Chemical formula: C₁₆H₁₈N₆O Molecular mass: 310.361 g/mol PubChem compound: 50914062
Delgocitinib is a pan Janus kinase (JAK) inhibitor that targets the activity of all four members of the JAK family of enzymes consisting of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) in a concentration dependent manner.
In human cells, inhibition of the JAK-STAT pathway by delgocitinib attenuates the signalling of several pro-inflammatory cytokines (including interleukin (IL)-2, IL-4, IL-6, IL-13, IL-21, IL-23, Granulocyte-Macrophage-Colony-Stimulating Factor (GM-CSF), and Interferon (IFN)-α) downregulating the immune and inflammatory responses in cells of relevance to CHE pathology.
In a thorough QT study in healthy subjects, there was no indication of a QTc prolonging effect of orally administered delgocitinib at single doses up to 12 mg (approximately 200 times the human 6 exposure following topical application, based on Cmax). Therefore, delgocitinib is not expected to affect cardiac repolarisation under conditions of clinical use.
The pharmacokinetics of delgocitinib cream were evaluated in a study involving 15 adult patients 22 to 69 years of age with moderate to severe CHE. Patients applied on average 0.87 g of delgocitinib 20 mg/g cream to the affected areas of the hands and wrists twice a day for 8 days.
The geometric mean (GSD) maximum plasma concentration (Cmax) and area under the concentration-curve from time 0 to 12 hours (AUC0-12) on Day 8 was 0.46 ng/mL (1.74) and 3.7 ng*h/mL (1.74), respectively. Steady state was reached by Day 8. The systemic exposure (AUC and Cmax) between Day 1 and Day 8 were similar.
Following twice daily application of delgocitinib 20 mg/g cream in DELTA 2, the geometric mean plasma concentration observed 2-6 hours after application at Day 113 was 48% lower than that at Day 8 (0.11 ng/mL and 0.21 ng/mL, respectively).
The relative bioavailability of delgocitinib following topical application is approximately 0.6% compared to administration via oral tablets.
Based on an in vitro study, plasma protein binding of delgocitinib is 22 to 29%.
As delgocitinib does not undergo extensive metabolism, the main plasma component is unchanged delgocitinib. Following oral administration, four metabolites (formed via oxidation and glucuronide conjugation) were detected at <2% of the average unchanged delgocitinib plasma concentrations. The limited metabolism of delgocitinib occurs primarily though CYP3A4/5 and to a lesser extent by CYP1A1, CYP2C19, and CYP2D6.
Based on in vitro data, delgocitinib does not inhibit or induce cytochrome P450 enzymes or inhibit transporter systems such as organic anion transporters (OAT), organic anion transporting polypeptides (OATP), organic cation transporters (OCT), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or multidrug and toxin extrusion proteins (MATE) at clinically relevant concentrations.
Delgocitinib is a substrate of P-glycoprotein (P-gp) and a weak substrate of human organic cation transporter 2 (OTC2) and human organic anion transporter 3 (OAT3).
Delgocitinib is primarily eliminated by renal excretion as approximately 70-80% of the total dose after oral administration was found unchanged in the urine.
Following repeated topical application of delgocitinib cream, the average half-life of delgocitinib was estimated to be 20.3 hours.
No formal studies of delgocitinib cream in patients with hepatic impairment have been conducted.
Due to the minimal systemic exposure of topically applied delgocitinib and limited metabolism of delgocitinib, changes in hepatic function are unlikely to have any effect on the elimination of delgocitinib.
Pharmacokinetic parameters of delgocitinib were analysed in 96 patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m²) in DELTA 2. There were no clinically relevant differences in the pharmacokinetics observed in patients with mild or moderate renal impairment compared to the overall study population. Renal function impairment is unlikely to result in clinically important changes in exposure to delgocitinib due to the minimal systemic exposure following topical administration.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, phototoxicity, local tolerability, skin sensitisation, and juvenile toxicity. Effects in repeat dose toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure following topical application.
In a 2-year dermal carcinogenicity study in mice, no local or systemic drug-related neoplastic findings were observed (at exposures up to approximately 600 times the human exposure based on AUC).
Orally administered delgocitinib did not result in effects on fertility at any dose level evaluated in male rats (exposures approximately 1 700 times the human exposure). In female rats, orally administered delgocitinib resulted in effects on female fertility (lower fertility index, fewer corpora lutea, and fewer implantations) at exposures approximately 5 800 times the human exposure. Post-implantation losses and a decrease in the number of live embryos were observed at exposures approximately 432 and 1 000 times the human exposure, respectively.
Orally administered delgocitinib did not result in adverse effects to the foetus in rats or rabbits at exposures approximately 120 and 194 times the human exposure, respectively. Teratogenic effects were not observed at any dose studied in rats or rabbits (exposures approximately 1 400 and 992 times the human exposure, respectively).
In rats, decreases in foetal weight and skeletal variations were observed at exposures 512 times the human exposure and a tendency toward an increase in post-implantation loss was observed at exposures approximately 1 400 times the human exposure. In rabbits, an increase in post-implantation 12 loss, a reduced number of live foetuses, and a tendency toward a decrease in foetal weights were observed at exposures approximately 992 times the human exposure.
No effects during pregnancy are anticipated, since systemic exposure to delgocitinib is negligible. As a precautionary measure, it is preferable to avoid the use of delgocitinib during pregnancy.
Orally administered delgocitinib in rats resulted in decreased foetal viability and reduced pup weights during the early postnatal period at exposures > 2 000 times the human exposure. There was no effect on behavioural and learning assessments, sexual maturation, or reproductive performance of the offspring at any dose studied.
Following oral administration to lactating rats, delgocitinib was secreted in milk at concentrations approximately 3-fold those in the plasma.
No effects on the breastfed newborn/infant are anticipated since the systemic exposure in the breast-feeding woman to delgocitinib is negligible. Delgocitinib can therefore be used during breast-feeding.
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