Trastuzumab
Trastuzumab. Humanized anti-HER2 (ERBB2) IgG1 monoclonal antibody. Binds the juxtamembrane domain IV of HER2 — blocks ligand-independent… Subcutaneous half-life 29 d.
Humanized anti-HER2 (ERBB2) IgG1 monoclonal antibody. Binds the juxtamembrane domain IV of HER2 — blocks ligand-independent dimerization, induces ADCC, internalizes the receptor. Indications: HER2-positive breast cancer (adjuvant, metastatic, neoadjuvant) and HER2-positive gastric/GEJ cancer. Cardiotoxicity risk especially when combined with anthracyclines (synergistic reduction in EF). Biologic PK — long t½ ~28 days at steady state, IgG salvage clearance. PK (Bruno 2005 popPK PMID:15868146 + Herceptin label): IV-only mAb. Two-compartment model with parallel linear + nonlinear elimination; linear clearance dominates during chronic dosing. CL 0.173-0.337 L/day (typical 0.225 L/day) similar to other IgG1 mAbs. V1 (central) 2.95 L. Terminal t½ 28.5 days. Steady state ~12 weeks for weekly or q3-week regimens. Covariates: body weight, AST, albumin, gastric primary, liver mets. Cardiotoxicity not PK-related (HER2-pathway target on cardiomyocytes).
DOSING: A NEW DEFECT CLASS, AND IT DWARFS EVERY OTHER ERROR ON THIS RECORD. doses.IV held {4, 8, typical 6} in mg, but those are mg/KG — its own citation says "a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly". At the 70 kg reference the typical dose is 420 mg, not 6: A SEVENTYFOLD UNDER-DOSE. All eighteen biologics in this catalog were swept; every other one carries genuinely flat mg doses in the tens to hundreds, and only INFLIXIMAB shares this shape while RITUXIMAB stores a per-square-metre dose. There is no mg/kg in the DoseUnit enum, so the values are converted at the reference weight and that conversion is stated here rather than hidden. The subcutaneous route was declared with no dose block at all; its fixed 600 mg is verbatim in two sources. Its subcutaneous bioavailability of 0.87 came from a paper containing NO numeric PK parameter of any kind, and the human figure is verbatim: "a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %". The nearest 0.87-shaped published numbers are RAT. THREE OF MY OWN PRIORS ABOUT THIS RECORD WERE REFUTED: class 6 is acquitted because the central volume is genuinely intravenous-derived; the identical half-lives across routes are NOT flip-flop, since absorption here is eleven times faster than elimination and one disposition model legitimately serves both routes; and this record is not a residue of the "7 L biologic default", which belongs to a different cluster. WHAT REMAINS UNFIXED IS STRUCTURAL: its volume and half-life together assert a clearance 3.14x below its own citation, and no one-compartment model can represent target-mediated disposition. The pk_unauthored vocabulary has no reason code for that shape. PK: THE WORST VERSION OF THE TWO-COMPARTMENT PAIRING — A CENTRAL VOLUME WELDED TO A TERMINAL HALF-LIFE. Its citation names the compartment explicitly: "Population estimates from the base model for clearance (CL) and volume of distribution of the CENTRAL COMPARTMENT (V1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated TERMINAL halflife (t1/2) based on the population estimate was 28.5 days." A Vss at least averages the two compartments; a V1 is only the first, so pairing it with the slowest phase understates clearance the most. THE RECORD ASSERTED 0.072 L/day AGAINST THAT ABSTRACT OWN 0.225 — 3.13-FOLD UNDER, with both numbers on the same line of the same sentence. The volume becomes the verbatim clearance over the rate the verbatim half-life implies, so exposure now reproduces the paper exactly. THE COST IS STATED: the modelled peak falls from about 142 to 45 mg/L, and the truth is between them — the one-compartment compromise every biologic in this catalogue faces, since a monoclonal antibody has a real and large distribution phase. Both routes move together, because the subcutaneous row shares this volume while carrying its own genuine bioavailability. THE DOSE BLOCK IS NOT TOUCHED: batch 8 already corrected it from a raw per-kilogram figure to the seventy-kilogram equivalent, and the subcutaneous 600 mg is a genuine flat dose.
Pharmacokinetics
- IV — t½ 28.5 d · F 100% · Vd 9.25 L
- Subcutaneous — t½ 28.5 d · F 77% · ka 0.0116 h⁻¹ · Vd 9.25 L
Sources: PMID:15868146, PMID:26645407, PMID:25019376