Olumiant® (Baricitinib)

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Baricitinib: Potential Drug-Drug Interactions

An established drug-drug interaction exists between baricitinib and OAT3 inhibitors. The recommended dose of baricitinib in patients taking an OAT3 inhibitor is 2 mg once daily. Other clinically relevant drug-drug interactions have not been identified.

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The information contained in this letter may not completely match the current local labeling for BARICITINIB. Please see local labeling approved in your country. If you require the local labeling, please request it through your Sales Representative.

Potential Drug-Drug Interaction Evaluations

In Vitro and Clinical Pharmacology Study Descriptions 

In vitro studies were conducted to

  • identify the CYP enzymes and transporters for which BARI is a substrate,
  • determine if BARI is an inhibitor or inducer of CYP enzymes or hepatic or renal transporters, and
  • predict transporter-mediated drug-drug interactions for BARI.1,2

Seven clinical pharmacology studies in healthy subjects and 1 clinical pharmacology study in patients with RA were conducted to assess potential drug-drug interactions with BARI. Each study was powered to evaluate statistically significant differences in exposure.1,2 See study details in Baricitinib Drug-Drug Interaction Studies.

Baricitinib Drug-Drug Interaction Studies2,3

Role of baricitinib

Study description

Population

Dosing

Substrate

PGP inhibitor: effect of cyclosporine on baricitinib PK

Healthy volunteers

Baricitinib 4 mg SD ± cyclosporine 600 mg SD

OAT3 inhibitor: effect of probenecid on baricitinib PK

Healthy volunteers

Baricitinib 4 mg SD ± probenecid 1000 mg MD/5d

CYP3A inhibitor or CYP2C19/CYP2C9/CYP3A4 inhibitor: effect of ketoconazole or fluconazole on baricitinib PK


Healthy volunteers


Baricitinib 10 mg SD ± ketoconazole 400 mg MD/6d

Baricitinib 10 mg SD ± fluconazole 200 mg MD/7d

CYP3A inducer:effect of rifampicin on baricitinib PK

Healthy volunteers

Baricitinib 10 mg SD ± rifampicin 600 mg MD/9d

Inhibitor

PGP substrate: effect of baricitinib on digoxin PK

Healthy volunteers

Digoxin 0.25 mg MD/16d + baricitinib 10 mg MD/5d

CYP3A substrate: effect of baricitinib on simvastatin PK

OATP1B1 substrate: effect of baricitinib on simvastatin acid PK

Healthy volunteers

Simvastatin 40 mg SD ± baricitinib 10 mg MD/5d

Inducer

CYP3A substrate: effect of baricitinib on Microgynon 
(EE + levo) PK

Healthy volunteers

Microgynon ( 30 µg EE + 150 µg levo) + baricitinib 10 mg MD/8d

Concomitant medication

Effect of baricitinib on MTX PK

Patients with RA

MTX 7.5 to 25 mg MD/4w + baricitinib 10 mg MD/26d

Abbreviations: CYP = cytochrome P450; d = daily doses; EE = ethinyl estradiol; levo = levonorgestrel; MD = multiple dose; MTX = methotrexate; OAT3 = organic anion transporter 3; PGP = P-glycoprotein; PK = pharmacokinetics; RA = rheumatoid arthritis; SD = single dose; w = weekly doses.

The potential for drug-drug interactions was determined based on the 90% CI for the ratio of geometric LS means being outside the no-effect limits 0.8 to 1.25, per regulatory guidance.4,5

Effect of Other Drugs on Baricitinib Pharmacokinetics

  • There were no clinically relevant effects on BARI PK when BARI was coadministered with
    • a CYP 3A inhibitor (ketoconazole),
    • a CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole),
    • a CYP3A inducer (rifampicin),
    • a Pgp inhibitor (cyclosporine), or
    • MTX.2

Cytochrome P450 Enzymes

In vitro studies indicate that BARI is a substrate for CYP3A4.2

In healthy subjects, there were no clinically relevant effects on BARI PK when BARI was coadministered with a

  • CYP3A inhibitor (ketoconazole),
  • CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole),
  • CYP3A inducer (rifampicin).2

OAT3 Transporters

In vitro studies indicate that BARI is a substrate for OAT3.1

In healthy subjects, co-administration of BARI with a strong OAT3 inhibitor, probenecid, resulted in a ~2 fold higher AUC(0-∞) compared with BARI alone.1 See Effect of Other Drugs on Baricitinib PK.

Effect of Other Drugs on Baricitinib PK2

Abbreviations: AUC = area under the curve; Cmax = maximum observed drug concentration; CYP = cytochrome P450; OAT3 = organic anion transporter 3; PGP = P-glycoprotein; PK = pharmacokinetics.

A physiologically-based PK model and a covariate analysis in the primary phase 2 and 3 population PK did not find a clinically relevant interaction between BARI and the less potent OAT3 inhibitors, ibuprofen and diclofenac.1,3

Therefore, the recommended dose of BARI in patients taking an OAT3 inhibitor with strong inhibition potential, like probenecid, is 2 mg once daily. No dose adjustment is needed when BARI is coadministered with OAT3 inhibitors with less inhibition potential, such as ibuprofen or diclofenac.3

Other Transporters

In vitro studies indicated that BARI is

  • a substrate of
    • Pgp,
    • BCRP, and
    • MATE2-K, and
  • not a substrate of
    • OCT1,
    • OCT2,
    • OATP1B1,
    • OATP1B3,
    • OAT1, and
    • MATE1.1

Other apical pathways, including MRPs and OAT4 have not been investigated with BARI.1

In healthy subjects, there were no clinically relevant effects on BARI PK when BARI was co-administered with a Pgp/BCRP inhibitor, cyclosporine.2

Effect of Baricitinib on the Pharmacokinetics of Other Drugs 

  • Co-administration with BARI had no clinically relevant effects on the PK of,
    • a CYP3A substrate (simvastatin or Microgynon®),
    • a OATP1B1 substrate (simvastatin acid)
    • a Pgp substrate (digoxin), or
    • an OAT1, OAT3, and BCRP substrate (MTX).2,3

Cytochrome P450 Enzymes

In vitro studies showed that BARI did not significantly inhibit or induce a panel of CYP450 enzymes (CYPs 3A, 1A2, 2B6, 2C9, 2C19, and 2D6).2,3

In healthy subjects, coadministration of BARI with CYP3A substrates, simvastatin, ethinyl estradiol, or levonorgestrel, resulted in no clinically meaningful changes in PK of these drugs.2,3 See Effect of Baricitinib on the PK of Other Drugs.

Effect of Baricitinib on the PK of Other Drugs2

Abbreviations: AUC = area under the curve; Cmax = maximum observed drug concentration; CYP = cytochrome; Pgp = P-glycoprotein; PK = pharmacokinetics.

Transporters

In vitro data indicates BARI

  • does not inhibit transporters
    • Pgp, or
    • OATP1B1, and
  • does inhibit transporters
    • OAT1, OAT2, OAT3,
    • OCT1, OCT2,
    • OATP1B3,
    • BCRP, and
    • MATE1 and MATE2-K.3

Clinically meaningful changes in the PK of drugs that are substrates for these transporters due to BARI inhibition are unlikely.3

In healthy subjects, when BARI was coadministered with a Pgp substrate digoxin or simvastatin, for which the active metabolite simvastatin acid is an OATP1B1 substrate, there were no clinically relevant effects on the PK of digoxin or simvastatin acid.2,3 See Effect of Baricitinib on the PK of Other Drugs.

Potential Drug-Drug Interactions from US Claims Data

An observational, retrospective, cross-sectional study of various US drug claims databases was performed. This analysis included 152,853 patients with rheumatoid arthritis.6 

Up to 10% of these patients had been prescribed a medication that may interact with BARI. Specifically, 

  • <0.1% had concomitant claims for a strong OAT3 inhibitor,
  • 1% had claims for the combination of a strong CYP3A4 and strong CYP2C19 inhibitor,
  • 3% had claims for a strong CYP3A4 inhibitor alone, and
  • almost 10% had claims for the combination of a moderate CYP3A4 and a strong CYP2C19 inhibitor.6 

The authors concluded from the study that DDIs were a risk for RA patients, and that these need to be recognized and managed to avoid therapeutic failures and adverse drug reactions.6   

Concomitant Use of Baricitinib with other RA Therapies

The following concomitant medications were allowed during the phase 3 clinical program

  • NSAIDs
  • analgesics
  • corticosteroids, and
  • conventional DMARDs.3

In patients with RA, the combination of MTX and BARI had no significant effect on the PK of BARI or the PK of MTX.2

References

1Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter-mediated drug-drug interactions for baricitinib. Clin Transl Sci. 2017;10(6):509-519. https://dx.doi.org/10.1111/cts.12486

2Payne C, Zhang X, Shahri N, et al. Evaluation of potential drug-drug interactions with baricitinib. Ann Rheum Dis. 2015;74(suppl 2):1063. European League Against Rheumatism abstract AB0492. https://doi.org/10.1136/annrheumdis-2015-eular.1627

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4European Medicines Agency. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. 2015. https://www.ema.europa.eu/documents/scientific-guideline/guideline-non-clinical-clinical-development-similar-biological-medicinal-products-containing_en-0.pdf

5Food and Drug Administration. Guidance for Industry: Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. 2016. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf

6Walton A, Paik J, Quebe A et al. Frequency of Prescription Claims for Drugs that MayInteract with Janus Kinase Inhibitors Among Patientswith Rheumatoid Arthritis in the US. Rheumatol Ther 2021. Published online January 23, 2021; https://doi.org/10.1007/s40744-020-00275-8

Glossary 

AUC = area under the concentration-time curve

BARI = baricitinib

BCRP = breast cancer resistance protein

CI = Confidence Interval

CYP = cytochrome P450

DMARD = disease-modifying antirheumatic drug

IC50 = inhibitory concentration of 50%

JAK = Janus kinase

LSMean = least squares mean

MATE = multidrug and toxin extrusion protein

MRP = multidrug resistance-associated protein

MTX = methotrexate

NSAID = nonsteroidal anti-inflammatory drug

OAT = organic anion transporter

Pgp = P-glycoprotein

PK = pharmacokinetic

RA = rheumatoid arthritis

STAT = signal transducers and activators of transcription

Tmax = time of maximum observed drug concentration

TYK = tyrosine kinase

Fecha de la última revisión: 2021 M03 11


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