Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis

@article{Mohamed2016PharmacokineticsSA,
  title={Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis},
  author={Mohamed-Eslam F Mohamed and Heidi S. Camp and Ping Jiang and Robert J. Padley and Armen Asatryan and Ahmed A. Othman},
  journal={Clinical Pharmacokinetics},
  year={2016},
  volume={55},
  pages={1547-1558}
}
BackgroundABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation.MethodsABT-494 single (1–48 mg or placebo; n = 56) and multiple (3–24 mg or placebo twice daily for 14 days; n… 
Population Pharmacokinetics of Upadacitinib Using the Immediate-Release and Extended-Release Formulations in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I–III Clinical Trials
TLDR
A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I–III clinical trials in healthy volunteers and subjects with RA and is appropriate to use for simulations and to evaluate the exposure–response relationship of up adacit inib.
Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials
TLDR
A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors.
Absence of Pharmacokinetic Interactions between the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate
TLDR
The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials, and results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.
Assessment of effect of CYP3A inhibition, CYP induction, OATP1B inhibition, and high‐fat meal on pharmacokinetics of the JAK1 inhibitor upadacitinib
TLDR
Upadacitinib was well tolerated when co-administered with ketoconazole, rifampin, or after a high-fat meal and results showed strong CYP3A inhibition and broad CYP induction result in a weak and moderate effect, respectively, on upadac itinib exposures.
Pharmacology, efficacy and safety of JAK inhibitors in Crohn's disease.
TLDR
Overall, JAK inhibitors constitute a new promising class of drugs, given the efficacy signals observed in pivotal clinical trials in several chronic inflammatory diseases.
Early phase studies of JAK1 selective inhibitors in rheumatoid arthritis
TLDR
Early phase (Phase I–II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit–risk profile for further evaluation in the later successfully performed Phase III trials.
Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials
TLDR
A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis to estimate oral bioavailability.
Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended‐Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials
TLDR
The use of upadacitinib 15‐ and 30‐mg doses of the ER formulation in the phase 3 trials in RA was supported and pharmacokinetics were characterized after the administration of single and multiple once‐daily doses.
Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.
TLDR
Upadacitinib's benefit-risk profile supports further development for treatment of CD and induced endoscopic remission in a significant proportion of patients, compared with placebo.
Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics
TLDR
The results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 26 REFERENCES
AB0390 Safety and Efficacy of ABT-494, A Novel Selective JAK1 Inhibitor, in Patients with Active Rheumatoid Arthritis and Inadequate Response or Intolerance To Anti-TNF Biologic Therapy
TLDR
This phase 2b study demonstrated the clinical efficacy of ABT-494 vs PBO when dosed in combination with MTX in TNF-IR pts with active RA and had an acceptable safety and tolerability profile.
THU0127 Pharmacodynamics of A Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects
TLDR
ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models and spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats.
JAK inhibition for the treatment of rheumatoid arthritis: a new era in oral DMARD therapy
TLDR
Emerging clinical results demonstrate that JAK inhibition is a validated new mechanism for the development of oral DMARD agents that is likely to join the armamentarium against RA in the near future.
Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis
TLDR
Tofacitinib is efficacious and well tolerated in patients with MTX-resistant RA up to a period of 24 weeks, however, haematological, liver function tests and lipoproteins should be monitored.
[Tofacitinib for the treatment of rheumatoid arthritis].
  • Yoshiya Tanaka
  • Medicine
    Nihon rinsho. Japanese journal of clinical medicine
  • 2016
TLDR
Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active RA patients with sDMARD-naïve, inadequately responsive to s DMARDs or TNF-inhibitors.
Selective JAK inhibitors in development for rheumatoid arthritis
  • P. Norman
  • Medicine
    Expert opinion on investigational drugs
  • 2014
TLDR
A review of the clinical development and available clinical results for those JAK inhibitors currently under investigation and the preclinical data on these, in addition to peficitinib, ABT-494, INCB-047986 and AC-410.
Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis.
TLDR
The contribution of common genetic polymorphisms in RFC-1, ATIC, and TS (28-bp tandem repeats located in the TS enhancer region [TSER*2/*3]) and of MTXPGs to the effect ofMTX in patients with rheumatoid arthritis is investigated.
A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis.
TLDR
There is strong evidence in favour of combination treatment for RA but there is still uncertainty about which regimen is preferable, and both combination DMARDs and TNF/MTX are more effective than MTX monotherapy.
The Operational Multiple Dosing Half-life: A Key to Defining Drug Accumulation in Patients and to Designing Extended Release Dosage Forms
TLDR
It is demonstrated for diazepam that the well-accepted concept that t1/2,z representing the great majority of the AUC will govern accumulation can be incorrect, and a new parameter, “operational multiple dosing half-life”, is defined, as equal to the dosing interval at steady-state where the maximum concentration at steady state is twice themaximum concentration found for the first dose.
Functional Half-Life is a Meaningful Descriptor of Steady-State Pharmacokinetics of an Extended-Release Formulation of a Rapidly Cleared Drug
TLDR
The t1/2F of valproic acid optimally characterises the expected steady-state Cmax to Cmin decrease of 33% in uninduced and 45% in induced adults following once-daily administration of divalproex-ER.
...
1
2
3
...