Olumiant ® (baricitinib) tabletter

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

Någon jämförande studie har inte genomförts mellan baricitinib och upadacitinib, inklusive farmakokinetiska studier.

Pharmacokinetic Characteristics of Baricitinib and Upadacitinib

The PK characteristics of BARI and upadacitinib are summarized in Table 1.

Absorption

Baricitinib is dosed once-daily. Upadacitinib was dosed once daily in phase 3 RA trials. The absorption profiles for achievement of Css are

  • within 48 hours of the first dose with minimal accumulation for BARI1, and

  • by day 4 with no significant accumulation observed for upadacitinib.2,3

Administration

Administration with meals was not associated with a clinically relevant effect on BARI exposure.4

Upadacitinib was administered without regard to food in phase 3 trials.2,5

Elimination Half-Life

The elimination T1/2 is approximately

  • 12.5 hours in patients with rheumatoid arthritis for BARI 4 , and

  • 16 hours for upadacitinib.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.4

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.4

No dose adjustment is required in patients with mild or moderate hepatic impairment. Baricitinib is not recommended for use in patients with severe hepatic impairment.4

Upadacitinib

Metabolism studies indicate upadacitinib is a non-sensitive substrate for CYP3A, with minor metabolic contribution from CYP2D62,3 Approximately 20% of upadacitinib was eliminated as unchanged drug in urine, with ~30% eliminated as metabolites in urine and feces.2,5

Based on a PK study, there was no clinically relevant effect on the PK of upadacitinib when administered to patients with mild and moderate hepatic impairment.5

Based on a PK study, there was limited effect on the PK of upadacitinib when administered to patients with renal impairment.6

Summary Pharmacokinetics

Table 1. Pharmacokinetic Characteristics for Baricitinib and Upadacitinib

 

Baricitinib

Upadacitiniba

Absorption

Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour and an absolute bioavailability of approximately 79%. 4The half-life is approximately 12.5 hours in patients with RA.4 Css are achieved within 48 hours of the first dose with minimal accumulation.1

Following oral administration of extended-release formulation, peak plasma levels were reached at 2 to 4 hours. Exposure was dose-proportional over the 15 to 30 mg dose range.2

The half-life is approximately 16 hours in healthy subjects. Css was achieved by day 4 with no significant accumulation observed.2,3

Food Effects

Administration with meals was not associated with a clinically relevant effect on exposure.4

Administration of upadacitinib after a high-fat meal increased AUC and Cmax by ~20%. This was not considered to be clinically relevant. Tmax was delayed by 2 hours.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.7

Population estimates of steady-state volume of distribution for ER formulation was 294 L.8 Upadacitinib is not extensively bound to plasma proteins.5

Metabolism and Elimination

Baricitinib metabolism is mediated by CYP3A4 with less than 10% 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.4

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.4

Metabolism studies indicate upadacitinib is a non-sensitive substrate for CYP3A, with minor metabolic contribution from CYP2D6.2,3

Approximately 20% of upadacitinib was eliminated as unchanged drug in urine, with ~30% eliminated as metabolites in urine and feces.2,5

 

Abbreviations: AUC = area under the curve; BCRP = breast cancer resistance protein; BID = twice daily; Cmax = maximum concentration; Css = steady state concentration; CYP = cytochrome P450; ER = extended-release; 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; RA = rheumatoid arthritis; t1/2 = elimination half-life; Tmax = time to maximum concentration; XR = extended-release.

a Initial pharmacokinetic studies were conducted with an immediate-release formulation that was utilized in some phase 1 and 2 studies. Phase 3 studies in RA utilized an extended-release formulation.

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. Mohamed ME, Zeng J, Marroun PJ, et al. Pharmacokinetics of upadacitinib with the clinical regimens of the extended-release formulation utilized in rheumatoid arthritis phase 3 trials. Clin Pharmacol Drug Dev. 2019;8(2):208-216. https://dx.doi.org/10.1002/cpdd.462

3. Mohamed MF, Camp HS, Jiang P, et al. Pharmacokinetics, safety, and tolerability of ABT-494, a novel selective JAK1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis. Clin Pharmacokinet. 2016;55(12):1547-1558. https://doi.org/10.1007/s40262-016-0419-y

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

5. Trueman S, Mohamed MF, Feng T, et al. Characterization of the effect of hepatic impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(9):1188-1194. https://doi.org/10.1002/jcph.1414

6. Mohamed MF, Trueman S, Feng T, et al. Characterization of the effect of renal impairment on upadacitinib pharmacokinetics. J Clin Pharmacol. 2019;59(6):856-862. https://dx.doi.org/10.1002/jcph.1375

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

8. Klunder B, Mittapalli RK, Mohamed ME, et al. Population pharmacokinetics of upadacitinib using the immediate-release and extended-release formulations in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I-III clinical trials. Clin Pharmacokinet. 2019;58(8):1045-1058. https://dx.doi.org/10.1007/s40262-019-00739-3

Glossary

BARI = baricitinib

Css = steady state concentration

CYP = cytochrome P450

eGFR = estimated glomerular filtration rate

PK = pharmacokinetic

RA = rheumatoid arthritis

T1/2 = half-life

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 M07 24


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