Modified-release formulation of decitabine and tetrahydrouridine combination not only increases exposure to decitabine but reduces exposure to unfavorable decitabine metabolites in healthy volunteers

Abstract Background: The modified-release fixed combination of decitabine and tetrahydrouridine (THU), NDec, is an investigational treatment for people with sickle cell disease. Decitabine directly induces fetal hemoglobin expression by inhibiting DNA methyltransferase 1 (DNMT1), while THU inhibits the rapid degradation of decitabine by cytidine deaminase (CDA). Aims: This study compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of NDec, in which THU is released before decitabine, with an immediate-release (IR) formulation, in which both components are released simultaneously. Methods: This Phase 1, single-center, randomized, crossover study enrolled healthy adult volunteers. While in a fed state, participants were administered a single oral dose of either NDec (three capsules) or IR decitabine–THU combination (three tablets), each providing a total dose of 15 mg decitabine and 750 mg THU. Each participant received a single dose of each formulation with a 7-day washout period in between doses. PK measures included total exposure, ie, area under the curve from 0 to infinity (AUC0–inf), maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), and half-life (t½) for decitabine and THU. AUC for decitabine metabolites was determined following their identification. Values are reported as geometric mean and coefficient of variation (CV). PD measures included percentage change from baseline in DNMT1 protein at 24 hours and in CDA activity at 3 and 6 hours after dosing. Results: Of 44 participants, 23 were male and 21 were female, with a mean age of 34 years (range: 20–59 years). Compared with the IR formulation, a single dose of NDec resulted in a greater AUC of decitabine (80.4 h∗ng/mL [CV 57.2%] NDec vs 50.7 h∗ng/mL [CV 36.6%] IR), a higher Cmax of decitabine (42.7 ng/mL [CV 70.8%] NDec vs 33.2 ng/mL [CV 54.6%] IR), and a delayed tmax (4.1 hr [CV 22.0%] NDec vs 1.3 hr [CV 57.7%] IR). The t½ of decitabine was 1.5 h (CV 23.5%) for NDec and 1.8 h (CV 20.9%) for IR. THU PK were comparable between formulations. Both formulations inhibited DNMT1; maximum change from baseline at 24 hours was −79.3% (standard deviation [SD] 11.9) with NDec and −75.3% (SD 13.5) with IR. CDA enzyme activity showed maximum change from baseline at 3 hours post-dose and continued to be inhibited in most participants when measured 6 hours post-dose. AUCs of the decitabine metabolites DM4 and DM8 (markers for exposure of 5-aza-2′-deoxyuridine and its unfavorable phosphorylation metabolites 5-aza-2′-deoxyuridine-monophosphate, 5-aza-2′-deoxyuridine-5‘-diphosphate, and 5-aza-2′-deoxyuridine-5‘-triphosphate) were reduced after administration of NDec compared with IR (DM4 AUC: < lower limit of quantification [NDec] vs 0.59 μM × h [IR]; DM8 AUC: 0.02 μM × h [NDec] vs 0.49 μM × h [IR]). No serious adverse events (AEs) were reported; 17 mild AEs and 4 moderate AEs were reported, all of which resolved. Conclusions: Staggered release of THU with decitabine in NDec resulted in optimal decitabine exposure with no unexpected safety concerns. A decrease in exposure to unfavorable CDA-mediated uridine metabolites with NDec compared with IR indicates that delaying release of decitabine after THU may reduce toxicity by promoting the oxidative degradation pathway of decitabine in preference to the phosphorylation pathway. These findings support the planned use of NDec to investigate clinical efficacy and safety in Phase 3 trials.