Molecular mass: 425.467 g/mol PubChem compound: 134821691
Deucravacitinib selectively inhibits the TYK2 enzyme (TYK2 belongs to the JAK family). Deucravacitinib binds to the regulatory domain of TYK2, stabilizing an inhibitory interaction between the regulatory and the catalytic domains of the enzyme. This results in allosteric inhibition of receptormediated activation of TYK2 and its downstream functions in cells. TYK2 mediates signalling of interleukin-23 (IL-23), interleukin-12 (IL-12), and type I interferons (IFN), which are naturally occurring cytokines involved in inflammatory and immune responses. Deucravacitinib inhibits the release of proinflammatory cytokines and chemokines.
In patients with psoriasis, deucravacitinib reduced psoriasis associated gene expression in psoriatic skin including reductions in IL-23-pathway and type I IFN pathway regulated genes. Deucravacitinib reduced IL-17A, IL-19 and β-defensin by 47-50%, 72% and 81-84%, respectively following 16 weeks of once daily treatment.
Deucravacitinib exhibited near complete oral absorption, dose-related increase in exposure, and no evident time-dependent pharmacokinetics.
Following oral administration of tablets, deucravacitinib exhibited rapid and near complete absorption. The median Tmax ranged from 2 to 3 hours and absolute oral bioavailability was 99% in healthy volunteers. Modest accumulation (<1.4-fold at steady state) was observed following once daily dosing.
Deucravacitinib can be administered without consideration for food or gastric pH modulators (H2 receptor blockers and proton pump inhibitors). Co-administration of food or gastric pH modulators did not affect total exposure (AUC[INF]) of deucravacitinib.
The volume of distribution at steady state (Vss), is 140 L, which is greater than total body water [42 L] indicating extravascular distribution. Deucravacitinib is 81.6% bound to human plasma proteins, primarily to human serum albumin.
Deucravacitinib distributes similarly between plasma and red blood cell components with blood-toplasma concentration ratio of 1.26.
In humans, deucravacitinib is metabolised via four primary biotransformation pathways, which include N-demethylation at the triazole moiety by cytochrome P-450 (CYP) 1A2 to form major metabolite BMT-153261, cyclopropyl carboxamide hydrolysis by carboxylesterase 2 (CES2) to form major metabolite BMT-158170, N-glucuronidation by uridine glucuronyl transferase (UGT) to form BMT-334616, and mono-oxidation by CYP 2B6/2D6 at the deuterated methyl group to form M11.
At steady state, deucravacitinib is the major circulating species constituting 49% of measured compound related components. Two major circulating metabolites, BMT-153261 and BMT-158170, were identified, both of which have half-lives comparable to the parent deucravacitinib. BMT-153261 has comparable potency to the parent compound and BMT-158170 is not pharmacologically active. The circulating exposure of BMT-153261 is much lower than the parent compound and therefore, the predominant pharmacological activity is attributed to the parent compound deucravacitinib.
Additionally, no unique to human metabolites and no long-lived circulatory metabolites were identified.
Deucravacitinib is eliminated via multiple pathways, including Phase I and II metabolism, along with direct renal and faecal elimination. Additionally, no single enzyme contributed more than 26% of total clearance. Deucravacitinib is extensively metabolised, with 59% of orally administered [14C]-deucravacitinib dose eliminated as metabolites in urine (37% of the dose) and faeces (22% of the dose). Unchanged deucravacitinib in urine and faeces represented 13% and 26% of the dose, respectively.
The terminal elimination half-life of deucravacitinib 6 mg in healthy human adults is 10 hours, with a total clearance of 15.3 L/h (CV 27%). Deucravacitinib is a substrate of efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and uptake transporter OCT1. Due to high passive permeability, high oral bioavailability and low affinity for these transporters, contribution of these transporters to deucravacitinib pharmacokinetics is minimal.
Deucravacitinib is not a substrate of transporters OATP, NTCP, OAT1, OAT3, OCT2, MATE1, or MATE2K.
The pharmacokinetics of single doses of deucravacitinib administered as tablets was linear across 3 mg to 36 mg dose range.
In vitro studies have shown no evidence that deucravacitinib and its major circulating metabolites, at clinically relevant exposures, inhibit major CYPs (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4), UGTs (1A1, 1A4, 1A6, 1A9, 2B7), CES2 and drug transporters (P-gp, BCRP, OATP1B1, OATP1B3, BSEP, MRP2, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K). Additionally, deucravacitinib does not induce CYP 1A2, 2B6, and 3A4.
Based on the population pharmacokinetic analysis, deucravacitinib mean steady state exposure (Cavg,ss) was higher, 31% in patients aged 65-74 years [n=87 of 1387 (6.3%)] and 53% in patients aged 75-84 years [n=13 of 1387 (0.94%)]. Exposures in patients aged ≥85 years old are not available.
Renal impairment has no clinically meaningful effect on deucravacitinib exposures based on a dedicated study where estimated glomerular filtration rate (eGFR) was determined using a modification of diet in renal disease (MDRD) equation. Compared to normal renal function group, deucravacitinib Cmax was altered by up to 15% and AUC[INF] increased by up to 48% across renal impairment groups (mild (eGFR: ≥60 to <90 mL/min), moderate (eGFR: ≥30 to <60 mL/min), severe (eGFR: <30 mL/min), and ESRD (eGFR: <15 mL/min)). Compared to the normal renal function group, BMT-153261 Cmax increased by up to 34% and AUC[INF] increased up to 84% across renal impairment groups.
Dialysis does not substantially clear deucravacitinib from systemic circulation (5.4% of dose cleared per dialysis).
Mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has no clinically meaningful effect on deucravacitinib exposures. Compared to normal hepatic function group, total deucravacitinib Cmax and AUC[INF] in mild and moderate hepatic impairment group increased by up to 10% and 40%, respectively while the unbound deucravacitinib Cmax and AUC(INF) increased by up to 26% and 60%, respectively. In severe (Child-Pugh Class C) hepatic impaired adults, total deucravacitinib Cmax was comparable and total AUC was 43% higher relative to matched healthy adults. In these adults, unbound Cmax and AUC(INF) increased by 62% and 131%, respectively. Deucravacitinib is not recommended for use in patients with severe hepatic impairment.
The AUC(0-T) of BMT-153261 decreased by 19%, 53% and 76% in subjects with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function, while Cmax of BMT-153261, decreased by 25%, 59%, and 79% in subjects with mild, moderate, and severe hepatic impairment, respectively.
Based on population pharmacokinetic modelling and simulation, females are expected to have an about 30% higher deucravacitinib mean steady-state exposure (Cmax,ss and Cavg,ss) compared to male.
Based on population pharmacokinetic modelling and simulation, patients with lower body weight (<60 kg) are expected to have a higher geometric mean steady-state exposure of deucravacitinib of 37.4% (Cmaxss) and 24.8% (Cavgss). Patients with a higher body weight (>90 kg) are expected to have a lower geometric mean steady-state deucravacitinib exposure of 24.8% (Cmax,ss) and 19.6% (Cavgss) (compared to patients with body weight 60-90 kg).
Race, and ethnicity did not have a clinically meaningful effect on deucravacitinib exposure.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
In the chronic toxicity study in rats, decreases in lymphocyte counts, bone marrow cellularity and lymphoid cellularity in tissues of the immune system were observed at exposure (AUC) at lowestobserved-effect-level (LOEL) approximately 9 times the recommended human dose (RHD). These effects were not associated with clinical signs of immunosuppression (e.g., infections). Decreases in platelet counts and red blood cell (RBC) mass parameters were observed at exposure (AUC) at the LOEL approximately 42 times the RHD. In the chronic toxicity study in monkeys, clinical and microscopic skin changes and decreased RBC mass parameters were observed at exposure (AUC) at LOEL approximately 7 times the RHD.
Deucravacitinib had no effects on fertility or early embryonic development in male and female rats at exposures (AUC) up to approximately 247 and 171 times the RHD, respectively. Deucravacitinib was neither embryo-lethal nor teratogenic at maternal exposures (AUC) up to approximately 266 times the RHD in rats or 91/20 (total/free) times the RHD in rabbits.
In a pre- and post-natal development study in rats, transiently lower pup body weights were noted during the pre-weaning period at maternal exposure (AUC) approximately 110 times the RHD. This effect fully recovered during the post-weaning period.
Following administration of radiolabelled deucravacitinib to lactating rats, deucravacitinib and/or its metabolites were present in the milk with milk-to-plasma concentration ratios of 2.7 to 30.9.
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