Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694).
This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) 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(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). 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(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.
Judson
I
I
Institute of Cancer Research, Sutton, Surrey, UK.
Maughan
T
T
Beale
P
P
Primrose
J
J
Hoskin
P
P
Hanwell
J
J
Berry
C
C
Walker
M
M
Sutcliffe
F
F
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D013876:Thiophenes; C068874:raltitrexed