Mass balance and metabolite profiling of 14C-guadecitabine in patients with advanced cancer

Abstract

Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14 C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m 2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14 C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14 Cguadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14 C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

“…Moreover, Savona et al investigated an oral fixed-dose combination of decitabine and cedazuridine, i.e., a CDA inhibitor, in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia [ 17 ] and demonstrated favorable decitabine PK through inhibition of CDA. Furthermore, a mass balance and metabolite profiling study of 14C-guadecitabine in patients with advanced cancer evidenced that most of the administered dose is excreted as degradation products/metabolites [ 118 , 119 ]. In fact, only 0.3% of the dose was recovered as ß-decitabine, and this shows the importance of CDA inhibition in blocking guadecitabine metabolic inactivation.…”

Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review

“…6 Similarly, a mass balance study of C-guadecitabine, a dinucleotide of decitabine and endogenous deoxyguanosine, showed that decitabine was mostly metabolized prior to excretion, with negligible (0.3%) unchanged drug detected in urine. 41 Deamination of decitabine is mediated by cytidine deaminase (CDA), which is highly expressed in the gut and liver. 5,40 Decitabine is not a substrate of cytochrome P450 enzymes, has an elimination half-life of approximately 35-45 min in its IV form, and shows no systemic accumulation after repeat doses.…”

Role of Epigenetics for the Efficacy of Cisplatin

“…Here, decitabine restored the expression of SOX2 by inducing SOX2 DNA demethylation and a combined treatment with cisplatin synergistically inhibited the proliferation of xenograft tumors [153]. Another advanced demethylating agent is guadecitabine, with decitabine being its active metabolite [154]. Guadecitabine was already tested in combination with cisplatin in different clinical trials.…”