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Following oral administration, baricitinib is rapidly absorbed with a median tmax of approximately 1 hour (range 0.5 - 3.0 h) and an absolute bioavailability of approximately 79 % (CV = 3.94 %). Food intake led to a decreased exposure by up to 14 %, a decrease in Cmax by up to 18 % and delayed tmax by 0.5 hours. Administration with meals was not associated with a clinically relevant effect on exposure.1
Given BARI’s short tmax 2 and what is understood about the transit time of oral drugs in the small intestine,3 it is anticipated that much of the absorption occurs in the upper gastrointestinal tract.
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
Baricitinib is a substrate of the Pgp, BCRP, OAT3, and MATE2-K transporters, which play roles in drug distribution.1 Baricitinib is a small molecule that has limited penetration across the blood brain barrier based on animal studies.2
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 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. 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. Baricitinib is not an inhibitor of the transporters OAT1, OAT2, OAT3, OCT2, OATP1B1, OATP1B3, BCRP, MATE1 and MATE2-K at clinically relevant concentrations.1
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 faeces. 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
Pharmacokinetics in Special Populations
Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of BARI. The mean effects of intrinsic factors on PK parameters, AUC and Cmax, were generally within the between-subject PK variability of BARI. The between-subject variability, as assessed by percent coefficient of variation, was approximately 41% for AUC and 22% for Cmax. 2
3. 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. 1st ed. Springer US (Online); 2011:27-48. http://dx.doi.org/10.1007/978-1-4614-1004-1
BARI = baricitinib
BCRP = breast cancer resistance protein
CYP = cytochrome P450
MATE = multidrug and toxin extrusion protein
OAT = organic anion transporter
Pgp = P-glycoprotein
▼ 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 M05 01