tofacitinib and Neutropenia

The treatment of rheumatoid arthritis has changed dramatically over the last two decades since the development of biological disease-modifying anti-rheumatic drugs (bDMARDs). Moreover, Janus kinase (JAK) inhibitors became available in 2013. JAK inhibitors are low-molecular-weight compounds, which exert anti-rheumatic effects by suppressing the action of JAK, an intracellular tyrosine kinase. Of note, biologics bind to extracellular proteins and block their activity. The availability of JAK inhibitors that are as effective as bDMARDs, despite the completely different route of administration and mode of action, has enabled the treatment of rheumatoid arthritis to enter a new stage. JAK inhibitors are useful in a variety of cases, including patients who inadequately responded to treatment with methotrexate and/or bDMARDs. Oral administration is convenient for patients. Nevertheless, the drugs should be carefully prescribed as they are metabolized in the liver and kidneys. Attention should also be paid to adverse events, such as infections including herpes zoster. It is necessary to understand the characteristics of JAK inhibitors and use these agents judiciously.

Topics: Adamantane; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Benzofurans; Cardiovascular Diseases; Herpes Zoster; Humans; Janus Kinases; Molecular Targeted Therapy; Neutropenia; Niacinamide; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides; Venous Thromboembolism

CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE(h), ktr(h), gamma, and k(circ)), disease effect parameters (DIS), and drug effect parameters (k(off) and k(D)). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.

Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Neutropenia; Piperidines; Pyrimidines; Pyrroles; Time Factors