Raltitrexed

Raltitrexed is a folate analogue belonging to the family of anti-metabolites and has potent inhibitory activity against the enzyme thymidylate synthase (TS). Compared to other antimetabolites such as 5-fluorouracil or methotrexate, raltitrexed acts as a direct and specific TS inhibitor. TS is a key enzyme in the de novo synthesis of thymidine triphosphate (TTP), a nucleotide required exclusively for deoxyribonucleic acid (DNA) synthesis. Inhibition of TS leads to DNA fragmentation and cell death. Raltitrexed is transported into cells via a reduced folate carrier (RFC) and is then extensively polyglutamated by the enzyme folyl polyglutamate synthetase (FPGS) to polyglutamate forms that are retained in cells and are even more potent inhibitors of TS. Raltitrexed polyglutamation enhances TS inhibitory potency and increases the duration of TS inhibition in cells which may improve antitumour activity. Polyglutamation could also contribute to increased toxicity due to drug retention in normal tissues.

Following intravenous administration at 3.0 mg/m², the concentration-time profile in patients was triphasic: Peak concentrations, found at the end of the infusion, were followed by a rapid initial decline in concentration. This was followed by a slow elimination phase. The key pharmacokinetic parameters are presented below:

Summary of mean pharmacokinetic parameters in patients administered 3.0 mg/m² Raltitrexed by intravenous infusion:

Key:

C_max: Peak plasma concentration.
AUC: Area under plasma-concentration time curve.
CL: Clearance.
CL_r: Renal clearance
V_ss: Volume of distribution at steady state.
t_½β: Half life of the second (β) phase.
t_½γ: Terminal half life.

The maximum concentrations of raltitrexed increased linearly with dose over the clinical dose range tested.

During repeated administration at three week intervals, there was no clinically significant plasma accumulation of raltitrexed in patients with normal renal function.

Apart from the expected intracellular polyglutamation, raltitrexed was not metabolised and was excreted unchanged, mainly in the urine, 40-50%. Raltitrexed was also excreted in the faeces with approximately 15% of the radioactive dose being eliminated over a 10 day period. In the [¹⁴C]-raltitrexed trial approximately half of the radiolabel was not recovered during the study period. This suggests that a proportion of the raltitrexed dose is retained within tissues, perhaps as raltitrexed polyglutamates, beyond the end of the measurement period (29 days). Trace levels of radiolabel were detected in red blood cells on Day 29.

Raltitrexed pharmacokinetics are independent of age and gender. Pharmacokinetics have not been evaluated in children.

Mild to moderate hepatic impairment led to a small reduction in plasma clearance of less than 25%.

Mild to moderate renal impairment (creatinine clearance of 25 to 65 ml/min) led to a significant reduction (approximately 50%) in raltitrexed plasma clearance.

Perivascular tolerance in studies in animals did not reveal any significant irritant reaction.

Acute toxicity

The approximate LD₅₀ values for the mouse and rat are 875-1249 mg/kg and >500 mg/kg respectively. In the mouse, levels of 750 mg/kg and above caused death by general intoxication.

Chronic toxicity

In one month continuous and six month intermittent dosing studies in the rat, toxicity was related entirely to the cytotoxic nature of the drug. Principal target organs were the gastrointestinal tract, bone marrow and the testes. In similar studies in the dog, cumulative dose levels similar to that used clinically, elicited only pharmacologically-related changes to proliferating tissue. Target organs in the dog were therefore similar to the rat.

Mutagenicity

Raltitrexed was not mutagenic in the Ames test or in supplementary tests using E. coli or Chinese hamster ovary cells. Raltitrexed caused increased levels of chromosome damage in an in vitro assay of human lymphocytes. This effect was ameliorated by the addition of thymidine, thus confirming it to be due to the anti-metabolic nature of the drug. An in vivo micronucleus study in the rat indicated that at cytotoxic dose levels, raltitrexed is capable of causing chromosome damage in the bone marrow.

Reproductive toxicology

Fertility studies in the rat indicate that raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. Raltitrexed caused embryo lethality and foetal abnormalities in pregnant rats.

Carcinogenicity

The carcinogenic potential of raltitrexed has not been evaluated.