Indications
Ritlecitinib is specifically indicated for the treatment of severe alopecia areata in both adults and adolescents aged 12 years and older. It should not be used in conjunction with other JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants due to potential safety concerns.
Pharmacodynamics
Ritlecitinib functions as a kinase inhibitor and facilitates a dose-dependent reduction in absolute lymphocyte counts, including T lymphocytes (CD3) and their subsets (CD4 and CD8). It also results in a decrease in natural killer (NK) cells (CD16/56), with these effects sustaining up to 48 weeks following the initiation of treatment. For patients receiving a daily dose of 50 mg, stable median lymphocyte levels are observed through the same period. At exposures up to 12 times the mean maximum level of this dose, ritlecitinib does not produce a clinically relevant impact on the QTc interval. Use of ritlecitinib has been linked to the occurrence of serious infections, malignancies (including non-melanoma skin cancer), major adverse cardiovascular events, thromboembolic events, and hypersensitivity reactions. Data from postmarketing safety analyses of other JAK inhibitors in similar patient populations suggest an increased risk of all-cause mortality, including sudden cardiovascular death, when compared to TNF blockers.
Absorption
The pharmacokinetic profile of ritlecitinib demonstrates that its AUC0-tau and Cmax increase approximately dose-proportionally up to 200 mg, reaching a steady state around day four. The drug exhibits an absolute oral bioavailability of roughly 64%, achieving peak plasma concentrations approximately one hour post oral administration. The presence of food does not significantly alter the systemic exposure to ritlecitinib, although ingestion with a high-fat meal can reduce Cmax by 32% and increase AUCinf by 11%. Clinical trials permitted administration of ritlecitinib without regard to meals.
Metabolism
Ritlecitinib undergoes metabolism via the cytochrome P450 (CYP) and glutathione-S-transferase (GST) enzyme pathways. Specific GST enzymes involved include cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1, and microsomal GST 1/2/3, in addition to several CYP enzymes such as CYP3A, CYP2C8, CYP1A2, and CYP2C9. Notably, no single metabolic pathway accounts for more than 25% of ritlecitinib's overall metabolism.
Mechanism of Action
Ritlecitinib functions by irreversibly inhibiting Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, specifically targeting the adenosine triphosphate (ATP) binding site. This inhibition prevents cytokine-induced STAT phosphorylation that is mediated by JAK3-dependent receptors, as well as suppresses immune receptor signaling reliant on the TEC kinase family. This mechanism is particularly relevant in the context of alopecia areata, an autoimmune disorder characterized by hair loss, primarily on the scalp but potentially affecting other areas, including the face. The condition arises when the immune privilege of hair follicles is compromised, often due to the overexpression of UL16-binding protein 3 (ULBP3). This protein binds to natural killer cell receptors and has been implicated in the pathogenesis of alopecia areata. Specifically, it facilitates the onslaught of cytotoxic CD8+ NKG2D+ T cells on hair follicles, driving follicle dystrophy through the activation of interferon-γ (IFN-γ) and interleukin-15 (IL-15) signaling pathways, which in turn engage the JAK/STAT molecular cascade. While JAK inhibitors, including ritlecitinib, show potential in mitigating the inflammatory pathways characteristic of alopecia areata, the exact mechanism of action remains to be fully understood.
