Pharmacokinetics of upadacitinib in pediatric patients with polyarticular course juvenile idiopathic arthritis

Background Upadacitinib is a Janus kinase inhibitor with preferential inhibition of JAK1 over other JAK isoforms that has been approved for the treatment of adults with moderate to severe rheumatoid arthritis (RA). Children with polyarticular course juvenile idiopathic arthritis (pcJIA) have similar clinical presentations compared to adult RA. In Phase 3 RA studies in adult patients, the median (5 th , 95 th percentiles) model-estimated area under the plasma upadacitinib concentration curve AUC over 0-24 hours (AUC 0-24 ) at steady state were 362 (216, 785) and 720 (434, 1531) ng·h/mL after multiple 15 mg and 30 mg once daily (QD) doses, respectively. Objectives The objective of this analysis was to characterize upadacitinib pharmacokinetics from a Phase 1 study in children with pcJIA. Methods Patients (N = 51) diagnosed with pcJIA were enrolled into one of four groups in an open-label, multiple-dose study (Group 1, 12 to < 18 years, low dose; Group 2, 12 to < 18 years, high dose; Group 3, 6 to < 12 years, low dose; Group 4, 2 to < 6 years, low dose). The low and high doses were selected to provide comparable plasma exposures in pediatrics to 15 mg and 30 mg QD doses of ER tablet formulation in adults, respectively. Patients received bodyweight-based upadacitinib doses either as twice-daily (BID) immediate-release (IR) oral solution or QD extended-release (ER) tablet formulation. Pharmacokinetic assessment was performed at steady state on Study Day 7, after which all patients might continue the study with low dose. Results Summary of the demographics of the enrolled patients are shown in Table 1. Pharmacokinetic results from 49 patients with evaluable drug concentrations on Study Day 7 were reported. In Group 1, the geometric mean upadacitinib maximum plasma concentration (C max ) and AUC 0-24 at steady state were 35.1 ng/mL and 269 ng·h/mL, respectively. In Group 2, the geometric mean upadacitinib C max and AUC 0-24 were 69.8 ng/mL and 553 ng·h/mL, respectively. In Group 3, the geometric mean upadacitinib C max and AUC 0-24 were 51.0 ng/mL and 346 ng·h/mL, respectively. In Group 4, the geometric mean upadacitinib C max and AUC 0-24 were 46.6 ng/mL and 369 ng·h/mL, respectively. The median time to maximum upadacitinib concentration was approximately 3 hours and 1 hour; and the harmonic mean functional half-life was approximately 5 hours and 2 hours for the QD ER tablet and the BID IR solution regimens, respectively. Upadacitinib apparent oral clearance increased in pcJIA patients with increasing bodyweight. The mean upadacitinib plasma concentration-time profiles of each group are presented by dosing regimen in Figure 1. Conclusion Upadacitinib plasma exposures in pediatric patients with pcJIA were comparable to adult RA patients at the evaluated dosing regimens with the ER tablet or IR solution and at both low and high dose levels. These results support the use of the current bodyweight-based dosing regimen in upadacitinib pediatric studies. Table 1. Demographics Summary of Enrolled Pediatric pcJIA Patients Group 1 (N = 9) Group 2 (N = 9) Group 3 (N = 19) Group 4 (N = 14 a ) Age b (years) Mean ± SD (Range) 14.9 ± 1.5 (13 – 17) 13.9 ± 1.2 (12 – 16) 9.5 ± 1.6 (6 – 12) 3.6 ± 1.5 (2 – 6) Weight (kg) Mean ± SD (Range) 61.3 ± 14.6 (42.0 – 92.9) 51.7 ± 13.0 (32.5 – 71.5) 37.8 ± 14.4 (19.7 ± 72.1) 15.1 ± 3.2 (11.0 ± 22.5) Sex Male, N (%) 2 (22.2) 1 (11.1) 4 (21.1) 3 (21.4) Female, N (%) 7 (77.8) 8 (88.9) 15 (78.9) 11 (78.6) Dose Form Oral Solution, N (%) 0 (0.0) 0 (0.0) 7 (36.8) 14 (100.0) Tablet, N (%) 9 (100.0) 9 (100.0) 12 (63.2) 0 (0.0) a.Two patients were excluded from pharmacokinetic analysis. One patient mistakenly received half dose and the other patient had incomplete PK sample collection. b.Age was determined at the time of screening. Figure 1. Mean Upadacitinib Plasma Concentration-Time Profiles in Pediatric pcJIA Patients REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Yuli Qian Shareholder of: AbbVie, Employee of: AbbVie, Anna Shmagel Shareholder of: AbbVie, Employee of: AbbVie, Shuai Hao Shareholder of: AbbVie, Employee of: AbbVie, Gerd Horneff Grant/research support from: AbbVie, Bayer, Chugai, GlaxoSmithKline, MSD, Novartis, Pfizer, Roche, Sanofi, and Sobi, Hermine Brunner Speakers bureau: Novartis, Pfizer, and GlaxoSmithKline, Consultant of: AMPEL, AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Idorsia, Cerocor, Horizon, Janssen, GlaxoSmithKline, F. Hoffmann-La Roche, Merck, Novartis, R-Pharm, and Sanofi, Grant/research support from: Bristol-Myers Squibb, F. Hoffmann-La Roche, Janssen, Novartis, and Pfizer. The funding was provided to Cincinnati Children’s Hospital in the past 3 years, where this author works as a full-time public employee. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment to third parties, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Wei Liu Shareholder of: AbbVie, Employee of: AbbVie, Mohamed-Eslam Mohamed Shareholder of: AbbVie, Employee of: AbbVie.