Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration-time profiles and dose/exposure-response (D/E-R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice-daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model-based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development.
CPT Pharmacometrics Syst Pharmacol 2017 12
PMID:Dose/Exposure-Response Modeling to Support Dosing Recommendation for Phase III Development of Baricitinib in Patients with Rheumatoid Arthritis. 2889 Dec 51

Maintaining platelet homeostasis is important to avoid spontaneous bleeding and organ damage. Thrombopoietin, the primary regulator of platelet production, is affected by and acts in part via Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-mediated mechanisms. Interleukin-6 is also partly responsible for inducing thrombopoietin production via the JAK-STAT pathway. Although current understanding suggests that JAK2 is a primary mediator of platelet regulation, the emerging data show that a JAK1-specific inhibitor resulted in the modulation of platelet numbers following dosing. To gain a mechanistic understanding, a model describing platelet regulation based on known physiology and JAK-STAT pathways was built. The model provides a tool to coalesce biological understanding of platelet physiology and an in silico experimental platform to explore drug effects on platelet homeostasis. In this article, we explain the model construction and demonstrate the use of JAK-inhibitor programs as informing probes of the physiology, gaining insights on dosing paradigms that avoid platelet-related safety concerns.
CPT Pharmacometrics Syst Pharmacol 2019 07
PMID:Evaluating the Role of Janus Kinase Pathways in Platelet Homeostasis Using a Systems Modeling Approach. 3104 23