Quantitative In Silico Reality Check on the Antiparasitic-Cancer-Cure Hypothesis: A Multi-Cancer PBPK and Network-Pharmacology Evaluation of Ivermectin and Fenbendazole Across Seven Solid and Hematologic Malignancies

Background.
Following anecdotal reports popularised on social media, oral self-administration of the veterinary
antiparasitics ivermectin (IVM) and fenbendazole (FBZ) is being adopted by a growing patient
population as putative cancer therapy. Genuine peer-reviewed in vitro evidence supports anti-tumour
activity for both compounds: IVM modulates the WNT/TCF, PAK1, MDR1/P-gp and KPNB1
axes, while FBZ destabilises microtubules at the colchicine binding site of β-tubulin and inhibits
glucose uptake via GLUT4 and HK-II. However, no controlled human phase II/III data exist, and
the quantitative gap between in vitro potency and clinically achievable plasma exposure has never
been formally evaluated across cancer types.
Methods.
We adapted the open-source CureNet eight-layer computational pharmacology pipeline [1] to
evaluate IVM and FBZ across seven malignancies: glioblastoma (GBM), acute myeloid leukaemia
(AML), triple-negative breast cancer (TNBC), colorectal cancer (CRC), non-small-cell lung cancer
(NSCLC), pancreatic ductal adenocarcinoma (PDAC) and cutaneous melanoma (MEL). Each
cancer was modelled with disease-specific gene sets, protein-protein interaction (PPI) topology,
target proteins (with PDB structures), pathway enrichment, fold-change priors and standard-of-care
chemotherapeutics. The CureNet pipeline executes ADMET filtering, target-disease overlap, network
pharmacology, empirical and (where feasible) AutoDock-GPU physics-based molecular docking,
100 ns equivalent molecular dynamics, Bliss/Loewe synergy analysis, an eight-variable ODE pathway
model and transcriptomic herb-drug-interaction analysis. We extended this pipeline with three
additional analytical rungs: (i) a physiologically-based pharmacokinetic (PBPK) plasma-versus-IC50 reality check parameterised by published human Cmax data, (ii) an allometric oral-dose extrapolation
comparing IC50-equivalent dose against documented safety ceilings, and (iii) a composite plausibility
score combining in-silico signal strength with pharmacokinetic feasibility.
Results.
Across all seven cancers, the in vitro IC50 values for both drugs (IVM 3–15 μM; FBZ 0.8–3.0 μM)
lie 0.6–30-fold above the maximum total-plasma Cmax achievable at the safety ceiling, and after
correction for plasma protein binding (IVM 93%, FBZ 95%) the free-drug fold-deficit ranges from
12.3× (FBZ in NSCLC) to 439.6× (IVM in CRC). The composite plausibility score classifies zero
of seven cancers as "promising", five as "worth further preclinical study" (TNBC, NSCLC, CRC,
MEL, AML; scores 42–51 of 100) and two as "implausible at safe doses" (PDAC, GBM; both 33).
The strongest in-silico signals — IVM–PAK1 (–5.2 kcal/mol) and FBZ–β-tubulin (–4.9 kcal/mol)
— recapitulate the established mechanisms but cannot be reached at safe oral doses without new
formulations. The triple-combination Layer-7 ODE predicts 87.9% cell death uniformly across
cancers when chemotherapy is combined with sub-IC50 IVM and FBZ, supporting a chemosensitiser
hypothesis rather than a monotherapy cure hypothesis.
Conclusions.
The anti-cancer biology of IVM and FBZ is mechanistically real, but the social-media "oral antiparasitic
cures cancer" narrative is not supported by quantitative pharmacokinetics at any tested
cancer. The free-drug plasma concentration achievable within the human safety envelope sits one
to three orders of magnitude below the in vitro killing concentration. Two specific paths preserve
scientific honesty: (a) intravenous or liposomal reformulation that raises Cmax 10–30-fold (most
promising in AML, where IC50 is lowest and the BCL-2/MCL-1 axis converges with venetoclax),
and (b) sub-IC50 chemosensitiser trials with established standard-of-care chemotherapy doing the
cytotoxic work (most promising in CRC with FOLFOX, NSCLC with osimertinib, and MEL with
vemurafenib). Until such data exist, oral self-medication at doses sufficient to match in vitro IC50 is
mathematically impossible without exceeding documented hepatotoxicity and neurotoxicity ceilings