Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Jämförelse av farmakokinetiska egenskaper med Tofacitinib

Baricitinib och tofacitinib har inte studerats i någon jämförande studie, inklusive farmakokinetiska studier.

Pharmacokinetic Characteristics of BARI and Tofacitinib

The PK characteristics of BARI, tofacitinib IR, and tofacitinib XR are summarized in Table 1.

Absorption

Both BARI and tofacitinib XR are dosed once-daily, and tofacitinib IR is dosed twice daily. The absorption profiles for achievement of Css are

  • within 48 hours of the first dose with minimal accumulation for BARI,1

  • 24 to 48 hours with negligible accumulation for tofacitinib IR, and

  • within 48 hours with negligible accumulation for tofacitinib XR.2

Administration

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

Tofacitinib IR and tofacitinib XR can be administered with or without food.2

Elimination Half-Life

The elimination T1/2 is approximately

  • 13 hours in patients with rheumatoid arthritis for BARI3

  • 3 hours for tofacitinib IR, and 

  • 6 hours for tofacitinib XR.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 faeces. 3

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.3

Tofacitinib

For tofacitinib, clearance mechanisms are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The hepatic metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19.2

For patients with RA and moderate to severe renal insufficiency, the recommended dose of tofacitinib is 5 mg once daily.2

For patients with RA and moderate hepatic impairment, the recommended dose of tofacitinib is 5 mg once daily. Tofacitinib is not recommended for use in patients with severe hepatic impairment.2

Summary Pharmacokinetics

Table 1. Pharmacokinetic Characteristics for Baricitinib and Tofacitinib1-4

 

Baricitinib

Tofacitinib IR

Tofacitinib XR

Absorption

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

Following oral administration, peak plasma concentrations are reached within 0.5-1 hour, t1/2 is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Css are achieved in 24-48 hours with negligible accumulation after BID administration.

Following oral administration, peak plasma concentrations are reached at 4 hours and t1/2 is ~6 hours. Css are achieved within 48 hours with negligible accumulation after once daily administration. AUC and Cmax of tofacitinib XR 11 mg administered QD are equivalent to those of tofacitinib 5 mg BID.

Food Effects

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

Coadministration of tofacitinib with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meals.

Coadministration of tofacitinib XR with a high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and Tmax was extended by approximately 1 hour.

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.

After IV administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

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.

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.

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Abbreviations: AUC = area under the curve; BCRP = breast cancer resistance protein; BID = twice daily; Cmax = maximum concentration; Css = steady state concentration; CYP = cytochrome P450; IR = immediate-release; IV = intravenous; MATE2-K = multidrug and toxin extrusion protein 2-K; N/A = not applicable; OAT3 = organic anion transporter 3; Pgp = P-glycoprotein; QD = once daily; t1/2 = elimination half-life; Tmax = time to maximum concentration; XR = extended-release.

References

1. Shi 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

2. Xeljanz [package insert]. New York, NY: Pfizer, Inc; 2018.

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

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

Glossary

BARI = baricitinib

Css = steady state concentration

CYP = cytochrome P450

eGFR = estimated glomerular filtration rate

IR = immediate-release

PK = pharmacokinetic

RA = rheumatoid arthritis

T1/2 = half-life

XR = extended-release

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2019 M04 18

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