Characterization of the in vitro inhibitory potential of the oligonucleotide imetelstat on human cytochrome P450 enzymes with predictions of in vivo drug-drug interactions.

Imetelstat, a 13-base oligonucleotide (5'-TAGGGTTAGACAA-3') is a potent, investigational telomerase inhibitor in clinical development for the treatment of hematologic myeloid malignancies. Modifications to imetelstat oligonucleotide chemistry include a N3'--P5' thio-phosphoramidate backbone linkage to improve biological stability and the addition of a palmitoyl tail at the 5'-position to enhance cellular membrane permeability. Other oligonucleotides have been previously shown to have in vitro test-system dependent outcomes where potent P450 inhibition in human liver microsomes (HLM) is observed but such inhibition is not observed in cryopreserved human hepatocytes (CHH). Outcomes in CHH are consistent with clinical reports where no interactions are observed. In the present study, imetelstat was evaluated for in vitro inhibition of eight P450 enzymes, namely CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in CHH (0.5 million cells/mL). Assays were performed using validated conditions, including short substrate times (10 min) and at the approximate substrate Km concentration. Imetelstat was found to have little to no inhibition of all P450 isoforms evaluated, with IC50 values >100 µM. Maximum percent inhibition values for each P450 isoform at 100 µM imetelstat were <20% except for CYP2C8 activity which was inhibited by 49%. Using a static mechanistic model, the predicted change in AUC of a victim drug co-administered with imetelstat was 1.04-fold, predicting no relevant clinical interaction. Overall, the results from this in vitro study suggest that clinical use of imetelstat is unlikely to affect the pharmacokinetics of concomitant therapies that undergo P450 mediated metabolism.