Clinical and preclinical pharmacokinetics of raltitrexed

Raltitrexed is a specific, folate-based inhibitor of thymidylate synthase w ith activity in advanced colorectal cancer comparable with that of fluorour acil (5-fluorouracil) plus folinic acid. Its activity is enhanced by rapid cellular entry and polyglutamation, with the polyglutamated derivatives hav ing approximately 100-fold greater inhibitory potency than the parent compo und. A number of phase I/pharmacokinetic studies have been performed, including schedules involving a 15-minute infusion every 3 weeks, weekly x 6 every 8 weeks, and every 2 weeks. The maximum tolerated dose (MTD) for the 3-weekly schedule was 3.5 to 4.5 mg/m(2) in adults and 6 mg/m(2) in a paediatric po pulation. The MTDs for the other schedules have not yet been reported. The disposition of raltitrexed in patients is best described by a 3-compart ment model with a terminal half-life (t1/2 gamma) of 260 hours, the latter being subject to significant interpatient variability. A similar protracted t1/2 gamma has been detected in all of the animal species studied. Togethe r with evidence from the mass-balance studies performed, this delayed elimi nation suggests considerable sequestration of raltitrexed in tissues, predo minantly as polyglutamate forms. Nevertheless, there has been no pharmacoki netic evidence of drug accumulation in plasma following repeated administra tion. On the basis of animal experiments, the oral bioavailability and pene tration of raltitrexed into cerebrospinal fluid are both likely to be limit ed in the clinical setting. Raltitrexed is over 90% bound to plasma protein over the concentration range of 20 to 100 mu mol/L. Apart from polyglutama tion, raltitrexed does not appear to be metabolised to a significant extent , and most of the excreted drug (approximately 20% of the administered dose ) is recovered unchanged in the urine within the first 24 hours post-admini stration. The average clearance of raltitrexed is 2.4 L/h (40 ml/min), and this value is significantly reduced in patients with compromised renal func tion (glomerular filtration rate of 25 to 65 ml/min). These patients are mo re likely to experience severe antiproliferative toxicity with raltitrexed. A careful evaluation of renal function, particularly in the elderly, is wa rranted. It has not been possible to establish strong correlations between the plasm a pharmacokinetics of raltitrexed and toxicity, and the cellular pharmacoki netics of raltitrexed may be more predictive. Studies in mice have demonstr ated that delayed administration of folinic acid can assist in the recovery of animals from antiproliferative toxicity, possibly by promoting the rele ase of polyglutamated drug from tissues. This approach should be evaluated as a rescue regimen in patients with severe proliferative toxicity.