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Abstract Number: 2864

Identification of Optimal Subcutaneous Doses of Tocilizumab in Children with Systemic Juvenile Idiopathic Arthritis

Hermine I. Brunner1, Nicola Ruperto2, Daniel J Lovell1, Gerd Horneff3, María Luz Gámir-Gámir4, Markus Hufnagel5, Joy Hsu6, Min Bao6, Wendy Douglass7, Navita L. Mallalieu6, Chris Wells7, Christopher M. Mela8 and Fabrizio De Benedetti9, 1Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2Pediatric Rheumatology International Trial Organization (PRINTO), Istituto Giannina Gaslini Pediatria II-Reumatologia, Genoa, Italy, 3Asklepios Clinic Sankt Augustin, and University Hospital of Cologne, Cologne, Germany, 4Hospital Ramon y Cajal Unidad de Reumatologia Pediatrica, Madrid, Spain, 5Department of Pediatrics and Adolescent Medicine, University Medical Center, Medical Faculty, University of Freiburg, Freiburg, Germany, 6Roche Innovation Center, New York, NY, 7Roche Products Ltd., Welwyn Garden City, United Kingdom, 8Roche Products Ltd, Welwyn Garden City, United Kingdom, 9IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: pharmacokinetics and tocilizumab, Systemic JIA

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Session Information

Date: Tuesday, October 23, 2018

Title: 5T107 ACR Abstract: Pediatric Rheum–Clinical II: Treatment Update (2862–2867)

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Efficacy and safety of intravenous (IV) tocilizumab (TCZ) were shown in patients (pts) with systemic JIA (sJIA) in the phase 3 TENDER study.1 This multicenter, open-label, phase 1b study investigated dosing regimens of subcutaneous (SC) TCZ in pts with sJIA relative to data from TENDER to identify the optimal SC regimen and ensure that Ctrough from SC regimens was equivalent to or higher than that from the IV regimen.

Methods: Pharmacokinetics (PK), pharmacodynamics (PD), and safety of TCZ SC were investigated in pts aged 1-17 years with sJIA and inadequate response to glucocorticoids; efficacy was an exploratory objective. Pts could be TCZ naive or could switch from TCZ IV to TCZ SC. Interim analysis was conducted after 24 pts had received TCZ SC for 14 weeks. TCZ SC was administered for 52 weeks according to body weight (BW): <30 kg received 162 mg every 10 days (Q10D) before interim analysis or 162 mg every 2 weeks (Q2W) after interim analysis; ≥30 kg received 162 mg every week (QW).

Results: In total, 51 pts were enrolled; 25 weighed <30 kg and 26 weighed ≥30 kg. Twenty-six pts (51%) were TCZ naive and 25 (49%) switched from TCZ IV. Interim analysis revealed higher than desired exposure in the <30 kg group, so dosing frequency was reduced from Q10D to Q2W. Median and range steady state Cmin were similar in both BW groups (Table). More than 95% (49/51) of pts treated with TCZ SC had model-computed steady state Cmin higher than the 5th percentile achieved with TCZ IV. Median and range AUC2weeks were similar in both BW groups (Table). Changes in IL-6, CRP, and ESR were similar for both BW groups. Almost all pts had ≥1 adverse event (AE; n = 50; 98.0%). Injection site reactions (ISRs) occurred in 21 pts (41.2%); most were mild, and none led to treatment interruption or withdrawal. The AE rate was 1200.3/100 pt-years (PY) (909.3/100 PY, excluding ISRs). The most common AEs were viral upper respiratory tract infection (13; 25.5%), neutropenia (13; 25.5%), and cough (12; 23.5%). Nine serious AEs occurred in 7 pts (13.7%; 19.3/100 PY); 5 were infections, all in the <30 kg group. Two deaths occurred, both in the <30 kg group. Median Juvenile Arthritis Disease Activity Score-71 improved from baseline to week 52 for TCZ-naive pts (<30 kg, –13.9; ≥30 kg, –12.4) and was maintained or improved further for pts who switched from TCZ IV (<30 kg, –0.7; ≥30 kg –0.2). At week 52, 29/43 pts (67.4%) had inactive disease (JADAS-71 <1.0).

Table

TCZ SC

TCZ IV

<30 kg TCZ
162 mg Q2W

n = 25

≥30 kg TCZ
162 mg QW

n = 26

<30 kg TCZ
12 mg/kg Q2W

n = 46

≥30 kg TCZ
8 mg/kg Q2W

n = 43

Model-computed steady state PK parameters, median (range)

Cmin,ss µg/mL

64.2

(16.6-135.9)

72.4

19.5-157.8)

65.9

(19.0-135.5)

70.7

(5.3-126.6)

Cmax,ss µg/mL

126.6

(51.7-265.8)

89.8

(26.4-190.2)

274.4

(148.8-444.0)

253.0

(119.6-404.3)

AUC2weeks,ss µg/mL×day

1298

(539-2792)

1154

(334-2370)

1734

(840-2712)

1631

(526-2779)

Conclusion: A PK-based strategy was successful in bridging TCZ SC to TCZ IV in pts with sJIA. Dosing regimens of 162 mg Q2W in pts <30 kg and 162 mg QW in pts ≥30 kg provided adequate exposure to support efficacy comparable to that of TCZ IV. Except for ISRs, safety results were consistent with the known safety profile of TCZ in sJIA. Reference: 1. De Benedetti F et al. N Engl J Med. 2012;367:2385-2395. Acknowledgment: The PRINTO and PRCSG Investigators. Medical writing: Sara Duggan, PhD, funded by F. Hoffmann-La Roche Ltd.


Disclosure: H. I. Brunner, Roche, BMS, Novartis, Pfizer, R-Pharm, Celgene, AstraZeneca, Jannsen, Ablynx, GSK, Takeda, Sanofi, 5,Roche, Novartis, Pfizer, 8,Roche, Novartis, Pfizer, BMS, 9; N. Ruperto, Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono, Hoffmann-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, NovoNordisk, Pfizer, Rewind Arms, R-Ph, 5,Abbott, BMS,, 2; D. J. Lovell, AstraZeneca, Amgen, Abbott, Pfizer, 5,Wyeth, 8; G. Horneff, None; M. L. Gámir-Gámir, None; M. Hufnagel, None; J. Hsu, Roche, 1,Roche, 3; M. Bao, Genentech, Inc., 3; W. Douglass, Roche, 1,Roche, 3; N. L. Mallalieu, Roche, 1,Roche, 3; C. Wells, Roche, 3; C. M. Mela, Roche, 3; F. De Benedetti, Abbvie, Sobi, Novimmune, Roche, Novartis, Sanofi, UCB, Pzifer, 2.

To cite this abstract in AMA style:

Brunner HI, Ruperto N, Lovell DJ, Horneff G, Gámir-Gámir ML, Hufnagel M, Hsu J, Bao M, Douglass W, Mallalieu NL, Wells C, Mela CM, De Benedetti F. Identification of Optimal Subcutaneous Doses of Tocilizumab in Children with Systemic Juvenile Idiopathic Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/identification-of-optimal-subcutaneous-doses-of-tocilizumab-in-children-with-systemic-juvenile-idiopathic-arthritis/. Accessed .
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