Mechanism Of Action
Baricitinib is a Janus kinase (JAK) 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 hematopoiesis
and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and
Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates
the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2,
JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2
and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by
JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of
specific JAK enzymes to therapeutic effectiveness is not currently known.
Baricitinib Inhibition Of IL-6 Induced STAT3 Phosphorylation
Baricitinib administration resulted in a dose
dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition
observed approximately 1 hour after dosing, which returned to near baseline by 24 hours. Similar levels of inhibition were
observed using either IL-6 or TPO as the stimulus.
Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with
OLUMIANT, and remained stable through at least 52 weeks. For most patients, changes in immunoglobulins occurred
within the normal reference range.
In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were
observed as early as one week after starting treatment with OLUMIANT and were maintained throughout dosing.
At a dose 10 times the maximum recommended dose, baricitinib does not prolong the
QT interval to any clinically relevant extent.
Following oral administration of OLUMIANT, peak plasma concentrations are reached approximately at 1 hour. A
dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of
baricitinib do not change over time. Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation
after once-daily administration.
The absolute bioavailability of baricitinib is approximately 80%. An assessment of food effects in
healthy subjects showed that a high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and
18%, respectively, and delayed the tmax by 0.5 hours. Administration with meals is not associated with a clinically relevant
effect on exposure. In clinical studies, OLUMIANT was administered without regard to meals.
After intravenous administration, the volume of distribution is 76 L, indicating distribution of baricitinib
into tissues. Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. Baricitinib is a
substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution.
The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients
with rheumatoid arthritis is approximately 12 hours.
Approximately 6% of the orally administered baricitinib dose is identified as metabolites (three from
urine and one from feces), with CYP3A4 identified as the main metabolizing enzyme. No metabolites of baricitinib were
quantifiable in plasma.
Renal elimination is the principal clearance mechanism for baricitinib through filtration and active
secretion as baricitinib is identified as a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. 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 feces. Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces
Effects Of Body Weight, Gender, Race, And Age
Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of
baricitinib (Figure 1). The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the
inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of
baricitinib are approximately 41% and 22%, respectively. [See Use In Specific Populations].
Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate,
severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal
function. The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (Figure 1) [see Use In Specific Populations].
Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment
group, respectively, compared to subjects with normal hepatic function (Figure 1) [see Use In Specific Populations].
Figure 1: Impact of Intrinsic Factors on Baricitinib Pharmacokineticsa,b
a Reference values for weight, age, gender, and race comparisons are 70 kg, 54 years, male, and white, respectively; reference groups for renal and hepatic impairment are subjects with normal renal and hepatic function, respectively.
b Effects of renal and hepatic impairment on baricitinib exposure were summarized from dedicated renal and hepatic impairment studies, respectively. Effects of other intrinsic factors on baricitinib exposure were summarized from population PK analysis.
Potential For Baricitinib To Influence The PK Of Other Drugs
In vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2,
2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, there were no clinically meaningful changes in the
pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with
In vitro studies suggest that baricitinib is not an inhibitor of the transporters, P-glycoprotein (Pgp) or Organic Anion
Transporting Polypeptide (OATP) 1B1. In vitro data indicate baricitinib does inhibit organic anionic transporter (OAT) 1,
OAT2, OAT3, organic cationic transporter (OCT) 1, OCT2, OATP1B3, Breast Cancer Resistance Protein (BCRP) and
Multidrug and Toxic Extrusion Protein (MATE) 1 and MATE2-K, but clinically meaningful changes in the pharmacokinetics
of drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically
meaningful effects on the PK of digoxin (Pgp substrate) or methotrexate (substrate of several transporters) when coadministered
Exposure changes of drugs following co-administration with baricitinib are shown in Figure 2.
Figure 2: Impact of Baricitinib on the Pharmacokinetics of Other Drugsa
a Reference group is administration of concomitant drug alone.
Potential For Other Drugs To Influence The PK Of Baricitinib
In vitro studies suggest that baricitinib is a CYP3A4 substrate. In clinical pharmacology studies there was no effect
on the PK of baricitinib when co-administered with ketoconazole (CYP3A inhibitor). There were no clinically meaningful
changes in the PK of baricitinib when co-administered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin
In vitro studies suggest that baricitinib is a substrate for OAT3, Pgp, BCRP and MATE2-K. In a clinical study,
probenecid administration (strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib AUC0-∞ with no
effect on Cmax and tmax [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. However, simulations with
diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on the PK of baricitinib. In
clinical pharmacology studies there was no clinically meaningful effect on the PK of baricitinib when co-administered with
cyclosporine (Pgp and BCRP inhibitor). Co-administration with methotrexate (substrate of several transporters) did not
have a clinically meaningful effect on the PK of baricitinib.
Exposure changes of baricitinib following co-administration with CYP inhibitors or inducers, transporter inhibitors,
as well as methotrexate and the proton pump inhibitor, omeprazole, are shown in Figure 3.
Figure 3: Impact of Other Drugs on the Pharmacokinetics of Baricitinibb
a Values are based on simulated studies.
b Reference group is administration of baricitinib alone.
The OLUMIANT clinical development program included two dose-ranging trials and four confirmatory
phase 3 trials. Although other doses have been studied, the recommended dose of OLUMIANT is 2 mg once daily.
The dose-ranging studies I (NCT01185353) and II (NCT01469013) included a 12-week randomized comparison of
baricitinib 1, 2, 4, and 8 mg versus placebo in 301 and 145 patients, respectively.
The results from the dose-ranging studies are shown in Table 5. In dose-ranging Study I, the observed ACR
response was similar for baricitinib 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for
baricitinib 8 mg daily. In dose-ranging Study II, there was not a clear trend of dose response, with similar response rates
for 1 mg and 4 mg and 2 mg and 8 mg.
Table 5: Proportion of Patients with ACR20 Response at Week 12 in Dose-Ranging Studies
||% ACR20 Responders
1 mg daily
2 mg daily
4 mg daily
8 mg daily
The efficacy and safety of OLUMIANT 2 mg once daily was assessed in two confirmatory phase 3 trials. These
trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according
to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years
of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies III and IV)
evaluated OLUMIANT 2 mg and baricitinib 4 mg.
Study III (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid
arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received
OLUMIANT 2 mg or 4 mg once daily or placebo added to existing background cDMARD treatment. From Week 16, nonresponding
patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of
patients who achieved an ACR20 response at Week 12.
Study IV (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid
arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic
DMARDs (TNFi-IR). Patients received OLUMIANT 2 mg or baricitinib 4 mg once daily or placebo added to background
cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The
primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.
The percentages of OLUMIANT-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease
Activity Score (DAS28-CRP) <2.6 in Studies III and IV are shown in Table 6.
Patients treated with OLUMIANT had higher rates of ACR response and DAS28-CRP <2.6 versus placebo-treated
patients at Week 12 (Studies III and IV) (Table 6).
In Study IV, higher ACR20 response rates (Figure 4) were observed as early as 1 week with OLUMIANT 2 mg
In Study IV, the proportions of patients achieving DAS28-CRP <2.6 who had at least 3 active joints at the end of
Week 24 were 18.2% and 10.5%, in the placebo and OLUMIANT 2 mg arms, respectively.
Table 6: Clinical Responsea
||Percent of Patients
|Placebo + cDMARDs
2 mg/day + cDMARDs
Δ (95% CI)b
|Placebo + cDMARDs
2 mg/day + cDMARDs
Δ (95% CI)b
27 (18, 35)
22 (12, 32)
19 (10, 28)
18 (8, 27)
21 (13, 28)
12 (5, 19)
20 (12, 28)
10 (2, 18)
15 (9, 20)
11 (5, 16)
17 (11, 24)
10 (4, 16)
a Patients who were rescued or discontinued treatment were considered as non-responders in the analyses.
b 95% confidence interval for the difference (Δ) in response rate between OLUMIANT treatment and placebo (Study III,
The effects of OLUMIANT treatment on the components of the ACR response criteria for Studies III and IV are
shown in Table 7.
Table 7: Components of ACR Response at Week 12 in Studies III and IVa
|Number of Tender Joints (0-68)
| Week 12
|Number of Swollen Joints (0-66)
| Week 12
| Week 12
|Patient Global Assessmentb
| Week 12
|Physician Global Assessmentb
| Week 12
|Disability Index (HAQ-DI)c
| Week 12
| Week 12
a Data shown are mean (standard deviation).
b Visual analog scale: 0=best, 100=worst.
c Health Assessment Questionnaire–Disability Index: 0=best, 3=worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
Figure 4: Percent of Patients Achieving ACR20
Physical Function Response
Improvement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQDI).
Patients receiving OLUMIANT 2 mg demonstrated greater improvement from baseline in physical functioning
compared to placebo at Week 24. The mean difference (95% CI) from placebo in HAQ-DI change from baseline at
Week 24 was -0.24 (-0.35, -0.14) in Study III and -0.23 (-0.35, -0.12) in Study IV.
Other Health Related Outcomes
General health status was assessed by the Short Form health survey (SF-36). In Studies III and IV, compared to
placebo, patients treated with OLUMIANT 2 mg demonstrated greater improvement from baseline in the physical
component summary (PCS) score and the physical function, role physical, bodily pain, vitality, and general health
domains at Week 12, with no consistent improvements in the mental component summary (MCS) scores or the role
emotional, mental health, and social functioning domains.