) pRED, Clinical Pharmacology, Roche Innovation Center Basel, Switzerland, F. Hoffmann-La Roche Ltd.
Objectives: To compare safety and efficacy responses in patients receiving intravenous or subcutaneous Rituximab (RTX IV/SC) using a population pharmacokinetic (PPK) model.
Methods: 1777 SC and 2962 IV concentrations in 255 patients from two phase 3 studies were analyzed. A PPK model was built with NONMEM software; several covariates were investigated. Diagnostics plots and various predictive check procedures were used for model evaluation.
Exposure-Response relationships (E-RR) were explored graphically in the largest phase 3 study in previously untreated CLL patients using data respectively from 87 and 86 patients in the IV and SC arms (Cycle 1: 375 mg/m2 IV, Cycles 2-6: 500 mg/m2 IV or 1600 mg SC). The analyzed endpoints were: occurrence of SAEs, Grade 3+ AEs, occurrence and grades of neutropenia, time course of neutrophil and B-cell counts, and best overall response (BOR).
Results: A linear two-compartment PPK model with time-dependent clearance (CL=CLinf+CLT∙exp(-kdest)) described RTX concentrations. Estimates of CLinf (207 mL/day), inter-compartment clearance (420 mL/day), central volume (4.99 L), peripheral volume (VP, 3.7 L), terminal half-life at Cycle 6 (32 days), absorption rate constant (0.372 1/day), and SC bioavailability (FSC, 63.3%) were typical for monoclonal antibodies. High CLT (1550 mL/day), possibly attributable to target-mediated elimination, decreased with a half-life of 17.4 days. Steady-state was achieved after six 28-day cycles.Clearances and volumes increased with BSA; VP was 9% lower in females; FSC decreased with increasing BMI. While fixed SC dosing lead to larger differences in exposure (Ctrough,ss and AUCτ,ss) between light and heavy patients compared to BSA-adjusted IV dosing, exposures for all body-size groups were not lower than exposures attained by IV dosing.Consistent with target-mediated elimination, CLT was higher in patients with higher WBC and tumor size at baseline, leading to lower initial exposure in patients with higher disease burden.There were no differences between IV and SC arms in safety E-RR and in B-cell response. Patients in all categories of BOR in the IV arm and patients with PR in the SC arm had the same exposures, while patients with CR in the SC arm had higher exposures.
Conclusions: The tested SC regimen provides equal or higher RTX exposure compared to the reference IV regimen across the whole range of body sizes. There are no differences between IV and SC treatments in E-RR. Thus, the switch to SC administration does not impair the anti-B-cell activity of RTX.