Olumiant® (Baricitinib)

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Baricitinib: Comparison of Pharmacokinetic Characteristics With Filgotinib

There have been no head to head clinical trials, including pharmacokinetic studies, between baricitinib and filgotinib.

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Pharmacokinetic Characteristics of Baricitinib and Filgotinib

The PK characteristics of BARI and filgotinib are summarized in Pharmacokinetic Characteristics for Baricitinib and Filgotinib. 

Absorption

Both BARI and filgotinib are dosed once-daily. The absorption profiles for achievement of Css is within 48 hours of the first dose with minimal accumulation for BARI.1

Steady-state concentrations of filgotinib are achieved in 2-3 days with negligible accumulation after once daily administration. Steady-state concentrations of GS-829845 are achieved in 4 days with approximately 2-fold accumulation after once daily dosing of filgotinib.2

Administration

Administration with meals was not associated with a clinically relevant effect on BARI exposure.3

There were no clinically relevant differences in exposures when filgotinib was administered with a high-fat or low-fat meal as compared to a fasted state.2

Elimination Half-Life

The elimination T1/2 is approximately

  • 13 hours in patients with rheumatoid arthritis for BARI3
  • 7 hours for filgotinib, and
  • 19 hours for filgotinib's primary metabolite GS-829845.2

Metabolism and Excretion

Baricitinib

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.3

The recommended dose of BARI in patients with an eGFR between 30 and 60 mL/min/1.73m2 is 2 mg once daily. Baricitinib is not recommended for use in patients with severe renal impairment (an eGFR of <30 mL/min/1.73m2).3

No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of BARI has not been studied in patients with severe hepatic impairment and is therefore not recommended.3

Filgotinib

Filgotinib is extensively metabolized with approximately 9.4% and 4.5% of an orally administered dose recovered as unchanged filgotinib in urine and feces, respectively. In a
clinical pharmacology study, filgotinib and its primary active metabolite GS-829845 accounted for the majority of radioactivity circulating in plasma (2.9% and 92%, respectively). No other major metabolites were identified.2

Approximately 87% of the administered dose was eliminated in the urine as filgotinib and its metabolites, and about 15% of the dose was eliminated in the feces. GS-829845 accounted for approximately 54% and 8.9% of dose recovered in urine and feces, respectively.2

A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). No dose adjustment is required in patients with mild renal impairment (CrCl ≥ 60 mL/min). The pharmacokinetics of filgotinib has not been studied in subjects with end stage renal disease (CrCl < 15 mL/min) and is therefore not recommended.2

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Filgotinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is therefore not recommended.2

Summary Pharmacokinetics

Pharmacokinetic Characteristics for Baricitinib and Filgotinib

 

Baricitinib

Filgotinib

Absorption

Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour and an absolute bioavailability of approximately 80%. 3The half-life is approximately 13 hours in patients with RA.3 Css are achieved within 48 hours of the first dose with minimal accumulation.1

Following oral administration, filgotinib was absorbed quickly and its median peak plasma concentration was observed 2 to 3 hours postdose after multiple dosing. The median peak plasma concentrations of its primary metabolite GS-829845 were observed 5 hours postdose after multiple dosing. The half-life is 7 hours for filgotinib and 19 hours for GS-829845. Css are achieved within 2-3 days for filgotinib and in 4 days for GS-829845.2

Food Effects

Administration with meals was not associated with a clinically relevant effect on exposure.3

There were no clinically relevant differences in exposures when filgotinib was administered with a high-fat or low-fat meal as compared to a fasted state.2

Distribution

Mean volume of distribution following IV infusion administration was 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins.3

Filgotinib and GS-829845 binding to human plasma proteins is low (55 - 59% and 39 - 44% bound, respectively). The blood-to-plasma ratio of filgotinib ranged from 0.85 to 1.1 indicating no preferential distribution of filgotinib and GS-829845 into blood cells.2

Metabolism and Elimination

Baricitinib metabolism is mediated by CYP3A4 with approximately 6% of the dose identified as undergoing biotransformation. No metabolites were quantifiable in plasma. In a clinical pharmacology study, baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%) and only 4 minor oxidative metabolites (3 in urine, 1 in feces) were identified.3

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 feces.3

Filgotinib is extensively metabolized with approximately 9.4% and 4.5% of an orally administered dose recovered as unchanged filgotinib in urine and feces, respectively. Filgotinib is primarily metabolized by CES2, and to a lesser extent by CES1. Both CES2 and CES1 form GS-829845, an active circulating metabolite that is approximately 10-fold less potent than the parent compound. In a clinical pharmacology study, filgotinib and GS-829845 accounted for the majority of radioactivity circulating in plasma (2.9% and 92%, respectively). No other major metabolites were identified.2

Approximately 87% of the administered dose was eliminated in the urine as filgotinib and its metabolites, while about 15% of the dose was eliminated in the feces.2

Abbreviations: AUC = area under the curve; BCRP = breast cancer resistance protein; CES1 = carboxylesterase 1; CES2 = carboxylesterase 2; Cmax = maximum concentration; Css = steady state concentration; CYP = cytochrome P450; IV = intravenous; MATE2-K = multidrug and toxin extrusion protein 2-K; OAT3 = organic anion transporter 3; Pgp = P-glycoprotein; RA = rheumatoid arthritis; t1/2 = elimination half-life; Tmax = time to maximum concentration.

References 

1Shi JG, Chen X, Lee F, et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol. 2014;54(12):1354-1361. http://dx.doi.org/10.1002/jcph.354

2Jyseleca [summary of product characteristics]. Gilead Sciences Ireland UC, Ireland.

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

Glossary

BARI = baricitinib

CrCl = creatinine clearance 

Css = steady state concentration

eGFR = estimated glomerular filtration rate

PK = pharmacokinetic

T1/2 = half-life

Fecha de la última revisión: 2020 M10 01


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