Olumiant ® (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information.For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).

Can Olumiant® (baricitinib) be used in rheumatoid arthritis patients with renal impairment?

The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min. Baricitinib is not recommended for use in patients with creatinine clearance < 30 mL/min.

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UK_cFAQ_BAR051A_RENAL_IMPAIRMENT_RA
en-GB

Information from the label

In rheumatoid arthritis, baricitinib (BARI) induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, as compared to placebo, which remained stable thereafter during up to 104 weeks of treatment. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules.1

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 events.1

Renal function was found to significantly affect baricitinib exposure.1

  • The mean ratios of area under the concentration-time curve (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.1
  • 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.1

Phase 3 clinical studies of rheumatoid arthritis

Dose adjustments implemented in clinical studies to account for renal function

Patients with an estimated glomerular filtration rate (eGFR) ≥40 and <60 mL/min/1.73 m2 received BARI 2 mg once daily regardless of whether they were assigned to the 2mg or 4mg BARI treatment arms.2

Patients were excluded from the phase 3 studies if they had an eGFR <40 mL/min/1.73m2 calculated based on the most recent available serum creatinine using the Modification of Diet in Renal Disease (MDRD) method.2

Patients by baseline renal function by study in the phase 3 rheumatoid arthritis clinical trial program2

Phase 3 Study (mITT)

Baseline eGFRa
< 60 mL/min/1.73 m2, n

Baseline eGFRa
≥ 60 mL/min/1.73 m2, n

RA-BEGIN (N=584)

MTX

8

202

Baricitinib 4 mg

5

154

MTX + Baricitinib 4 mg

10

205

RA-BEAM (N=1305)

Placebo

23

465

Baricitinib 4 mg

15

472

Adalimumab

16

314

RA-BUILD (N=684)

Placebo

18

209

Baricitinib 2 mg

15

214

Baricitinib 4 mg

19

207

RA-BEACON (N=527)

Placebo

17

159

Baricitinib 2 mg

12

162

Baricitinib 4 mg

10

167

Abbreviations: eGFR = estimated glomerular filtration rate; mITT = modified intent-to-treat; MTX = methotrexate; SCr = serum creatinine.

aeGFR was calculated by the Modification of Diet in Renal Disease of 175 x (SCr [mg/dL])-1.154 x (age [yrs])-0.203 x (0.742 if female) x (1.210 if black).

Integrated safety analysis performed using renal function subgroups

Patients with renal function impairment who were randomized to BARI 4 mg, but whose adjusted BARI dose was 2 mg, were analyzed in the 4-mg group.2

Subgroup analyses were performed in BARI-treated patients using the renal function subgroups of none (n=1552), mild (n=1446), and moderate (n=175) dysfunction.

Compared to patients with no renal impairment, patients with mild and moderate renal impairment had higher numerical exposure adjusted incidence rates (EAIRs) of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and (adverse events) AEs leading to permanent discontinuation.2 Please find more details in Overview of adverse events by baseline renal impairment in baricitinib-treated patients. 

Overview of adverse events by baseline renal impairment in baricitinib-treated patients2

Adverse Events

Normal RIa
n=1552
(2399.5 PYE)

Mild RIb
n=1446
(2291.7 PYE)

Moderate RIc
n=175
(249.9 PYE)

All BARI RAd
n=3439
(5130.4 PYE)

n (%)

EAIR

n (%)

EAIR

n (%)

EAIR

n (%)

EAIR

Total TEAEs

1192 (76.8)

49.7

1203 (83.2)

52.5

151 (86.3)

60.4

2546 (80.2)

51.5

Renal and urinary TEAEs

46 (3.0)

1.9

56 (3.9)

2.4

19 (10.9)

7.6

121 (3.8)

2.4

Total SAEs

167 (10.8)

7.0

219 (15.1)

9.6

45 (25.7)

18.0

431 (13.6)

8.7

Renal and urinary SAEs

6 (0.4)

0.3

4 (0.3)

0.2

1 (0.6)

0.4

11 (0.3)

0.2

D/C due to AE or deathe

97 (6.3)

4.0

120 (8.3)

5.2

22 (12.6)

8.8

239 (7.5)

4.8

Death

0

0

7 (0.5)

0.3

1 (0.6)

0.4

8 (0.3)

0.2

Abbreviations: AE = adverse event; BARI = baricitinib; D/C = discontinuation; EAIR = exposure adjusted incidence rate; eGFR = estimated glomerular filtration rate; PYE = patient-years of exposure; RA = rheumatoid arthritis; RI = renal impairment; SAEs = serious adverse events; SOC = system organ class; TEAEs = treatment emergent adverse events.

aNormal RI = eGFR ≥90 mL/min/1.73 m2.

bMild RI = eGFR ≥60 to 90 mL/min/1.73 m2.

cModerate RI = eGFR ≥30 to <60 mL/min/1.73 m2.

dAll BARI RA includes all patients who received any dose of BARI from 1 phase 2 and 5 phase 3 trials including a long-term extension study with data through 01JAN2016.

eOne discontinuation was due to AE from the renal and urinary SOC in a patient with normal renal function.

Pharmacokinetics 

Renal elimination

Renal elimination is the principal mechanism for baricitinib’s clearance through glomerular filtration and active secretion via

  • OAT3,
  • Pgp,
  • BCRP and
  • MATE2-K.1

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.1

Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%).2

The elimination half-life of BARI is approximately 13 hours in patients with RA.2

Baricitinib exposure by renal function

Renal study in non-rheumatoid arthritis patients

Baricitinib exposure was evaluated in patients with mild, moderate, and severe renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis, compared with healthy subjects with normal renal function.2

The dose-normalized geometric mean ratios of BARI exposure (AUC) relative to healthy subjects from each of the renally-impaired cohorts were

  • 1.41 for mild
  • 2.22 for moderate
  • 4.05 for severe
  • 3.18 for ESRD with hemodialysis predose, and
  • 2.41 for ESRD with hemodialysis postdose.2

The mean terminal half-life by subgroup was

  • 8.4 hours with normal renal function
  • 10 hours with mild renal impairment, and
  • 19 hours with severe renal impairment or ESRD.2

These results suggest that renal impairment significantly affects exposure to BARI, leading to increased exposure with decreasing renal function. Baricitinib does appear to be dialyzable.2

Renal analysis in rheumatoid arthritis patients

In a phase 2 and 3 population PK simulation analysis, patients with RA showed a less pronounced effect on BARI exposure by eGFR subgroup than observations in non-RA subjects. The estimated AUC ratio compared to normal renal function was

  • 1.30 for mild, and
  • 1.62 for moderate.2

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266.

Appendix

Renal function subgroups for pharmacokinetic and safety analyses

Renal impairment subgroups were defined using the eGFR ranges from the National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease. Subgroups by baseline eGFR included

  • none or normal defined as eGFR ≥90 mL/min/1.73 m2
  • mild defined as eGFR ≥60 to <90 mL/min/1.73 m2
  • moderate defined as eGFR ≥30 to <60 mL/min/1.73 m2
  • severe defined as eGFR 15 to <30 mL/min/1.73 m2, and
  • ESRD defined as requiring hemodialysis.2,3

Renal impairment was classified using the MDRD estimation of GFR calculation of

eGFR = 175 x (SCr [mg/dL])-1.154 x (age [yrs])-0.203 x (0.742 if female) x (1.210 if black)

The most recent available SCr was used in the equation.2

Date of Last Review: 30 March 2021


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