Chemical formula: C₁₄H₂₁N₅O₂S Molecular mass: 323.42 g/mol PubChem compound: 78323835
Abrocitinib is a Janus kinase (JAK)1 inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of haematopoiesis and immune cell function. JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Inhibition of JAK1 modulates the signalling pathways by preventing the phosphorylation and activation of STATs.
In biochemical assays, abrocitinib has selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase 2 (TYK2, 43-fold). In cellular settings, it preferentially inhibits cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, and spares signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of selective enzymatic inhibition of specific JAK enzymes to clinical effect is not currently known.
Treatment with abrocitinib was associated with dose-dependent reduction in serum biomarkers of inflammation in atopic dermatitis [interleukin-31 (IL-31), interleukin-22 (IL-22), eosinophil count, and thymus and activation-regulated chemokine (TARC)], JAK1 signalling [natural killer (NK) cell count and interferon gamma-induced protein 10 (IP-10)] or both [high sensitivity C-reactive protein (hsCRP)]. These changes were reversible after treatment discontinuation.
Mean absolute lymphocyte count increased by 2 weeks after starting treatment with abrocitinib and returned to baseline by Month 9 of treatment. Most patients maintained an ALC within the reference range. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts. The clinical significance of these changes in B cell and NK cell counts is unknown.
The effect of abrocitinib on the QTc interval was examined in subjects who received a single supratherapeutic dose of abrocitinib 600 mg in a placebo- and positive-controlled thorough QT study. A concentration-dependent QTc prolonging effect of abrocitinib was seen; the mean (90% confidence interval) for the increase in QTc interval was 6.0 (4.52, 7.49) msec, indicating the lack of a clinically relevant effect of abrocitinib on QTc interval at the dose tested.
Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The oral absorption of abrocitinib is rapid and peak plasma concentrations are reached within 1 hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration. Both Cmax and AUC of abrocitinib increased dose proportionally up to 200 mg. Co-administration of abrocitinib with a high-fat meal had no clinically relevant effect on abrocitinib exposures (AUC and Cmax increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours). In clinical studies, abrocitinib was administered without regard to food.
After intravenous administration, the volume of distribution of abrocitinib is about 100 L. Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites distribute equally between red blood cells and plasma.
The in vitro metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabelled study, abrocitinib was the most prevalent circulating species, with mainly 3 polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl) and M4 (pyrrolidinone pyrimidine). At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite. Of the 3 metabolites in circulation, M1 and M2 have similar JAK inhibitory profiles as abrocitinib, while M4 was pharmacologically inactive. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety.
The elimination half-life of abrocitinib is about 5 hours. Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged active substance. The metabolites of abrocitinib, M1, M2 and M4 are excreted predominantly in urine, and are substrates of OAT3 transporter.
Body weight, gender, CYP2C19/2C9 genotype, race and age did not have a clinically meaningful effect on abrocitinib exposure.
Based on population pharmacokinetic analysis, there was no clinically relevant difference in mean abrocitinib steady-state exposures in adolescent patients compared to adults at their typical body weights.
Interaction studies have been performed in adults only. The pharmacokinetics of abrocitinib in children under 12 years of age have not yet been established.
In a renal impairment study, patients with severe (eGFR <30 mL/min) and moderate (eGFR 30 to <60 mL/min) renal impairment had approximately 191% and 110% increase in active moiety AUCinf, respectively, compared to patients with normal renal function (eGFR ≥90 mL/min). Pharmacokinetics of abrocitinib have not been determined in patients with mild renal impairment, however, based on the results observed in other groups, an increase of up to 70% in active moiety exposure is expected in patients with mild renal impairment (eGFR 60 to <90 mL/min). The increase of up to 70% is not clinically meaningful as the efficacy and safety of abrocitinib in atopic dermatitis patients with mild renal impairment (n=756) was comparable to the overall population in Phase 2 and 3 clinical studies. The eGFR in individual patients was estimated using Modification of Diet in Renal Disease (MDRD) formula.
Abrocitinib has not been studied in patients with ESRD on renal replacement therapy. In Phase 3 clinical studies, abrocitinib was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had approximately 4% decrease and 15% increase in active moiety AUCinf, respectively, compared to patients with normal hepatic function. These changes are not clinically significant, and no dose adjustment is required in patients with mild or moderate hepatic impairment. In clinical studies, abrocitinib was not evaluated in patients with severe (Child Pugh C) hepatic impairment, or in patients screened positive for active hepatitis B or hepatitis C.
Decreased lymphocyte counts and decreased size and/or lymphoid cellularity of organs/tissues of the immune and haematopoietic systems were observed in nonclinical studies and were attributed to the pharmacological properties (JAK inhibition) of abrocitinib.
In toxicity studies of up to 1 month of abrocitinib dosing in rats at an age comparable to adolescent human age of ≥12 years, a microscopic bone dystrophy finding, considered transient and reversible, was noted, and exposure margins at which no bone finding was noted were 5.7 to 6.1 times the human AUC at the maximum recommended human dose (MRHD) of 200 mg. No bone findings were observed in rats at any dose in the 6-month toxicity study (up to 25 times the human AUC at the MRHD of 200 mg) or in any of the toxicity studies in cynomolgus monkeys (comparable to human age of ≥8 years; up to 30 times the human AUC at the MRHD of 200 mg).
Abrocitinib was not mutagenic in the bacterial mutagenicity assay (Ames assay). It was not aneugenic or clastogenic based on the results of the in vivo rat bone marrow micronucleus assay.
No evidence of tumorigenicity was observed in the 6-month Tg.rasH2 mice administered abrocitinib at oral doses up to 75 mg/kg/day and 60 mg/kg/day in female and male mice, respectively. In the 2-year carcinogenicity study, higher incidence of benign thymoma was noted in female rats at the lowest dose tested. Thus, a lowest observed adverse effect level (LOAEL) is set in females at exposures equal to 0.6 times the human AUC at the MRHD of 200 mg. In males the no observed adverse effect level (NOAEL) was set at exposures equal to 13 times the human AUC at the MRHD of 200 mg. The human relevance of benign thymoma is unknown.
Abrocitinib had no effects on male fertility or spermatogenesis. Abrocitinib resulted in effects on female fertility (lower fertility index, corpora lutea, implantation sites and post-implantation loss), but no fertility effects were noted at exposures equal to 1.9 times the human AUC at the MRHD of 200 mg. The effects reversed 1 month after cessation of treatment.
No foetal malformations were observed in embryo-foetal development studies in rats or rabbits. In an embryo-foetal development study in pregnant rabbits, effects on embryo-foetal survival were noted at the lowest dose tested with exposures equal to 0.14 times the unbound human AUC at the MRHD of 200 mg. Increased litter incidences of unossified hindlimb phalanges and tarsals and forelimb phalanges were observed with effects on forelimb phalanges noted at exposures equal to 0.14 times the unbound human AUC at the MRHD of 200 mg.
In an embryo-foetal development study in pregnant rats, while increased embryo-foetal lethality was noted, none was observed at exposures equal to 10 times the human AUC at the MRHD of 200 mg. Increased incidence of skeletal variations of short 13th ribs, reduced ventral processes, thickened ribs, and unossified metatarsals were noted in the foetuses, but none were observed at exposures equal to 2.3 times the human AUC at the MRHD of 200 mg.
In a pre- and postnatal development study in pregnant rats, dams had dystocia with prolonged parturition, offspring had lower body weights and lower postnatal survival. No maternal or developmental toxicity was observed in either dams or offspring at exposures equal to 2.3 times the human AUC at the MRHD of 200 mg.
Administration of abrocitinib to juvenile rats (comparable to a 3 month old human) resulted in macroscopic and microscopic bone findings. When dosing was initiated at postnatal Day 10 (at exposures ≥0.8 times the human AUC at the MRHD of 200 mg), macroscopic bone findings (malrotated and/or impaired use of forelimbs or hindlimbs or paws, fractures, and/or femoral head abnormalities) were noted. Only the microscopic bone dystrophy finding (similar to that observed in rat general toxicity studies of up to 1 month) was fully reversible after cessation of treatment.
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