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Clinical Trial
. 2017 Dec 28;15(1):86.
doi: 10.1186/s12969-017-0212-y.

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study

Nicolino Ruperto  1 , Hermine I Brunner  2 , Zbigniew Zuber  3 , Nikolay Tzaribachev  4 , Daniel J Kingsbury  5 , Ivan Foeldvari  6 , Gerd Horneff  7 , Elzbieta Smolewska  8 , Richard K Vehe  9 , Anasuya Hazra  10 , Rong Wang  11 , Charles A Mebus  11 , Christine Alvey  11 , Manisha Lamba  11 , Sriram Krishnaswami  11 , Thomas C Stock  10 , Min Wang  10 , Ricardo Suehiro  10 , Alberto Martini  12 , Daniel J Lovell  2 ; Pediatric Rheumatology International Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG)
Affiliations
Clinical Trial

Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study

Nicolino Ruperto et al. Pediatr Rheumatol Online J. .

Abstract

Background: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA.

Methods: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated.

Results: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed.

Conclusions: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program.

Trial registration: ClinicalTrials.gov: NCT01513902 .

Keywords: Dosing; Janus kinase inhibitor; Juvenile idiopathic arthritis; Pediatric; Pharmacokinetics; Safety; Tofacitinib.

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Conflict of interest statement

Ethics approval and consent to participate

This study was conducted according to the ethical principles originating in the Declaration of Helsinki and in compliance with International Council for Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed. The final study protocol and amendments, developed in collaboration with the PRINTO/PRCSG coordinating centers, and informed consent documentation were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committees at each of the investigational centers participating in the study. Written, informed consent was provided by the parents/legal guardians of the patients who chose to participate in the study, and by the child if appropriate.

Consent for publication

Not applicable

Competing interests

N Ruperto has acted as a consultant and has participated in speaker bureaus for AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer Inc., R-Pharm, Roche, Sanofi, Servier, and Takeda. N Ruperto works as a full-time public employee of the public hospital Istituto Giannina Gaslini Hospital, which has received funds from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer Inc., and Sobi for the coordination activity of the PRINTO network.

HI Brunner has acted as a consultant for Abbvie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Janssen, Novartis, Pfizer Inc., R-Pharm, Roche, Sanofi, Takeda, and UCB.

Z Zuber has no conflicts of interest to disclose.

N Tzaribachev has no conflicts of interest to disclose.

DJ Kingsbury has received clinical trial support from Pfizer Inc.

I Foeldvari has acted as a consultant for AbbVie, Chugai, Novartis, and Pfizer Inc.

G Horneff has received research funds from, has acted as a consultant for, and has participated in speaker bureaus for AbbVie, Chugai, Novartis, Pfizer Inc., and Roche.

E Smolewska has no conflicts of interest to disclose.

RK Vehe has no conflicts of interest to disclose.

A Hazra is a former employee of Pfizer Inc.

R Wang, CA Mebus, C Alvey, M Lamba, S Krishnaswami, TC Stock, M Wang, and R Suehiro are employees and stock owners of Pfizer Inc.

A Martini does not have any conflict of interest to declare since March 2016, when he became the Scientific Director of the Gaslini Institute because this role does not allow him to render private consultancy resulting in personal income. A Martini performed consultancy activities on behalf of the Gaslini Institute for AbbVie, Boehringer, Novartis, and R-Pharm. A Martini is the Scientific Director of the public hospital Istituto Giannina Gaslini Hospital, which has received funds from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer Inc., and Sobi for the coordination activity of the PRINTO network.

DJ Lovell has received grant/research support from National Institutes of Health, and NIAMS, has acted as a consultant for AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forest Research Institute, Genentech, GlaxoSmithKline, Horizon, Janssen, Johnson & Johnson, Novartis, Pfizer Inc., Roche, Takeda, and UBC, and has participated in speaker bureaus for Genentech.

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Figures

Fig. 1
Fig. 1
Median tofacitinib plasma concentration–time profiles for each cohort. aMean tofacitinib plasma concentration–time profile for adult patients who received tofacitinib 5 mg BID in a Phase 2 dose-ranging study in patients with active rheumatoid arthritis [20]. BID twice daily
Fig. 2
Fig. 2
Log-linear regression analysis of individual CL/F (L/h) of plasma toficitinib versus body weight and 90% confidence region. Regression equation ln(CL/F)���= 3.5018 + 0.370973 × ln(weight/70). Weight has been standardized to an average adult weight of 70 kg first, then log-transformed. N = 8 for CL/F in Cohort 2 due to incomplete pharmacokinetics sampling for 1 patient. CL/F apparent plasma clearance
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