Upadacitinib
Upadacitinib. JAK1-selective inhibitor — designed for higher JAK1 selectivity vs tofacitinib (less JAK2/JAK3 hit, theoretically less… Oral half-life 3.8 h.
JAK1-selective inhibitor — designed for higher JAK1 selectivity vs tofacitinib (less JAK2/JAK3 hit, theoretically less anemia/lymphopenia). Indications: rheumatoid arthritis, atopic dermatitis, ulcerative colitis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, giant cell arteritis. CYP3A4 substrate. Black-box warning for MACE / malignancy / VTE (JAK class effect from ORAL Surveillance). PK (Rinvoq label, 15 mg ER PO qd): t½ 9-14 h, Tmax 2-3 h fasting / 4 h fed, F 76% relative to IR (absolute F not stated). Apparent CL/F 53.7 L/h, V/F 294 L. Steady state by day 4 with no accumulation. CYP3A4 substrate (avoid strong CYP3A4 inhibitors).
PK: A THREE-FOLD EXPOSURE ERROR WHOSE CAUSE ITS OWN CITATION STATES OUT LOUD. The volume is verbatim and IS the extended-release figure, answering the formulation concern, and pinning bioavailability at unity is right because no intravenous form exists — THE PAPER RELATIVE BIOAVAILABILITY OF 76 PERCENT IS A DIFFERENT QUANTITY AND THE RECORD CORRECTLY DECLINED TO STORE IT, avoiding the trap that has caught other records. The defect is the half-life, an unsupported midpoint of a label range, welded to a volume the same paper describes as the sum of two compartments from a model with "mixed zero- and first-order absorption with lag time for the ER formulation". THE FIX IS UNUSUALLY CLEAN: that paper states a FUNCTIONAL half-life of three to four hours, and the value that makes the stored volume reproduce the paper own verbatim clearance falls inside that range — in a one-compartment model the single half-life must carry the whole exposure, so the functional one is the correct one. AND IT FIXES THE ABSORPTION FOR FREE: the stored rate implied a peak outside the label window and now lands inside a verbatim "2 to 4 hours for the ER formulation". THE BIOAVAILABILITY MUST NOT BE TOUCHED — lowering it would also close the exposure gap arithmetically, but against an apparent volume that would be creating one defect to paper over another. NOTE THE NEAR-IDENTITY WITH BARICITINIB THREE-FOLD GAP: same class, same defect.
Pharmacokinetics
- Oral — t½ 3.8 h · F 100% · ka 0.4 h⁻¹ · Vd 294 L
Sources: PMID:30945116