Navitoclax
Navitoclax. BH3-mimetic Bcl-2 / Bcl-xL inhibitor — induces apoptosis in senescent cells (senolytic). Major dose-limiting platelet drop from Bcl-xL on megakaryocytes.…
BH3-mimetic Bcl-2 / Bcl-xL inhibitor — induces apoptosis in senescent cells (senolytic). Major dose-limiting platelet drop from Bcl-xL on megakaryocytes. Original oncology indications largely abandoned for venetoclax (Bcl-2 selective); senolytic research interest persists. PK (Wilson Lancet Oncol 2010 Phase I PMID:21282543 + lymphatic-transport PK PMID:24212376): Low aqueous solubility, high logP — F ~30% in humans (56.5% in fed dogs, lower in fasted state — strong food effect). Apparent Vd ~0.5–0.7 L/kg (~35–50 L), t½ 22.2 h, Tmax 5–6 h (slow absorption via mixed portal + lymphatic uptake). Exposure dose-proportional 50–425 mg/d. Phase I dose-limiting toxicity was thrombocytopenia (Bcl-xL on-target effect on platelets), which paved the way for the more Bcl-2-selective venetoclax (Venclexta).
PK REMOVED. THE WHOLE BLOCK IS CONSTRUCTED, AND THE ARITHMETIC REPRODUCES EXACTLY. Fixing the stored absorption rate and forcing a peak at exactly 11.000 h back-solves a half-life of 22.1791, WHICH ROUNDS TO THE STORED 22.2 AT ITS FULL STORED PRECISION — so with a round volume and a round bioavailability beside it, the record is two guesses, an assumed round peak time, and one derived digit presented as a measurement. Its citation is a genuine, on-topic, correctly-attributed phase-one paper CONTAINING NOT ONE NUMERIC PK PARAMETER: no rate, no volume, no bioavailability, no half-life, no peak, no exposure. Six further human studies were chased and every one reports dose levels, ratios or model structure only — the population analysis says merely "The population PKs were adequately characterized by two-compartment models" without publishing an estimate. Navitoclax was never approved and its development was discontinued, SO THERE IS NO LABEL TO FALL BACK ON: this is not the label-only shape, it is an absence of published human pharmacokinetics.
Sources: PMID:21282543