Ekaterina Gibiansky (1), Leonid Gibiansky (1), Michael Brewster (2), Candice Jamois (3), Vincent Buchheit (3), Nicolas Frey(3)
(1) QuantPharm LLC, North Potomac, MD, USA; (2) Roche Products Ltd, Welwyn, UK; (3) F. Hoffmann-La Roche Ltd, Basel, Switzerland
Objectives: Obinutuzumab (Gazyva, G), approved for treatment of CLL and FL [1], is a humanized type II anti-CD20 monoclonal antibody with a glycoengineered Fc region. G population PK model for patients with CLL and NHL was established earlier [2]. The aim of the analysis was to update the model with new data of patients with DLBCL and MCL and to identify covariates of G exposure.
Methods: Serum concentrations (16,301) of 961 patients (6 Phase I-III trials) were analyzed. A 2-compartment population PK model with time-dependent clearance [CL=CLinf+CLT∙exp(-kdest)] described G PK. The full model approach was used for covariate model development. Diagnostics plots and various predictive check procedures were used for model evaluation.
Results: Typical G CLinf, CLT, central and peripheral volumes, and inter-compartment clearance were CLinf =0.074 L/day, CLT=0.154 L/day, VC=2.72 L, VP=1.23 L, and Q=1.32 L/day. CLinf, VC, and VP increased with body weight. CLinf, VC, and CLT were 18%, 19%, and 45% higher in males. CLinf decreased with age and serum albumin, and increased with baseline tumor size (TS). CLT also increased with TS, leading to initially lower exposure in patients with high TS. For patients with iNHL and DLBCL, differences in steady-state exposure due to demographics and TS were within 35% for respective dosing regimens.
Typical CLT declined with half-life t1/2=6.3 days; thus, CL declined to CLinf after a month of dosing. Simulations showed that for the proposed dosing regimens (1000 mg IV Q3W or Q4W with additional doses on Days 8 and 15 of cycle 1), G concentrations reach steady-state levels after cycle 1.
CLinf was 47%, 107%, and 38% higher for CLL, MCL, and SLL, compared to iNHL or DLBCL. CLT was 125% and 180% higher for CLL and MCL compared to other tumor types. CLT declined slower (t1/2=21 day) in MZL. Simulations of iNHL dosing regimen indicated that at the end of the Induction period (cycle 6), AUCτ and Ctrough were 15-18% higher in patients with MZL and 27-36% lower in patients with SLL, compared to FL. Steady-state exposure during Maintenance was nearly identical for MZL and FL, but was 33-50% lower for SLL.
kdes was higher with concomitant fludarabine/cyclophosphamide (t1/2=2.4 days), and lower with bendamustine (10.7 days) or CHOP (20.4 days). However, more frequent dosing of G when administered with CHOP (Q3W) prevented lower G exposures.
Conclusions: The updated model described G PK for different tumor types and concomitant chemotherapies.
References:
[1] GAZYVA prescribing information. http://www.gene.com/download/pdf/gazyva_prescribing.pdf.
[2] E. Gibiansky, L. Gibiansky, D. Carlile, C. Jamois, V. Buchheit, N. Frey, Population Pharmacokinetics of Obinutuzumab (GA101) in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin’s Lymphoma and Exposure-Responses in CLL, CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e144; doi:10.1038/psp.2014.42.
Reference: PAGE 25 (2016) Abstr 5956 [www.page-meeting.org/?abstract=5956]
Poster: Drug/Disease modeling - Oncology