Influence of mesna on the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients

Mesna, a reactive thiol, often encounters cisplatin and carboplatin in combination protocols involving oxazaphosphorines and platinum drugs. This co-administration might be unfavorable based on the inactivation of platinum drugs by thiol groups in vitro. We investigated whether mesna influences the pharmacokinetics of platinum drugs when co-administered with cisplatin or carboplatin. The pharmacokinetics of platinum drugs were investigated in 18 pediatric patients receiving either cisplatin or carboplatin in a combination with or without mesna. In cisplatin patients, a decrease in the distribution clearance of total platinum was observed when mesna was co-administered (CLd, 2.2 +/- 0.1 mL/min.kg; n = 3), compared to cisplatin without mesna (CLd, 4.8 +/- 1.5 mL/min.kg; n = 5) (p = 0.029, t-test). This might have been caused by an influence of mesna in slowing down the protein binding of cisplatin since a trend (p = 0.057) in prolonged distribution half-life of total platinum was also observed when mesna was present (t(1/2a) 65 +/- 21 min; n = 3) compared to cisplatin without mesna (t(1/2a), 32 +/- 18 min; n = 5). However, the impact of these changes on the area under the concentration time curve (AUC), total clearance (CLt), and volume of distribution (V) for total platinum and ultrafilterable platinum species was hardly noticeable. In carboplatin patients, when mesna was co-administered: AUC (2.5 +/- 0.4 mg.min/mL.400 mg/m2; n = 5) CLt, (6.8 +/- 5.1 mL/min.kg; n = 6), and V (0.7 +/- 0.4 L/kg; n = 6) for ultrafilterable platinum species were not significantly different from when carboplatin were administered without mesna: AUC (2.3 +/- 1.3 mg.min/mL.400 mg/m2; n = 4), CLt (5.8 +/- 4.6 mL/min.kg; n = 5), and V (1.1 +/- 1.1 L/kg; n = 5). Hence, mesna does not significantly influence the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients.     

The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function

This study was performed to identify any relationship between age and cisplatin (CDDP) pharmacokinetics in lung cancer patients. CDDP was given at a dose of 80 mg/m² by 1-h intravenous infusion to 23 lung cancer patients. All patients had normal renal, hepatic, and bone marrow functions. We measured ultrafilterable platinum (U-Pt) and total plasma platinum (T-Pt) using atomic absorption spectrometry. There was significant correlation between the age of the patients and U-Pt pharmacokinetic parameters such as the area under the plasma concentration versus time curve (AUC), total clearance (Cl), and peak plasma concentration (Cmax) as well as the AUC of T-Pt (P<0.05). We performed univariate regression analysis to examine the influence of factors aside from age on the AUC of U-Pt and T-Pt. Creatinine and GPT levels were significantly related to the AUC of U-Pt, and creatinine clearance and creatinine concentrations were significantly related to the AUC of T-Pt. Therefore, stepwise multiple-regression models for the AUC of U-Pt and T-Pt were developed to assess an age effect. Age was consistently an independent and significant predictor of the AUC of U-Pt and T-Pt.     

Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function

cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Following the end of the infusion, plasma levels of total platinum and ultrafilterable (Mr less than 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum t alpha 1/2 = 98 min; t beta 1/2 range, 399 to greater than 1440 min; free platinum t alpha 1/2 = 87 min; t beta 1/2 = 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). However, the plasma clearance of free platinum did correlate positively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [t 1/2 - 37 degrees; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.     

Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function.

The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplatin in cancer patients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable) platinum, intact lobaplatin, creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable platinum and intact lobaplatin revealed almost identical patterns. The elimination of ultrafilterable platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. The calculated creatinine Cl was linearly correlated with the total body clearance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated well with the creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.     

Nonlinear renal clearance of ultrafilterable platinum in patients treated with cis-dichlorodiammineplatinum (II)

Summary Nonlinear renal clearance of ultrafilterable platinum was observed in 5 of 7 patients given cis-dichlorodiammineplatinum (II) in doses of 50–140 mg/m² by short-term infusion (2h). Average renal clearance determined during and 24 h after infusion ranged from 100 to 543 ml/min and always exceeded creatinine clearance, suggesting that ultrafilterable platinum was renally secreted. Saturable tubular reabsorption was postulated on the basis that renal clearance was highest at peak plasma and urinary levels and fell as the levels declined. Although an overall relationship between dose and renal clearance was not apparent, one patient receiving the highest dose (140 mg/m²) had elevated average renal clearance (485 ml/min), probably associated with saturation of reabsorption, whereas a patient receiving 50 mg/m² had the lowest average renal clearance (100 ml/min), indicating that either active secretion was lower, or tubular reabsorption was saturated. One patient also showed urine-flow-dependent changes in renal clearance. Four patients had transient rises in ultrafilterable platinum levels, which were attributed to changes in renal tubular reabsorption. The results suggest that renal clearance of ultrafilterable platinum is probably dependent on cis-DDP dose, urine flow rate, and individual variability in the extent of active secretion and tubular reabsorption. A sensitive HPLC method was applied and ultrafilterable platinum was detected in the plasma of all patients 24 h after infusion. Renal tubular reabsorption may result in prolonged plasma levels of ultrafilterable platinum, which could contribute to the drug's antitumour effect.     

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated withcis-diamminedichloroplatinum(II)

Summary It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m² CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (C_max), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group andP-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering C_max and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.     

Disposition of total and free cisplatin on two consecutive treatment cycles in patients with ovarian cancer

Summary The disposition of total and ultrafilterable cisplatin was determined in 12 women with ovarian carcinoma receiving cyclophosphamide 500 mg/m², adriamycin 50 mg/m² and cisplatin 50 mg/m² during their first and second course. Plasma samples were obtained over 96 h following the completion of the cisplatin infusion and assayed for total platinum by atomic absorption spectroscopy. Plasma samples obtained up to 4 h after cisplatin infusion contained measurable ultrafilterable (free) cisplatin. The mean disposition of free cisplatin conformed to a two-compartment model with a mean terminal half-life (±SD) of 46.2±20.2 min during the first course and 37.8±18.0 min during the second course of therapy.The mean disposition of total cisplatin conformed to a three-compartment model with a mean terminal half-life (±SD) of 57.8±19.3 h during the first course and 86.6±33.3 h during the second course of therapy. We found that the mean total cisplatin levels were significantly higher during the second course than the first course and the total body clearance of total platinum decreased from the first to the second course. Divided urine collections were obtained over 24 h after completion of cisplatin infusion, but cisplatin was not always detectable at all time intervals. The total fraction recovered was 0.14 and 0.12 of administered dose after the first and the second course, respectively. Renal clearance was 0.61±0.32 l/h/m² and 0.45±0.16 l/h/m² for the first and the second course, respectively.We conclude that: (1) urinary platinum excretion is variable between patients and with time; (2) a trend to decreased renal clearance of platinum from first to second course may be due to a decrease in renal excretion of cisplatin; and (3) the body's elimination pathways clear less platinum upon repeat administration.Supported in part by a grant from Adria Laboratories, Columbus, Ohio     

Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethyldithiocarbamate or atomic absorption spectroscopy

The pharmacokinetics of the cisplatin (DDP) species detected by measurement of diethyldithiocarbamate (DDTC)-reactive species (DDTC-DDP) were compared to the pharmacokinetics of the species detected by measurement of total ultrafilterable platinum in patients receiving DDP alone or in combination with the nephroprotective agent sodium thiosulfate. The doses of DDP studied were 100 mg/m² (11 courses given to eight patients) and 202.5 mg/m² (five courses given to four patients) given as 2 h i.v. infusions, the latter with concurrent thiosulfate. When DDP was given alone (100 mg/m²) the two assays yielded the same area under the curve (AUC) values for DDTC-DDP and total ultrafilterable platinum during the first 4 h after the start of infusion; however, beyond 4 h post-infusion, the AUC for total ultrafilterable platinum was consistently greater than that for DDTC-DDP. When DDP was given with thiosulfate (202.5 mg/m²), the AUC for total ultrafilterable platinum was significantly greater than that of DDTC-DDP during the whole sampling period. The ratio of the AUC for total ultrafilterable platinum to DDTC-DDP, when DDP was given with thiosulfate, was barely significantly greater than that when DDP was given alone. These data indicate that during and immediately following a short infusion of DDP the major platinum-containing species present in plasma ultrafiltrate are still capable of reacting with nucleophilic sites on molecules such as DDTC; however, as the reactive species are eliminated, longer half-lived non-reactive ultrafilterable platinum species begin to predominate. They also indicate that although thiosulfate does neutralize a measurable amount of DDP in the plasma on the schedule employed, this degree of neutralization is not sufficient to explain the protection against DDP-induced nephrotoxicity produced by thiosulfate.     

Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin

Summary The kinetics of platinum (Pt) was studied in 12 patients suffering from non-small-cell lung cancer or pleural mesothelioma. Each subject received an infusion of cisplatin (CDDP, 80 mg/m²), and six patients were pretreated with glutathione (GSH, 2.5 g given i.v.) at 15 min prior to the cisplatin infusion. After a 3- to 4-week interval, all patients were given a second course of treatment on the same schedule. A biexponential model was fitted to plasma concentrations of total and ultrafilterable Pt. The excretion of Pt in urine was evaluated during the first 48 h after the CDDP infusion. Following the administration of CDDP alone or with GSH pretreatment, the pharmacokinetic parameters of Pt did not significantly differ between the treatments. Also, the unbound fraction determined at each sampling time did not vary significantly between the treatments. However, it is noteworthy that the mean values obtained for the terminal half0life, the volume of distribution, the renal clearance, the percentage of the dose excreted in the urine, and the mean residence time of total Pt were higher in patients who had been pretreated with GSH, suggesting that SGH might increase both the rate of Pt elimination and the extent of Pt distribution and, as a consequence of the latter, might prolong the residence time of Pt in the body. In addition, the unbound fraction of Pt from the 4th to the 48th h was higher following the first dose of CDDP+GSH than after treatment with CDDP alone. Because of the rather high variability in the values of the parameters obtained, further work is planned using a larger number of patients.     

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum

Summary It has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m² by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m² furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.     

Pharmacokinetics of consecutive low-dose cisplatin

The present study investigated the optimal mode of cisplatin (CDDP) dosing in terms of pharmacokinetics. Ten patients with stage Ic ovarian cancer were randomly assigned to receive either bolus-CDDP (70 mg/m(2), 2-h infusion on day 1) or consecutive low-dose (CLD)-CDDP (10 mg/m(2), 4-h infusion for 7 consecutive days) in the adjuvant setting. Maximum concentration (C-max) of total and filterable platinum for the bolus-CDDP group were significantly higher than those for the CLD-CDDP group. Whereas, filterable drug exposure defined by the area under the concentration-time curve (AUC) was approximately 2-fold higher for the CLD-CDDP group. Urine excretion rates, which were considered to be related with nephrotoxicities, were significantly lower for the CLD-CDDP. Anti-tumor effect of CDDP has been reported to be dependent on the AUC rather than C-max of filterable platinum. Thus, CLD-CDDP dosing may possibly deliver an improved therapeutic index as compared to the usual bolus dosing method, especially for patients with pelvic tumors which eventually involve the urinary tract leading to impaired renal function.     

Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Karnofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (CCr) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment CCr. Patients with CCr greater than or equal to 40 ml/min received 400 mg/sq m; patients with CCr 20 to 39 ml/min received 250 mg/sq m; and patients with CCr 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppression, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in CCr due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with CCr. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to CCr, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with CCr of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.     

Pharmacokinetics of cisplatin and the effect of sodium thiosulfate

The pharmacokinetics of cisplatin (cis-dichlorodiammineplatinum (II), CDDP) have been studied in 11 patients. Plasma and urine CDDP concentrations were determined by flameless atomic absorption spectrophotometry. The treatment schedule was administered either by a 3-hour and 4-hour i.v. infusion or a 1.5-hour i.a. infusion. In the 3-hour i.v. infusion, the peak level of plasma total CDDP was 4.09 micrograms/ml after the end of infusion and non-protein-bound CDDP was 0.78 microgram/ml. Plasma total CDDP level declined with two peaks, the half-life of the alpha phase being 3.3 hours and that of the beta phase being 5.29 days. The half-life of non-protein-bound CDDP was 1.6 hours. CDDP might have remained for a long time, because CDDP values were obtained 3 weeks after infusion and urinary recovery of CDDP showed low values. Its urinary recovery was 40.3% of the dose infusion in the first 24 hours and 48.0% in 96 hours. The protein-binding of CDDP was inhibited by sodium thiosulfate(STS) and renal urinary excretion was enhanced. Our data suggest that STS can be applied as a neutralizer of CDDP.     

A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240)

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.     

Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity

Ultrafilterable platinum (UP) disposition was studied in 22 cancer patients receiving their first course of cisplatin (50 to 140 mg/m2) by two-hour infusion. UP plasma and urinary platinum levels were quantitated using a high-performance liquid chromatographic (HPLC) assay, which was selective for cisplatin and active platinum metabolites. Creatinine clearance was determined in all patients at the time of the pharmacokinetic studies and ranged from 58 to 214 mL/min. Creatinine clearance was a poor predictor of UP disposition in patients, probably as a consequence of the complex renal clearance mechanism for UP in the human kidney, which involves both tubular secretion and reabsorption. However, the peak plasma level of UP was closely related to the area under curve (AUC) of UP (r2 = .831), P less than .0001) and was significantly correlated with the decline in creatinine clearance observed after four courses of cisplatin therapy to 12 of the patients (r2 = .727, P less than .005). Cisplatin dose and the AUC of UP were less satisfactory predictors of the change in creatinine clearance with four courses of therapy (r2 = .488, P less than .025 and r2 = .623, P less than .005). The large interpatient variability in all the parameters of cisplatin disposition measured in this study suggested that there may be a role for individualization of cisplatin dosage based on a peak level obtained in the first course of therapy. Longer term infusion of cisplatin could also be justified.     

Studies on the appropriate administration of cisplatin based on pharmacokinetics and toxicity

Ninety-six patients with non-small cell lung cancer were treated with cisplatin (80-150 mg/m2). The pharmacokinetics of cisplatin were studied in 27 of these patients. Cisplatin was administered intravenously for 30-120 min. Plasma concentrations of total platinum and ultrafilterable (non-protein-bound) platinum were monitored by flameless atomic absorption spectrophotometry. Maximum total platinum levels in plasma were attained at the end of infusion, and thereafter decayed in a biphasic fashion, with an initial phase half-life (t1/2 alpha) of 10.2 to 14.6 min and a secondary phase half-life (t1/2 beta) of 41.7 to 81.3 h. The half-life was prolonged as the dosage was increased. Non-protein-bound platinum was rapidly cleared to below the measurable level within 4 hours at 80 mg/m2 and 120 mg/m2 of cisplatin, but declined in a biphasic manner, with t1/2 alpha of 31.2 min and t1/2 beta of 20.1 h at 150 mg/m2 of cisplatin. Toxicities were increased according to dosage, and decreased with a 50 mg/m2 X 3 days regime. Nephrotoxicity and ototoxicity were the dose-limiting factors in the single-dose escalation scheme used. In conclusion, the optimal dosage of cisplatin appeared to be 120 mg/m2 considering its toxicity.     

Pharmacokinetics of carboplatin (CBDCA) and tissue concentration of platinum in gynecologic organs

A pharmacokinetics and platinum concentration in the gynecologic organs were measured following the intravenous drip infusion of 375 mg/m2 of CBDCA. Total platinum (TP) in plasma decreased biphasically and free platinum (FP) was almost monophasically eliminated. The t 1/2 of FP was about 51 min. and the percentage of FP out of TP at four hours after administration was more than 92%, which was much higher proportion compared with that of cisplatin (CDDP). A cumulative excretion of platinum in the urine within 24 hours was 69%. The platinum concentration in the benign part of portio and endocervix were higher than that of malignant portion, although there were no significant differences in other pelvic organs such as ovary and tubes. However, pelvic lymph-nodes showed less platinum concentration both in metastatic and non-metastatic tissues. Platinum concentration in the tissue did not change significantly with lapse of time. Bone marrow suppression was observed especially in the patients who had received chemotherapy or radiotherapy. No renal toxicity was observed even without any hydration and gastro-intestinal toxicity was much milder than that of CDDP.     

Improvement in the regimen for combined CDDP and CPT-11 chemotherapy

Combination therapy with cisplatin (CDDP) and irinotecan hydrochloride (CPT-11) is expected to be effective against refractory tumors. The antitumor effect of CPT-11 is believed to depend on the area under the concentration-time curve (AUC) of SN 38, which is a metabolite of the prodrug CPT-11. Of the major adverse effects of CPT-11, leukopenia is dependent on the AUC of CPT-11 and severe diarrhea is believed to be dependent on the peak concentration (Cmax) of SN 38. Considering these properties of CPT-11, we investigated the administration of a new regimen. METHOD: The subjects were patients with gynecological cancer who consented to intra-arterial [IA] infusion. The patients received CDDP (30 mg/m2 over 2 hours) concurrently with CPT-11 (40 mg/m2 over 24 hours) at 2-week intervals. Plasma concentrations of platinum and CPT-11 were measured before and after administration. To prevent binding of SN 38 to the large intestinal mucosa, we performed 1) alkalization, 2) detoxification of SN 38, and 3) clearance of the large intestine. RESULT: 1) A decrease in tumor diameter or negative conversion on cytology and reduced tumor marker levels were observed in patients receiving IA infusion. 2) No serious adverse reactions occurred, except grade 3 diarrhea in one patient given infusion at the initial dose. 3) The rate of conversion from CPT-11 to SN 38 was about 10%, which was higher than the 3% rate after standard 90-minute intra-venous [i.v.] infusion. 4) In the patients treated with IA infusion, CPT-11 levels in venous blood were one thirty-third of those in arterial blood. 5) Regarding the venous blood concentration of platinum when CDDP (30 mg/m2) was administered, the AUC of free platinum in patients given IA infusion was about 2.5 times that after i.v. infusion. CONCLUSION: The IA infusion treatment produced a good clinical response with good compliance.     

Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. Belgian Study Group for Ovarian Carcinoma

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50-100 mg/m2 per course) plus carboplatin (CBDCA: 300-400 mg/m2 per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine greater than 1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/m2 per course and CDDP at 100 mg/m2 per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy.     

Phase II study of gemcitabine and cisplatin in patients with advanced or metastatic bladder cancer: long-term follow-up of a 3-week regimen

BACKGROUND: Bladder cancer is the fifth most common cancer among men and the seventh among women. At diagnosis, at least 25% of bladder cancer tumors are locally or systemically advanced. Systemic chemotherapy is the only current modality for advanced or metastatic transitional cell carcinoma of the bladder. Recently, a phase III randomized study has demonstrated that the regimen with gemcitabine (GMC) and cisplatin (CDDP) had a survival advantage similar to the standard M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin), with a better safety profile. AIM: It was the aim of this study to evaluate the tumor response rate, the median time to progression, the median survival and toxicity in a 21-day schedule with GMC and CDDP in patients with advanced/metastatic bladder cancer. PATIENTS AND METHODS: From September 1998 to December 2000, 27 patients with advanced/metastatic transitional cell carcinoma were enrolled. All patients received 1,200 mg/m(2) GMC administered as a 30-min intravenous infusion on days 1 and 8, and 75 mg/m(2) CDDP as a 1-hour infusion on day 2. Cycles were repeated every 21 days. The patients had a median age of 59.8 years (range 39-75) and an Eastern Cooperative Oncology Group performance status of 0-2. RESULTS: Twenty-five patients were valuable for toxic effects, length of survival and tumor response. The statistical analysis was performed in May 2004. Mean and median follow-up were 20.23 and 13.2 months (range 2-68), respectively. The overall remission rate (complete response + partial response) was 48% (95% CI 28.4-67.6%). The median time to progression was 9 months (range 2-56). The median duration of survival for all patients was 13.2 months (range 2-68+), with 1-year and 23-month survival rates of 60 and 20%, respectively. There was no grade 4 toxicity or treatment-related death. Grade 3 anemia was observed in 4 patients (16%) and grade 3 thrombocytopenia occurred in 6 patients (24%). No grade 3-4 nausea/vomiting or neutropenia was observed. CONCLUSION: GMC and CDDP is an active schedule with a good safety profile in a 21-day regimen. It may be a valid alternative to the standard 28-day regimen due to its high tumor response and survival with a low incidence of toxicity, especially in pretreated and metastatic patients.