Olumiant® ▼ (baricitinib): Farmakokinetik

Pharmacokinetic Properties of Baricitinib

Absorption

Following oral administration, baricitinib is rapidly absorbed with a median t_max of approximately 1 hour (range 0.5 - 3.0 h) and an absolute bioavailability of approximately 79 % (CV = 3.94 %).¹

Food intake led to a decreased exposure by up to 14 %, a decrease in C_max by up to 18 % and delayed t_max by 0.5 hours. Administration with meals was not associated with a clinically relevant effect on exposure.¹

Given BARI’s short t_max and what is understood about the transit time of oral drugs in the small intestine, it is anticipated that much of the absorption occurs in the upper gastrointestinal tract.²

Distribution

Mean volume of distribution following intravenous infusion administration was 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50 % bound to plasma proteins.¹

Metabolism

Baricitinib metabolism is mediated by CYP3A4, with less than 10 % of the dose identified as undergoing biotransformation.¹

No metabolites were quantifiable in plasma. In a clinical pharmacology study, baricitinib was excreted predominately as the unchanged active substance in urine (69 %) and faeces (15 %) and only 4 minor oxidative metabolites were identified (3 in urine; 1 in faeces) constituting approximately 5 % and 1 % of the dose, respectively.¹

In vitro, baricitinib

• is a substrate for CYP3A4, OAT3, Pgp, BCRP and MATE2-K, and

• may be a clinically relevant inhibitor of the transporter OCT1.¹

Baricitinib is not an inhibitor of the transporters

• OAT1, OAT2, OAT3,

• OCT2,

• OATP1B1, OATP1B3,

• BCRP,

• MATE1 and MATE2-K

at clinically relevant concentrations.¹

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

Mean apparent clearance (CL/F) and half-life in patients with rheumatoid arthritis was 9.42 L/hr (CV = 34.3 %) and 12.5 hrs (CV = 27.4 %), respectively. Cmax and AUC at steady state are 1.4- and 2.0–fold higher, respectively, in subjects with rheumatoid arthritis compared to healthy subjects.¹

Mean apparent clearance (CL/F) and half-life in patients with atopic dermatitis was 11.2 L/hr (CV = 33.0 %) and 12.9 hrs (CV = 36.0 %), respectively. Cmax and AUC at steady state in patients with atopic dermatitis are 0.8-fold those seen in rheumatoid arthritis.

Renal Impairment

Renal function was found to significantly affect baricitinib exposure.¹

• The mean ratios of 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 C_max 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

Hepatic Impairment

There was no clinically relevant effect on the PK of baricitinib in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment.¹

Elderly

Age ≥ 65 years or ≥ 75 years has no effect on baricitinib exposure (C_max and AUC).¹

Other Intrinsic Factors

• Body weight,

• sex,

• race, and

• ethnicity

did not have a clinically relevant effect on the PK of baricitinib.¹

The mean effects of intrinsic factors on PK parameters (AUC and C_max) were generally within the inter-subject PK variability of baricitinib. Therefore, no dose adjustment is needed based on these patient factors.¹

References

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

2. Wilson CG. The organization of the gut and the oral absorption of drugs: anatomical, biological, and physiological considerations in oral formulation development. In: Wilson CG, Crowley PJ, eds. Controlled Release in Oral Drug Delivery. 1^st ed. Springer US (Online); 2011:27-48. http://dx.doi.org/10.1007/978-1-4614-1004-1

Glossary

AD = atopic dermatitis

AUC = area under the concentration-time curve

BARI = baricitinib

BCRP = breast cancer resistance protein

C_max = maximum concentration

CYP = cytochrome P450

MATE = multidrug and toxin extrusion protein

OAT = organic anion transporter

Pgp = P-glycoprotein

PK = pharmacokinetic

RA = rheumatoid arthritis

T_1/2 = half-life

t_max = time of maximum observed drug concentration

▼ 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.