Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694)

Abstract

Summary This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1 694) after a single intravenous dose of 3.0 mg m-2, comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min-') with eight cancer patients with normal renal function (creatinine clearance >65 ml min-'). The primary end points were area under the plasma raltitrexed concentration-vime curve from the start of the infusion to the last determined concentration (AUCo_) and AUC to infinity (AUCo); secondary end points were peak corncentrations of ralftitrexed (C,n,,) and elimination half-life (t,>). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml-' for AUCo._. (ratio 1.97; 95% Cl 1.36-2.84); 2961.5 compared with 1457.0 ng h ml-' for AUCo_ (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC,, and AUCo_ respectively. 50-lOO h (Clarke et al. 1996). This prolonged t1,, may represent hydrolysis of the polvalutamated

Population pharmacokinetics of raltitrexed in patients with advanced solid tumours

“…The present study investigated the pharmacokinetics of raltitrexed in patients with advanced solid tumours using a population pharmacokinetic approach. The findings of the pharmacokinetic properties of raltitrexed in the study were in agreement with those obtained using a conventional pharmacokinetic analysis approach [6–9]. The concentration–time profile of raltitrexed was best described by a three‐compartment pharmacokinetic model and the clearance and volume of distribution of raltitrexed were found to be in close agreement with those previously reported [8, 11].…”

“…The pharmacokinetics and clinical toxicity of raltitrexed have previously been evaluated in patients with renal impairment [9]. Although a direct relationship has not been defined between creatinine clearance and the degree of clinical toxicity of raltitrexed, it was reported that the raltitrexed clearance is approximately halved in patients with mild to moderate renal function impairment [9]. These patients exhibit a significantly prolonged half‐life and a greater AUC than patients with normal renal function [9].…”

“…The clinical studies included a European [6] and a US [7] Phase I dose‐finding studies, a radiolabel mass‐balance study [8], and an open‐label study evaluating the effect of renal function on the pharmacokinetics of raltitrexed [9]. Raltitrexed was administered intravenously as a short infusion at intervals of 3 weeks.…”

“…The clinical pharmacokinetics of raltitrexed have been studied in patients with cancer using conventional pharmacokinetic analyses [6–9]. Plasma concentrations of raltitrexed reach a peak during or shortly after infusion ( t max = 10–25 min) and then decline triexponentially [6, 8] with mean half‐lives t 1/2α , t 1/2β and t 1/2γ of 12 min, 103 min and 257 h, respectively [8].…”

“…It mainly undergoes renal elimination with 40–50% of the dose excreted unchanged in the urine and approximately 15% of the dose excreted unchanged in the faeces [8, 11]. Renal function has been reported to influence the pharmacokinetics of raltitrexed, with the mean raltitrexed clearance approximately halved in patients with mild to moderate renal impairment (mean clearance reduced from 66.7 to 32.3 ml min −1 in patients with normal and impaired renal function, respectively) [9]. The effect of hepatic impairment on the pharmacokinetics of raltitrexed has not been fully defined.…”