Cerivastatin
Cerivastatin. HMG-CoA reductase inhibitor (statin) — withdrawn worldwide 2001-08-08 after 52 confirmed fatal rhabdomyolysis cases, predominantly… Oral half-life 3 h.
HMG-CoA reductase inhibitor (statin) — withdrawn worldwide 2001-08-08 after 52 confirmed fatal rhabdomyolysis cases, predominantly attributable to coadministration with gemfibrozil. Mechanism of the fatal DDI: CYP2C8 inhibition by gemfibrozil glucuronide raises cerivastatin AUC ~6× (Backman 2002 PMID:12496749 — verbatim AUC 559% of control). Bayer paid $1.15 billion to settle lawsuits over the withdrawal. Retained in the registry for historical reference and as the canonical CYP2C8 DDI cautionary tale. PK (Baycol label + Mück 2000 PMID:10976657 review): Absolute F 60% (range 39–101%) due to presystemic first-pass, Tmax 2–3 h, terminal t½ 2–4 h, plasma protein binding >99%, apparent Vd ~0.3 L/kg (~21 L). Dual CYP2C8/CYP3A4 metabolism — the latter pathway only ~50% effective when both routes are inhibited, which is why gemfibrozil (CYP2C8 inhibitor, AUC ↑5.59× Wave 2a v1.1) and itraconazole (CYP3A4) produced lethal rhabdomyolysis combinations and led to the August 2001 worldwide withdrawal after 52 fatal cases.
PK: F 0.6 is verbatim and is now cited to the primary that measured it against a real intravenous bolus rather than to the sponsor review quoting it. WITHDRAWAL DOES NOT INVALIDATE THESE KINETICS, which is worth stating plainly: cerivastatin was withdrawn worldwide in 2001 for a pharmacodynamic and drug-interaction safety reason, rhabdomyolysis chiefly with gemfibrozil through enzyme and transporter inhibition, not because its pharmacokinetics were mischaracterised, and both pharmacokinetic sources predate the withdrawal. V 21 L is the stated 0.3 L/kg scaled to 70 kg and is a true steady-state volume, so pairing it with the absolute bioavailability is correct. The half-life of 3 h is the UPPER ENDPOINT of a stated "2 to 3 hours" and is additionally route-specific, exceeding the intravenous 1.5-2.4 h, a mild absorption-limited slope. ka 0.7 is dropped and probably collides with "approximately 70% of the administered dose is excreted as metabolites in the faeces". ANALYTE UNDERSTATEMENT WORTH RECORDING: three metabolites are "all 3 ... active inhibitors ... with a similar potency to the parent drug", so a parent-only curve captures a fraction of the enzyme inhibition. The record second reference is a gemfibrozil interaction study reporting only ratios.
Pharmacokinetics
- Oral — t½ 3 h · F 60% · Vd 21 L
Sources: PMID:12496749, PMID:10976657, PMID:9208342