Chemical formula: CH₄N₂O₂ Molecular mass: 76.055 g/mol PubChem compound: 3657
Hydroxycarbamide is an orally active antineoplastic agent.
Although the mechanism of action has not yet been clearly defined, hydroxycarbamide appears to act by interfering with synthesis of DNA by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein.
One of the mechanisms by which hydroxycarbamide acts is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerisation of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. In all clinical studies, there was a significant increase in HbF from baseline after hydroxycarbamide use.
Recently, hydroxycarbamide has shown to be associated with the generation of nitric oxide suggesting that nitric oxide stimulates cyclic guanosine monophosphatase (cGMP) production, which then activates a protein kinase and increases the production of HbF. Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells. It appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.
After oral administration hydroxycarbamide is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients. Following oral administration of hydroxycarbamide oral solution in children aged 6 months to 18 years with sickle cell disease, peak plasma concentrations are reached in 0 to 2 hours. Mean peak plasma concentrations and AUCs increase proportionally with increase of dose.
In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxycarbamide oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxycarbamide oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p=0.0467), indicating a faster rate of absorption.
In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p=0.14).
Hydroxycarbamide distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48–0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported. The extent of protein binding of hydroxycarbamide is unknown.
It appears that nitroxyl, the corresponding carboxylic acid and nitric oxide are metabolites: Urea has also been shown to be a metabolite of hydroxycarbamide. Hydroxycarbamide at 30, 100 and 300 µM is not metabolised in vitro by cytochrome P450s of human liver microsomes. At concentrations ranging from 10 to 300 µM, hydroxycarbamide does not stimulate the in vitro ATPase activity of recombinant human P glycoprotein (P-gp), indicating that hydroxycarbamide is not a P-gp substrate. Hence, no interaction is to be expected in case of concomitant administration with substances being substrates of cytochromes P450 or P-gp.
The total body clearance of hydroxycarbamide in adult patients with Sickle Cell Disease is 0.17 L/h/kg.
The respective value in children was similar, 0.22 L/h/kg.
A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxycarbamide excreted unchanged into the urine comprised about 50%.
In adult cancer patients, hydroxycarbamide was eliminated with a half-life of approximately 2-3 hours.
In a single dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 hours.
Although there is no evidence of an age effect on the pharmacokinetic-pharmacodynamic relationship, elderly patients may be more sensitive to the effects of hydroxycarbamide and therefore consideration should be given to starting with a lower initial dose and more cautious dose escalation. Close monitoring of blood parameters is advised.
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dose of hydroxycarbamide in patients with renal impairment. In an open single-dose study in adult patients with Sickle Cell Disease the influence of renal function on pharmacokinetics of hydroxycarbamide was assessed. Patients with normal (CrCl>90 ml/min), mild (CrCl 60-89 ml/min), moderate (CrCl 30-59 ml/min), severe (CrCl 15-29 ml/min) renal impairment, and End Stage Renal Disease (CrCL <15 ml/min) received hydroxycarbamide as a single dose of 15 mg/kg body weight. In patients, whose CrCl was below 60 ml/min or patients with End Stage Renal Disease the mean exposure to hydroxycarbamide was approximately 64% higher than in patients with normal renal function.
It is recommended that the starting dose is reduced by 50% in patients with CrCl <60 ml/min.
Close monitoring of blood parameters is advised in these patients.
There are no data that support specific guidance for dose adjustment in patients with hepatic impairment, but, due to safety considerations, hydroxycarbamide is contraindicated in patients with severe hepatic impairment. Close monitoring of blood parameters is advised in patients with hepatic impairment.
Preclinical toxicity studies have demonstrated the most commonly observed effects include bone marrow depression in rats, dogs and monkeys. In some species cardiovascular and haematological effects have also been observed. Observations in monkeys have also shown lymphoid atrophy and degeneration of the small and large intestine. Toxicology studies have also demonstrated testicular atrophy with decreased spermatogenesis and sperm count in rats and decreased testis weight and reduced sperm counts in mice as well. While in dogs reversible spermatogenic arrest was noted.
Hydroxycarbamide is unequivocally genotoxic and although conventional long-term carcinogenicity studies have not been conducted, hydroxycarbamide is presumed to be a transspecies carcinogen which implies a carcinogenic risk to humans.
Hydroxycarbamide crosses the placental barrier, demonstrated by dams exposed to hydroxycarbamide during gestation. Embryotoxicity manifesting as decreased foetal viability, reduced live litter sizes, and developmental delays has been reported in species including mice, hamsters, cats, dogs, and monkeys at doses comparable to human doses. Teratogenic effects manifested as partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae.
Hydroxycarbamide administered to male rats at 60 mg/kg body weight/day (about double the recommended usual maximum dose in humans) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females.
Overall, exposure to hydroxycarbamide produces abnormalities in several experimental animal species and affects the reproductive capacity of male and female animals.
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