2018 - Montreux - Switzerland

PAGE 2018: Drug/Disease modelling - Paediatrics
Nicolas Frey

Bridging from Intravenous to Subcutaneous Formulation of Tocilizumab for Optimal Dose Regimens in Systemic Juvenile Idiopathic Arthritis

Leonid Gibiansky (1), Ekaterina Gibiansky (1), Nicolas Frey (2), Navita L. Mallalieu (3), Claire Petry (2), Jean-Eric Charoin (2), Min Bao (4), Christopher Mela (5), Wendy Douglass (5), Joy C. Hsu (3)

(1) QuantPharm LLC, North Potomac, MD, USA, (2) Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland, (3) Roche Innovation Center, New York, NY, USA, (4) Genentech, South San Grancisco, CA, USA, (5) Roche Products Limited, Welwyn, UK

Objectives: 

Tocilizumab (TCZ) is a recombinant humanized anti-human IgG1 monoclonal antibody directed against the interleukin-6 receptor (IL-6R) that binds specifically to both soluble (sIL-6R) and membrane-bound IL-6R, thereby inhibiting IL 6 mediated signaling. The intravenous (IV) TCZ formulation is approved in the European Union, United States, and Japan for adult rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis (sJIA), and polyarticular juvenile idiopathic arthritis (pJIA). The subcutaneous (SC) formulation of TCZ is approved for the treatment of RA and giant cell arteritis.

The mechanism of action for TCZ is well understood, and the efficacy has shown to be well correlated with the target saturation of IL-6 receptors. The exposure-response relationships between TCZ steady-state Ctrough (Ctrough,ss) and PD/efficacy parameters were well established for the IV formulation for sJIA indicating that TCZ steady-state Ctrough was a good surrogate of the target saturation. Hence, bridging from IV to SC formulation for TCZ in sJIA was based on exposure achieved at Ctrough,ss. Utilizing the population PK models developed for the IV formulation for sJIA in combination with prior knowledge on the SC formulation from the adult RA population, SC dose regimens that were able to achieve similar ranges of Ctrough,ss as the IV dose regimen were recommended for sJIA patients.

The objective was to confirm the adequacy of the SC dose regimens of TCZ proposed for sJIA using a pharmacometrics approach.

Methods:

Prior to study start, SC regimens 162 mg Q10D (< 30 kg) and QW (≥ 30 kg) were recommended for sJIA patients in JIGSAW118, a phase Ib, open-label, multi-center study to investigate the PK, PD, and safety following TCZ SC administration in patients with sJIA aged 1 to 17 years. An interim analysis was planned at Week 14 to confirm that the proposed SC regimens would achieve similar Ctrough,ss compared with the approved IV regimens. At interim analysis, the Ctrough,ss achieved following 162 mg Q10D (< 30 kg) and QW (≥ 30 kg) were at the higher end of the exposure predicted prior to study start for all patients across the entire body weight range. Bioavailability was estimated to be around 95% based on data from 28 patients available at the time of interim analysis, which was higher than that observed in adult RA patients (~80%). This resulted in higher than anticipated Ctrough,ss following the 162 mg Q10D SC regimen, and the SC regimen for patients with BW < 30 kg was changed to 162 mg Q2W SC. For patients with BW ≥ 30 kg, the Ctrough,ss were similar to that achieved following IV administration, so the 162 mg SC QW regimen was considered adequate and was not changed.

At the end of the 52-week study, TCZ serum concentrations from JIGSAW118 (25 patients < 30 kg [162 mg SC Q10D (n = 8) or Q2W (n = 17)] and 26 patients ≥ 30 kg [162 mg SC Q2W]) were pooled with TCZ IV data from TENDER (Phase 3, randomized, double-blind study in sJIA patients aged 2 to 17 years with 46 patients < 30 kg [12 mg/kg IV Q2W] and 43 patients ≥ 30 kg [8 mg/kg IV Q2W]). A total of 1710 quantifiable serum samples from 140 sJIA patients were analyzed using a two-compartment model with parallel linear and Michaelis-Menten elimination. Covariate analysis was conducted to identify covariates that may influence disposition of tocilizumab in sJIA patients. Graphical analyses were conducted to evaluate effects of tocilizumab SC exposure on pharmacodynamics biomarkers, key safety parameters, and exploratory efficacy measures.

Results: 

The study met its primary objective as more than 95% of sJIA patients in JIGSAW118 achieved Ctrough,ss higher than the 5th percentile achieved with TCZ IV in TENDER. In addition, changes over time in pharmacodynamic biomarkers sIL-6R, CRP, and ESR were similar following both SC regimens, and to those achieved with the approved IV regimens. Graphical exposure-safety analyses confirmed there was no apparent association between exposure and occurrence of any SAEs, AEs in “Infections and Infestations” SOC, or neutropenia AE. Results of graphical exposure-efficacy analyses for sJIA patients following the SC regimens demonstrated that variability in TCZ exposure was not associated with the variability in efficacy parameters Juvenile Arthritis Disease Activity Score 71 and Childhood Health Assessment Questionnaire–Disability Index scores.

Conclusions: 

Results of these analyses confirmed that tocilizumab 162 mg SC Q2W (< 30 kg) and QW (≥ 30 kg) regimens are adequate for the treatment of sJIA.




Reference: PAGE 27 (2018) Abstr 8731 [www.page-meeting.org/?abstract=8731]
Poster: Drug/Disease modelling - Paediatrics
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