Indications
Deucravacitinib is a targeted therapeutic agent indicated for adult patients with moderate-to-severe plaque psoriasis who are eligible for systemic treatment or phototherapy. The use of deucravacitinib in combination with other potent immunosuppressants is not recommended due to potential safety concerns.
Pharmacodynamics
Deucravacitinib functions as a tyrosine kinase 2 (TYK2) inhibitor, effectively modulating immune pathways involved in inflammatory conditions like plaque psoriasis. In clinical trials, deucravacitinib significantly reduced the expression of psoriasis-related genes in a dose-dependent manner, impacting the IL-23 and type I IFN pathways. Over a 16-week treatment period with a daily dose, reductions were observed in inflammatory markers such as IL-17A, IL-19, and beta-defensin by 47 to 50%, 72%, and 81 to 84%, respectively. Importantly, deucravacitinib does not disrupt JAK2-dependent hematopoietic functions.
Absorption
Following oral administration, deucravacitinib exhibits dose-proportional increases in plasma Cmax and AUC over a 3 mg to 36 mg dose range in healthy individuals. For a 6 mg daily dose, the steady state Cmax and AUC24 values were measured at 45 ng/mL and 473 ng·hr/mL, respectively, while the active metabolite BMT-153261 showed Cmax and AUC24 values of 5 ng/mL and 95 ng·hr/mL. The oral bioavailability of deucravacitinib is approximately 99%, with a median Tmax of two to three hours. A high-fat, high-calorie meal was found to decrease Cmax and AUC by 24% and 11%, respectively, and delay Tmax by one hour, although these changes are not deemed clinically significant.
Metabolism
Deucravacitinib is primarily metabolized through N-demethylation by cytochrome P-450 (CYP) 1A2, forming the major metabolite BMT-153261, which retains pharmacological activity similar to the parent compound. Approximately 20% of systemic drug exposure is attributed to BMT-153261. Additional metabolic pathways involve CYP2B6, CYP2D6, carboxylesterase (CES) 2, and uridine glucuronyl transferase (UGT) 1A9.
Mechanism of Action
Deucravacitinib functions through a distinct allosteric inhibition of the tyrosine kinase 2 (TYK2) enzyme, which is integral to specific immune pathways. TYK2, a member of the Janus kinase (JAK) family, specifically facilitates the signaling of inflammatory cytokines associated with both adaptive and innate immune responses, including interleukin (IL)-12 and IL-23, as well as type I interferons. These cytokines are instrumental in the pathogenesis of immune-mediated conditions such as psoriasis and psoriatic arthritis. IL-23, for example, fosters the activation and proliferation of Th17 cells, leading to the secretion of inflammatory mediators like IL-17 and tumor necrosis factor-alpha, which in turn spur the production of cytokines and chemokines by epidermal cells. This cascade attracts and activates cells of the innate immune system, ultimately prolonging inflammatory responses in the skin and joints typical of psoriatic arthritis.
