Chemical formula: C₁₆H₁₇N₇O₂S Molecular mass: 371.42 g/mol PubChem compound: 44205240
Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50 values of 5.9, 5.7, 53 and >400 nM, respectively.
Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.
Administration of baricitinib resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed 2 hours after dosing which returned to near baseline by 24 hours.
Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment, and remained stable at a lower value than baseline through at least 104 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range.
Mean absolute lymphocyte count increased by 1 week after starting treatment, returned to baseline by week 24, and then remained stable through at least 104 weeks. For most patients, changes in lymphocyte count occurred within the normal reference range.
In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as 1 week after starting treatment and were maintained throughout dosing.
In clinical trials, baricitinib induced a mean increase in serum creatinine levels of 3.8 μmol/L after two weeks of treatment, which remained stable thereafter. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules. Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse reactions. In alopecia areata, mean serum creatinine continued to increase up to week 52. In atopic dermatitis and alopecia areata, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) at week 4, with no further decreases thereafter.
In an in vitro human skin model treated with pro-inflammatory cytokines (i.e., IL-4, IL-13, IL-31), baricitinib reduced epidermal keratinocyte pSTAT3 expression, and increased the expression of filaggrin, a protein that plays a role in skin barrier function and in the pathogenesis of atopic dermatitis.
Following oral administration of baricitinib, a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The PK of baricitinib is linear with respect to time.
Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour (range 0.5-3.0 h) and an absolute bioavailability of approximately 79% (CV=3.94%). Food intake led to a decreased exposure by up to 14%, a decrease in Cmax by up to 18% and delayed tmax by 0.5 hours. Administration with meals was not associated with a clinically relevant effect on exposure.
Mean volume of distribution following intravenous infusion administration was 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins.
Baricitinib metabolism is mediated by CYP3A4, with less than 10% of the dose identified as undergoing biotransformation. No metabolites were quantifiable in plasma. In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69%) and faeces (15%) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in faeces) constituting approximately 5% and 1% of the dose, respectively. In vitro, baricitinib is a substrate for CYP3A4, OAT3, Pgp, BCRP and MATE2-K, and may be a clinically relevant inhibitor of the transporter OCT1. Baricitinib is not an inhibitor of the transporters OAT1, OAT2, OAT3, OCT2, OATP1B1, OATP1B3, BCRP, MATE1 and MATE2-K at clinically relevant concentrations.
Renal elimination is the principal mechanism for baricitinib’s clearance through glomerular filtration and active secretion via OAT3, Pgp, BCRP and MATE2-K. In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the faeces.
Mean apparent clearance (CL/F) and half-life in patients with rheumatoid arthritis was 9.42 L/hr (CV=34.3%) and 12.5 hrs (CV=27.4%), respectively. Cmax and AUC at steady state are 1.4- and 2.0-fold higher, respectively, in subjects with rheumatoid arthritis compared to healthy subjects.
Mean apparent clearance (CL/F) and half-life in patients with atopic dermatitis was 11.2 L/hr (CV=33.0%) and 12.9 hrs (CV=36.0%), respectively. Cmax and AUC at steady state in patients with atopic dermatitis are 0.8-fold those seen in rheumatoid arthritis.
Mean apparent clearance (CL/F) and half-life in patients with alopecia areata was 11.0 L/hr (CV=36.0%) and 15.8 hrs (CV=35.0%), respectively. Cmax and AUC at steady state in patients with alopecia areata are 0.9-fold those seen in rheumatoid arthritis.
Renal function was found to significantly affect baricitinib exposure. The mean ratios of AUC in patients with mild and moderate renal impairment to patients with normal renal function are 1.41 (90% CI: 1.15-1.74) and 2.22 (90% CI: 1.81-2.73), respectively. The mean ratios of Cmax in patients with mild and moderate renal impairment to patients with normal renal function are 1.16 (90%CI: 0.92-1.45) and 1.46 (90%CI: 1.17-1.83), respectively.
There was no clinically relevant effect on the PK of baricitinib in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment.
Age ≥65 years or ≥75 years has no effect on baricitinib exposure (Cmax and AUC).
The half-life in paediatric patients from 2 to less than18 years was 8 to 9 hours.
Exposure in paediatric patients weighing <30 kg and ≥30 kg:
In patients <30 kg with a mean age and range of 8.1 (2.0-16.0) years, the mean and CV% for AUC and Cmax was 381 h*ng/mL (76%) and 62.1 ng/mL (39%), respectively. In patients ≥30 kg with mean age and range of 14.1 (9.0–17.0), the mean and CV% for AUC and Cmax was 438 h*ng/mL (68%) and 60.7 ng/mL (30%), respectively.
Exposure in paediatric patients weighing 10 to <20 kg and 20 to <30 kg:
In patients 10 to <20 kg with a mean age and range of 5.1 (2.0-8.0) years, the mean and CV% for AUC and Cmax was 458 h*ng/mL (81%) and 77.6 ng/mL (38%), respectively. In patients 20 to <30 kg with mean age and range of 10.3 (6.0–16.0), the mean and CV% for AUC and Cmax was 327 h*ng/mL (66%) and 51.2 ng/mL (22%), respectively.
The mean half-life in paediatric patients from 2 to less than 18 years was 13 to 18 hours.
Exposure in paediatric patients weighing <30 kg and ≥30 kg:
In patients <30 kg with a mean age and range of 6.4 (2.0-11.1) years, the mean and CV% for AUC and Cmax was 404 h*ng/mL (78%) and 60.4 ng/mL (28%), respectively. In patients ≥30 kg with mean age and range of 13.5 (6.2–17.9), the mean and CV% for AUC and Cmax was 529 h*ng/mL (102%) and 57.0 ng/mL (42%), respectively.
Exposure in paediatric patients weighing 10 to <20 kg and 20 to <30 kg:
In patients 10 to <20 kg with a mean age and range of 4.8 (2.0-6.9) years, the mean and CV% for AUC and Cmax was 467 h*ng/mL (80%) and 73.4 ng/mL (21%), respectively. In patients 20 to <30 kg with mean age and range of 7.5 (4.8–11.1), the mean and CV% for AUC and Cmax was 363 h*ng/mL (72%) and 52.0 ng/mL (21%), respectively
Body weight, age, sex, race, and ethnicity did not have a clinically relevant effect on the PK of baricitinib in adult patients. The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. Therefore, no dose adjustment is needed based on these patient factors.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.
Decreases in lymphocytes, eosinophils and basophils as well as lymphoid depletion in organs/tissues of the immune system were observed in mice, rats and dogs. Opportunistic infections related to demodicosis (mange) were observed in dogs at exposures approximately 7 times the human exposure. Decreases in red blood cell parameters were observed in mice, rats and dogs at exposures approximately 6 to 36 times the human exposure. Degeneration of the sternal growth plate was observed in some dogs, at low incidence and also in control animals, but with a dose-effect relationship regarding severity. At present it is not known whether this is clinically relevant.
In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively). No adverse foetal effects were observed at exposures 2 times the human exposure based on AUC.
In a combined male/female rat fertility study, baricitinib decreased overall mating performance (decreased fertility and conception indices). In female rats there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos. Since there were no effects on spermatogenesis (as assessed by histopathology) or semen/sperm endpoints in male rats, the decreased overall mating performance was likely the result of these female effects.
Baricitinib was detected in the milk of lactating rats. In a pre- and postnatal development study, decreased pup weights and decreased postnatal survival were observed at exposures 4 and 21 times, respectively, the human exposure.
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