Chemical formula: C₁₀H₁₁ClFN₅O₃ Molecular mass: 303.677 g/mol PubChem compound: 119182
Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is believed to be due to 3 mechanisms:
Clofarabine must first diffuse or be transported into target cells where it is sequentially phosphorylated to the mono- and bi-phosphate by intracellular kinases, and then finally to the active conjugate, clofarabine 5'-triphosphate. Clofarabine has high affinity for one of the activating phosphorylating enzymes, deoxycytidine kinase, which exceeds that of the natural substrate, deoxycytidine.
In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminase and decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilst the affinity of clofarabine triphosphate for DNA polymerase and ribonucleotide reductase is similar to or greater than that of deoxyadenosine triphosphate.
In vitro studies have demonstrated that clofarabine inhibits cell growth in and is cytotoxic to a variety of rapidly proliferating haematological and solid tumour cell lines. It was also active against quiescent lymphocytes and macrophages. In addition, clofarabine delayed tumour growth and, in some cases, caused tumour regression in an assortment of human and murine tumour xenografts implanted in mice.
The pharmacokinetics of clofarabine were studied in 40 patients aged between 2 to 19 years old with relapsed or refractory ALL or AML. The patients were enrolled into a single phase I (n=12) or two phase II (n=14/n=14) safety and efficacy studies, and received multiple doses of clofarabine by intravenous infusion.
Pharmacokinetics in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML following administration of multiple doses of clofarabine by intravenous infusion:
| Parameter | Estimates based on non-compartmental analysis (n=14/n=14) | Estimates based on other analysis |
|---|---|---|
| Distribution: | ||
| Volume of distribution (steady state) | 172 l/m² | |
| Plasma protein binding | 47.1% | |
| Serum albumin | 27.0% | |
| Elimination: | ||
| β half-life of clofarabine | 5.2 hours | |
| Half-life of clofarabine triphosphate | >24 hours | |
| Systemic clearance | 28.8 l/h/m² | |
| Renal clearance | 10.8 l/h/m² | |
| Dose excreted in urine | 57% | |
Multivariate analysis showed that the pharmacokinetics of clofarabine are weight dependent and although white blood cell (WBC) count was identified as having an impact on clofarabine pharmacokinetics, this did not appear sufficient to individualise a patient’s dosage regimen based on their WBC count. Intravenous infusion of 52 mg/m² clofarabine produced equivalent exposure across a wide range of weights. However, Cmax is inversely proportional to patient weight and, therefore, small children may have a higher Cmax at the end of infusion than a typical 40 kg child given the same dose of clofarabine per m². Accordingly, longer infusion times should be considered in children weighing 20 kg.
Clofarabine is eliminated by a combination of renal and non-renal excretion. After 24 hours, about 60% of the dose is excreted unchanged in the urine. Clofarabine clearance rates appear to be much higher than glomerular filtration rates suggesting filtration and tubular secretion as kidney elimination mechanisms. However, as clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system, pathways of non-renal elimination currently remain unknown.
No apparent difference in pharmacokinetics was observed between patients with ALL or AML, or between males and females.
No relationship between clofarabine or clofarabine triphosphate exposure and either efficacy or toxicity has been established in this population.
There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients. However, the pharmacokinetics of clofarabine in adults with relapsed or refractory AML following administration of a single dose of 40 mg/m² clofarabine by intravenous infusion over 1 hour were comparable to those described above in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML following administration of 52 mg/m² clofarabine by intravenous infusion over 2 hours for 5 consecutive days.
There are currently insufficient data to establish the safety and efficacy of clofarabine in patients 65 years of age or older.
To date, there are limited data on the pharmacokinetics of clofarabine in paediatric patients with decreased creatinine clearance. However, these data indicate that clofarabine may accumulate in such patients (see figure below).
Population pharmacokinetic data from adult and paediatric patients suggest that patients with stable moderate renal impairment (creatinine clearance 30 – <60 ml/min) receiving a 50% dose reduction achieve similar clofarabine exposure to those with normal renal function receiving a standard dose.
Clofarabine AUC0-24hours by baseline estimated creatinine clearance in patients aged between 2 to 19 years old with relapsed or refractory ALL or AML (n=11/n=12) following administration of multiple doses of clofarabine by intravenous infusion (creatinine clearance estimated using Schwartz formula):
There is no experience in patients with hepatic impairment (serum bilirubin >1.5 x ULN plus AST and ALT >5 x ULN) and the liver is a potential target organ for toxicity.
Toxicology studies of clofarabine in mice, rats and dogs showed that rapidly proliferating tissues were the primary target organs of toxicity.
Cardiac effects were observed in rats consistent with cardiomyopathy and contributed to signs of cardiac failure after repeated cycles of treatment. The incidence of these toxicities was dependent on both the dose of clofarabine administered and the duration of treatment. They were reported at exposure levels (Cmax) approximately 7 to 13 fold (after 3 or more dosing cycles) or 16 to 35 fold (after one or more dosing cycles) higher than clinical exposures. The minimal effects seen at lower doses suggest that there is a threshold for toxicities on the heart and nonlinear plasma pharmacokinetics in the rat may play a role in the observed effects. The potential risk for humans is unknown.
Glomerulonephropathy was reported in rats at exposure levels 3 to 5 fold higher than the clinical AUC after 6 dosing cycles of clofarabine. It was characterised by minor thickening of the glomerular basement membrane with only slight tubular damage and was not associated with changes in serum chemistry.
Hepatic effects were observed in rats following chronic administration of clofarabine. These likely represent the superimposition of degenerative and regenerative changes as a result of treatment cycles, and were not associated with changes in serum chemistry. Histological evidence of hepatic effects was seen in dogs following acute administration of high doses, but was also not accompanied by changes in serum chemistry.
Dose related toxicities on male reproductive organs were observed in mice, rats and dogs. These effects included bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells in rats at exaggerated exposure levels (150 mg/m²/day), and cell degeneration of the epididymis and degeneration of the seminiferous epithelium in dogs at clinically relevant exposure levels (>7.5 mg/m²/day clofarabine).
Delayed ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at the only dose used of 225 mg/m²/day clofarabine.
Clofarabine was teratogenic in rats and rabbits. Increases in postimplantation loss, reduced foetal body weights and decreased litter sizes together with increases in the number of malformations (gross external, soft tissue) and skeletal alterations (including retarded ossification) were reported in rats receiving doses which produced approximately 2 to 3 fold the clinical exposure (54 mg/m²/day) and in rabbits receiving 12 mg/m²/day clofarabine. (There are no exposure data in rabbits.) The threshold for developmental toxicity was considered to be 6 mg/m²/day in rats and 1.2 mg/m²/day in rabbits. The no-observable effect level for maternal toxicity in rats was 18 mg/m²/day and in rabbits was more than 12 mg/m²/day. No fertility studies have been conducted.
Genotoxicity studies demonstrated that clofarabine was not mutagenic in the bacterial reverse mutation assay, but did induce clastogenic effects in the non-activated chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells and in the in vivo rat micronucleus assay.
No carcinogenicity studies have been performed.
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