What known drug–drug interactions exist between ivermectin and common chemotherapy or targeted agents?
Executive summary
Preclinical literature shows repeated, drug‑level interactions between ivermectin and multiple chemotherapy or targeted agents—mostly beneficial pharmacodynamic synergies (enhanced tumor cell kill, reversal of multidrug resistance) and modulation of pathways like P‑glycoprotein (P‑gp), EGFR/ERK/Akt/NF‑κB and AKT/mTOR [1] [2] [3]. However, clinical pharmacokinetic interaction data are scarce and translational gaps exist: effective in vitro concentrations often exceed achievable human plasma levels, leaving true clinical drug–drug interaction risk and benefit unproven [4].
1. Ivermectin and efflux pumps: a biochemical ally to paclitaxel, docetaxel and other P‑gp substrates
Multiple studies report that ivermectin interacts with P‑gp both as a substrate and as an inhibitor/modulator, which can increase intracellular concentrations of chemotherapeutics that are P‑gp substrates and thereby reverse resistance to agents such as paclitaxel and docetaxel in cell and animal models [5] [6] [7]. Preclinical NSCLC work specifically found ivermectin could overcome paclitaxel resistance by downregulating drug efflux via ABCB1/P‑gp mechanisms [6]. These are pharmacodynamic and cellular‑transport interactions reported in vitro and in vivo, not demonstrated clinical drug–drug interactions with validated safety or dosing guidance [5] [6].
2. Pathway modulation: EGFR, AKT/mTOR and multi‑target synergy with targeted agents
Mechanistic papers show ivermectin directly or indirectly modulates oncogenic signaling cascades—binding EGFR extracellular domains and inhibiting the EGFR/ERK/Akt/NF‑κB axis to lower P‑gp expression and sensitize tumor cells to cytotoxics, and inhibiting AKT/mTOR signaling in breast cancer models—which suggests synergy with EGFR‑directed and PI3K/AKT/mTOR pathway inhibitors in preclinical systems [2] [3] [8]. Reports of ivermectin enhancing sorafenib activity in hepatocellular carcinoma or augmenting gemcitabine cytotoxicity in pancreatic models are framed as combinatory antitumor effects mediated by multi‑pathway targeting rather than classic metabolic drug–drug interactions [9] [3].
3. Documented synergies with specific chemotherapies: gemcitabine, taxanes, anthracyclines, cytarabine
Preclinical and early translational studies report ivermectin synergizes with gemcitabine in pancreatic cancer models and with paclitaxel or docetaxel in ovarian, lung and breast cancer cell systems and animal models, producing greater apoptosis, mitochondrial dysfunction, or tumor regression than single agents alone [3] [10] [11]. In hematologic models, ivermectin showed additive or synergistic interactions with cytarabine and daunorubicin in AML cell lines but not in normal cells [1]. These data document pharmacodynamic enhancement and resistance reversal, not established clinical interaction profiles [10] [1].
4. Immunotherapy interactions: making “cold” tumors hot — a non‑classical interaction
Ivermectin has been reported to induce immunogenic cancer cell death and to synergize with PD‑1 checkpoint blockade in breast cancer models, converting immunologically cold tumors into hot ones and enabling checkpoint inhibitors to work where they otherwise failed [12]. This represents an interaction at the level of tumor‑immune biology rather than a metabolic or transporter‑mediated drug–drug interaction, and suggests potential combinatory regimens with immunotherapies that require clinical validation [12].
5. Limits of the evidence and unanswered pharmacokinetic questions
The majority of citations are preclinical—cell lines and animal models—highlighting mechanisms and promising combinations but not establishing human‑level drug–drug interaction safety, dosing adjustments, or pharmacokinetic interactions; translational hurdles include that effective in vitro ivermectin concentrations often exceed achievable human plasma concentrations [4] [13]. Explicit clinical pharmacokinetic interaction studies between ivermectin and commonly used chemotherapies or targeted agents are not reported in the provided literature, and therefore assertions about clinical interaction risks (including potential increased ivermectin toxicity when combined with P‑gp inhibitors) cannot be confirmed from these sources [4].
6. Competing narratives and hidden agendas
The literature emphasizes drug repurposing eagerness—low development cost and abundant preclinical signals—while cautioning that enthusiasm must yield to rigorous clinical trials to define safety, effective exposures, and true interaction profiles [4] [13]. Some sources frame ivermectin as a chemosensitizer and anti‑resistance agent [2] [1], which could bias interpretation toward benefit; independent clinical pharmacology studies are needed to rule out unforeseen adverse interactions in patients receiving complex oncologic regimens.