Acalabrutinib
Acalabrutinib. Second-generation covalent BTK inhibitor — designed for higher BTK selectivity than ibrutinib (less off-target EGFR/ITK/TEC).… Oral half-life 1.8 h.
Second-generation covalent BTK inhibitor — designed for higher BTK selectivity than ibrutinib (less off-target EGFR/ITK/TEC). Indications: CLL/SLL, mantle cell lymphoma. Lower rates of atrial fibrillation, hypertension, and bleeding vs ibrutinib in head-to-head ELEVATE-RR. CYP3A4 substrate; PPIs reduce absorption ~70% — requires acid for solubility. PK (Calquence label, SS 100 mg PO bid): Cmax 563 ng/mL (29% CV), AUC24 1843 ng·h/mL (38% CV), Tmax median 0.9 h, t½ 1 h, F 25%, Vss 101 L (52% CV), protein binding 97.5%. Short t½ explains bid dosing despite irreversible BTK binding (target turnover is what matters).
PK: THE HALF-LIFE IS LABEL-VERBATIM AND PHYSICALLY IMPOSSIBLE BESIDE ITS OWN VOLUME. The label gives both "terminal elimination half-life (t1/2) was 1 (59%) hour" and "The geometric mean (% CV) STEADY-STATE volume of distribution (Vss) was approximately 101 (52%) L", and the record paired them — an ORAL terminal half-life with an INTRAVENOUS steady-state volume. With the measured intravenous clearance of 39.4 L/h, a 1 h half-life forces a terminal volume of 56.8 L, WHICH IS SMALLER THAN Vss. A terminal volume can never be smaller than the steady-state volume, so the half-life is pinned at no less than 1.78 h — consistent with the separately published "elimination half-life values of <2 hours". CLASS 6 IS ACQUITTED HERE AND THAT MATTERS, because my prior was that every volume in this drug class must be apparent: this label writes CL/F and Vd,ss/F explicitly elsewhere, so a plain Vss is intravenous, and a human intravenous microtracer arm exists. Dividing 101 L by F is CORRECT. F 0.25 is verbatim twice over. THE ANALYTE IS CLEAN: ACP-5862 runs two to three times the parent exposure at about half the potency, but it is a separate species with its own half-life and volume, and none of its numbers have leaked into this record.
Pharmacokinetics
- Oral — t½ 1.8 h · F 25% · ka 2.2 h⁻¹ · Vd 101 L
Sources: PMID:30442651, PMID:30556110