Decitabine is a nucleoside metabolic inhibitor that is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA.
Cytidine deaminase (CDA) is an enzyme that is responsible for the degradation of cytidine nucleosides, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. Cedazuridine inhibits CDA. Oral administration of cedazuridine with decitabine increases the systemic exposure of decitabine via inhibition of first pass metabolism of decitabine in the gut and liver by CDA.
The pharmacokinetic (PK) parameters of decitabine and cedazuridine were studied following administration of decitabine/cedazuridine combination at the recommended dose in patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML), and AML.
Decitabine AUC exposures equivalent to those achieved with intravenous infusion of decitabine at 20 mg/m² was achieved with the recommended dose of decitabine/cedazuridine for 5 consecutive days. The geometric mean ratio (GMR) of 5-day total decitabine AUC0-24h between decitabine/cedazuridine and intravenous decitabine was 99% for patients with MDS/CMML and 100% for patients with AML (90% confidence interval [CI] 93%, 106% and 91%, 109% for MDS/CMML and AML, respectively).
At steady state (achieved with the second dose), circulating plasma concentrations were typically 1.8 times and 1.1 times the Day 1 plasma concentrations for decitabine and cedazuridine, respectively.
In the MDS population (highest number of subjects available; data from AML were similar), decitabine mean (% coefficient of variation [CV]) AUC0-24h exposure at steady state was 189 (55%) ng×h/mL and Cmax was 145 (55%) ng/mL, respectively. Cedazuridine mean AUC0-24h exposure at steady state (Day 2) was 3290 (45%) ng×h/mL and Cmax was 349 (49%) ng/mL.
After oral administration of decitabine/cedazuridine, the median time to peak concentration (tmax) at steady state was 3 hours (range: 0.5 to 7.9) for cedazuridine and 1 hour (range: 0.3 to 3) for decitabine. Co-administered with cedazuridine increased decitabine oral relative bioavailability to achieve systemic AUC exposures seen with intravenous decitabine. The bioavailability of cedazuridine was 20.7% (range: 12.7% to 25.6%).
In a crossover food effect study conducted in 16 patients, administration of the medicinal product with a high-fat, high-calorie meal reduced the overall decitabine exposure (AUC) by approximately 40% and Cmax by 54%. Cedazuridine time to maximum concentration (tmax) was slightly delayed but its systemic exposure was not significantly affected by the meal.
Decitabine is approximately 5% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution at steady state is 417 L (54%).
Cedazuridine is approximately 35% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution for cedazuridine is 296 L (51%).
Decitabine is metabolised primarily via deamination by cytidine deaminases and also physiochemical degradation at physiological conditions.
The primary metabolic pathway for cedazuridine is conversion to its epimer by physiochemical conversion in GI tract preabsorption.
Following a single oral dose of decitabine/cedazuridine, the mean (CV%) terminal elimination half-life (t1/2) of decitabine was 1.2 (23%) hours. The apparent oral clearance (CL/F) was 197 L/h at steady state. The main pathway of elimination for decitabine is metabolic/degradation. Metabolites and degradation products are excreted mainly renally.
Following a single oral dose of decitabine/cedazuridine, the mean (CV%) t1/2 of cedazuridine was 6.3 (18%) hours. The mean (CV%) apparent oral clearance (CL/F) was 25.6 (159%) L/h at steady state.
The two major elimination pathways of cedazuridine are renal elimination as parent drug and conversion to its epimer (which is then renally excreted). Following a single oral dose of 100 mg radiolabeled cedazuridine, 46% (17.1% unchanged) of the administered dose was recovered in urine and 51% was recovered in the faeces.
An approximately dose-proportional increase in peak concentrations (Cmax) and AUC over the dosing interval was observed for decitabine over a dose range from 20 mg to 40 mg in combination with 100 mg cedazuridine.
Exposure for cedazuridine over the dose range evaluated from 40 mg to 100 mg once daily were dose proportional.
Age, sex, body weight, and body surface area did not have a clinically relevant effect on the PK parameters of decitabine or cedazuridine after dosing with decitabine/cedazuridine combination.
The PK of decitabine and cedazuridine have not been formally studied in patients with impaired renal function. Patients with normal renal function (N=65) as well as mild (N=129) and moderate (N=103) renal impairment were included in the clinical studies. Renal impairment increases the exposure of cedazuridine (as renal elimination of parent drug is a major elimination pathway) and potentially also increases the exposure of decitabine (due to inhibition of decitabine metabolism caused by increased cedazuridine exposure). Decitabine is mainly metabolised and not excreted renally as unchanged drug. Only three patients with severe renal impairment and no patient with end stage renal disease were included in the studies.
The PK of decitabine and cedazuridine have not been formally studied in patients with hepatic impairment. Very few patients with impaired liver function were included in the clinical studies. Large effects of hepatic impairment on decitabine or cedazuridine exposure are not expected as cedazuridine is not hepatically metabolised and decitabine is metabolised by cytidine deaminase, which is present in several tissues.
Carcinogenicity studies with decitabine, cedazuridine, or their combination have not been conducted.
Decitabine was mutagenic in in vitro and in vivo studies. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.
Cedazuridine was mutagenic in the reverse bacterial mutation assay (Ames assay) and was genotoxic in the in vitro chromosomal aberration study using human lymphocytes. Cedazuridine was negative for the genotoxicity assessment in three in vivo studies including the mouse micronucleus, Comet assay, and the Pig-A assay.
Fertility and repeat-dose toxicity studies in animals showed adverse outcomes on reproductive function and fertility.
In male mice given intraperitoneal injections of 0.15, 0.3, or 0.45 mg/m² decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, testes weights were reduced, abnormal histology was observed, and significant decreases in sperm number were found at doses ≥0.3 mg/m². In females mated to males dosed with ≥0.3 mg/m² decitabine, pregnancy rate was reduced, and preimplantation loss was significantly increased.
Decitabine was administered orally to male rats at 0.75, 2.5, or 7.5 mg/kg/day in cycles of 5-days-on/23-days-off for a total of 90 days. Low testes and epididymis weights, abnormal histology, and reduced sperm number were observed at doses ≥ 0.75 mg/kg (approximately ≥3 times the exposure in patients at the recommended clinical dose based on AUC).
Cedazuridine was administered orally to male and female mice at 100, 300, or 1,000 mg/kg/day in cycles of 7-days-on/21-days-off for a total of 91 days. Adverse reactions including abnormal histology in the testes, epididymis, and ovaries, as well as reduced sperm numbers were observed at the 1,000 mg/kg dose (approximately 108 times the exposure in patients at the recommended clinical dose). These findings showed evidence of reversibility following 3 weeks off-dose.
Evidence from the literature indicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studies provide sufficient evidence that decitabine has genotoxic potential. Data from the literature also indicate that decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryo-foetal development and post-natal development. Multi-cycle repeat-dose toxicity studies in rats and rabbits indicated that the primary toxicity was myelosuppression, including effects on bone marrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observed and in males, testicular atrophy that did not reverse over the scheduled recovery periods.
Decitabine administration to neonatal/juvenile rats showed a comparable general toxicity profile as in older rats. Neurobehavioural development and reproductive capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression.
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