s-1-(combination) and Renal-Insufficiency

  Cytotoxic anticancer drugs are the most challenging therapeutic agents among all medicines with relatively narrow efficacy profiles. Therefore, medical oncologists have to practically manage the risk of severe toxic effects to optimize treatment outcomes. Dose and treatment-schedule recommendations for cytotoxic anticancer agents are determined on the basis of clinical trials. Patients enrolled in clinical trials are those likely to receive the drug in clinical practice, excluding those with conditions such as organ dysfunction, obesity, advanced age, or comorbidity. On the other hand, the 'real world' includes large numbers of such patients who do not meet the eligibility criteria of clinical trials. However, there is a paucity of data from sufficiently powered pharmacokinetic and pharmacodynamic studies to support dosage recommendations in such patients. Consequently, dose levels and treatment schedules for chemotherapy in these subjects are somewhat arbitrary and not evidence-based. Pharmacokinetic and pharmacodynamic studies of patients in the 'real world' are needed to address this issue. In this review article, we describe general aspects of clinical pharmacology in cancer patients enrolled in clinical trials and those in the 'real world,' and introduce recent findings regarding the pharmacokinetic and pharmacodynamic properties of irinotecan and S-1 in 'real world' cancer patients.

Topics: Age Factors; Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Humans; Irinotecan; Neoplasms; Obesity; Oxonic Acid; Patient Selection; Polypharmacy; Renal Insufficiency; Tegafur

Topics: Aged; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Nomograms; Oxonic Acid; Renal Insufficiency; Tegafur

S-1 is a combination of tegafur [metabolized to 5-fluorouracil (5-FU)] with the modulators gimeracil (5-chloro-2,4-dihydroxypyridine) and oteracil potassium. 5-Chloro-2,4-dihydroxypyridine maintains plasma 5-FU concentrations by inhibiting dihydropyrimidine dehydrogenase, a pyrimidine catabolism enzyme that degrades 5-FU. As 50% of 5-chloro-2,4-dihydroxypyridine is excreted in urine, renal insufficiency may increase its blood level, increasing 5-FU concentrations. We investigated whether special dose modification is needed in the presence of renal insufficiency.. We compared steady state pharmacokinetics of 5-FU for the initial S-1 dose and reduced doses in patients with head and neck cancer requiring dose reduction due to renal and non-renal toxicities.. Chemoradiotherapy with S-1 and cisplatin was administered every 5 weeks for two courses with a radiation dose totaling 70 Gy over 33-35 fractions. Two additional courses of adjuvant chemotherapy were administered in the case of an objective response. The S-1 and/or cisplatin dose was reduced in response to renal, hematologic or other toxicities. The primary endpoint was the change in area under the plasma concentration-versus-time curve from time 0-10 hours (5-FU AUCss 0-10) between the initial and reduced S-1 doses.. Although the mean 5-FU levels in patients with non-renal toxicities significantly decreased between the full and reduced dose, the full-dose and reduced-dose mean maximum 5-FU plasma concentrations at steady state (Css max) and AUCss 0-10 in patients with renal insufficiency were similar.. Standard S-1 dose reduction for renal toxicity did not result in a significant decrease in 5-FU levels at steady state. A greater reduction to lower plasma 5-chloro-2,4-dihydroxypyridine may be necessary in patients with renal insufficiency.

Topics: Aged; Area Under Curve; Cisplatin; Dose-Response Relationship, Drug; Drug Combinations; Female; Head and Neck Neoplasms; Humans; Kidney; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Renal Insufficiency; Tegafur

TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT.. We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles.. The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function.. The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.

Topics: Administration, Oral; Algorithms; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Computer Simulation; Drug Combinations; Fluorouracil; Humans; Kidney; Kinetics; Models, Biological; Oxonic Acid; Pyridines; Renal Insufficiency; Tegafur; Time Factors; Uracil

S-1 plus oxaliplatin appears effective in chemo-naïve patients with advanced gastric cancer. However, comprehensive safety and efficacy data for S-1 plus oxaliplatin is limited for patients with impaired renal function.. We retrospectively extracted data from advanced gastric cancer patients with normal renal function (normal group, CLcr ≥ 60 ml/min), who were treated with standard doses of S-1 (80 mg/m2) plus oxaliplatin (100 mg/m2), and patients with impaired renal function (impaired group, CLcr < 60 ml/min) who were treated with standard or reduced doses of S-1 (60 mg/m2 or 40 mg/m2) plus standard doses of oxaliplatin. Treatment efficacy and safety between the groups were compared.. Data from 100 normal patients and 42 patients with impaired renal function were extracted. Baseline characteristics differed significantly between the two groups, including age (median, 64 vs 72 years, P < 0.0001) and body surface area (median, 1.68 vs 1.51 m2, P < 0.0001). In the impaired group, 66.6% (28/42) started with a reduced dose. Within the impaired group, more patients had a reduced initial S-1 dose when CLcr <50 ml/min (77.3%). The median progression-free and overall survival between the normal and impaired groups was 6.1 vs 5.7 months (P = 0.698) and 16.1 vs 18.5 months (P = 0.638), respectively.. S-1 plus oxaliplatin in advanced gastric cancer patients with impaired renal function appears safe and has demonstrated efficacy given appropriate dose modification.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Male; Middle Aged; Oxaliplatin; Oxonic Acid; Renal Insufficiency; Retrospective Studies; Stomach Neoplasms; Tegafur; Treatment Outcome

S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided.. We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis.. The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies.. We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Topics: Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Prognosis; Prospective Studies; Renal Insufficiency; Stomach Neoplasms; Tegafur; Tissue Distribution

S-1 is a novel oral fluorouracil antitumor drug that combines tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the DPD inhibitory effect and lead to increased 5-fluorouracil (5-FU) concentrations. We sought to determine the influence of impaired renal function on the pharmacokinetics of S-1 in an animal model and in patients with gastric cancer.. An experimental renal failure model induced by cisplatin was developed in rabbits, and plasma concentrations of FT, 5-FU, CDHP and Oxo were determined after S-1 injection. Four patients with various degrees of renal impairment with unresectable gastric cancer were recruited to the study, and the pharmacokinetics in these four patients were analyzed following single and consecutive S-1 administrations.. In experimental renal failure, plasma clearance of CDHP and 5-FU was retarded corresponding to the degree of renal impairment and there was a close correlation between creatinine clearance (CLcr) and plasma CDHP and 5-FU clearance. In the single administration study, half standard dose was used in three patients (CLcr > or = 50 ml/min) and one-third in the other (CLcr <50 ml/min). In patients with CLcr more than 75 ml/min, C(max), T(max), AUC((0-infinity)), and T(1/2) of 5-FU and CDHP were not different between single and consecutive administrations. In contrast, in patients with mild and moderate renal dysfunction (CLcr 55 and 36 ml/min, respectively), the T(1/2) values of CDHP with consecutive administrations (7.6 and 15.3 h, respectively) were longer than the values with single administration (4.6 and 8.2 h, respectively). The T(1/2) of 5-FU was 5.7 h with single administration and 8.5 h with consecutive administration in patients with moderate renal impairment. The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml). There was also a strong correlation between CLcr and plasma CDHP clearance. Based on the pharmacokinetics following multiple consecutive administrations, S-1 administration resulted in no severe adverse reactions in any of the four patients.. CDHP clearance was prolonged in the presence of renal impairment, leading to a delayed T(1/2), and high AUC of 5-FU. These findings demonstrate that administration of S-1 to patients with impaired renal function may need individualized dosing and pharmacokinetic monitoring.

Topics: Aged; Animals; Antimetabolites, Antineoplastic; Cisplatin; Disease Models, Animal; Drug Combinations; Humans; Kidney Function Tests; Male; Middle Aged; Oxonic Acid; Pyridines; Rabbits; Renal Insufficiency; Stomach Neoplasms; Tegafur