Ibrutinib
Ibrutinib. First-in-class covalent BTK (Bruton tyrosine kinase) inhibitor — irreversible Michael acceptor that binds Cys481 in the BTK ATP pocket.… Oral half-life 5 h.
First-in-class covalent BTK (Bruton tyrosine kinase) inhibitor — irreversible Michael acceptor that binds Cys481 in the BTK ATP pocket. Indications: CLL/SLL, mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, cGVHD. Strong CYP3A4 substrate (F ~3%; raising it to ~10% with mild inducers, contraindicated with strong inhibitors due to risk of atrial fibrillation + bleeding). Off-target effects on EGFR, ITK, TEC, HER2 account for the rash + diarrhea + AF profile. PK (Imbruvica label, SS 560 mg PO qd): AUC 953 ± 705 ng·h/mL, t½ 4-6 h, Tmax 1-2 h, absolute F 2.9% fasted (doubles to ~6% with food — administration with food recommended). Apparent V/F ~4200 L; true Vd ~122 L. CYP3A4 substrate; massive food effect + strong inducer/inhibitor sensitivity.
PK PROVENANCE, moved here from source_label when that field was shortened to a citation that names the label revision: FDA label: Imbruvica 560 mg PO qd: Tmax 1-2 h, t half 4-6 h, F 2.9% fasted. V_L 122 is NOT a true volume — the label gives Vd 683 L and Vd,ss/F ~10,000 L. It is a fitted surrogate (4200 x F) the solver re-divides by F, reproducing the label AUC 708 ng*h/mL to 1.7%. Do not replace with 683. PK: THE NUMBERS ARE RIGHT, THE PROSE IS A FABRICATED CONSTRUCT, AND NOBODY SHOULD "CORRECT" THIS RECORD FIELD BY FIELD. At 420 mg it predicts an exposure of 720 ng.h/mL against the label verbatim "The mean steady-state AUC (% coefficient of variation) observed in patients at 420 mg with CLL/SLL is 708 (71%) ng x h/mL" — 1.7%. But its source_label claimed a "true Vd ~122 L" and an "apparent V/F ~4200 L", and the label says neither: "The volume of distribution (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10,000 L." NOTE THAT 4200 x 0.029 IS 121.8. THE STORED VOLUME WAS MANUFACTURED BY MULTIPLYING AN APPARENT VOLUME BY F AND RELABELLING THE PRODUCT A TRUE VOLUME, which the solver then divides by F again, restoring it. It is self-cancelling, which is why the exposure lands — and ANYONE WHO REPLACES IT WITH THE LABEL REAL 683 L INTRODUCES A 5.6x ERROR. Two further errors also cancel: the stored F is the FASTED single-dose figure, "Absolute bioavailability of ibrutinib in fasted condition was 2.9%", while the exposure it reproduces is from patients dosing without regard to food, where the measured availability is two to three times higher. The half-life is the midpoint of a printed "4 hours to 6 hours". Its refs[] was EMPTY.
Pharmacokinetics
- Oral — t½ 5 h · F 3% · ka 1.23 h⁻¹ · Vd 122 L
Sources: PMID:26382728