Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma

Purpose SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin.Methods Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC_ECF) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via ³²P-postlabeling.Results Mean±SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2±1.9, 11.9±3.0, and 3.5±0.3 g/g, respectively. After cisplatin, mean±SD AUC_ECF of unbound Pt was 0.72±0.46 g/ml·h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean±SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1±3.3, 3.5±1.3, and 2.1±0.3 fmol Pt/g DNA, respectively.Conclusion This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

Long-term pharmacokinetic behavior of platinum after cisplatin administration

Purpose: The platinum concentration in plasma was studied in 19 patients treated by 3 or 4 successive courses of chemotherapy including cisplatin for head and neck cancers.Methods: Cisplatin was given i.v. daily at 25 mg/m² by 1-h infusions for 4 days every 3 weeks. Total and ultrafiltrable platinum were measured in plasma using an inductively coupled plasma mass spectrometry (ICPMS) technique.Results: A progressive accumulation of total platinum in plasma was observed with consecutive infusions. The mean (±SD) total plasma platinum level detected at the end of cisplatin infusion was 1134±234, 1407±268, and 1618±282 g/l at the end of the first, second, and third courses, respectively. The minimal platinum concentration measured before the second and third courses also increased to 221±59 and 309±76 g/l, respectively. The steady state was not reached before the third course. However, differences in the evolution of platinum plasma levels were found among the 19 patients. In 14 patients the pharmacokinetics of platinum was characterized by low initial levels, a progressive accumulation, and a long terminal half-life with a very late steady state. In 5 patients, the pharmacokinetic behavior of platinum was different: platinum levels were directly high, without progressive accumulation, the steady state being reached as early as the first course. Significant levels of ultrafiltrable platinum were found throughout the treatment, even during the intervals between courses with this very sensitive analytical method. A close equilibrium between ultrafiltrable and total platinum (ratio, 6%) persisted for as long as 3 weeks after cisplatin administration.Discussion: These results underline the importance of individual differences in platinum metabolism. The relationship between total and ultrafiltrable platinum are discussed.     

Pharmacokinetics of cisplatin in patients receiving interleukin-2-containing treatment regimens

Summary Plasma cisplatin pharmacokinetics were determined in 6 patients enrolled in a phase I trial of combined high-dose cisplatin and Interleukin-2 (IL-2) therapy. Cisplatin (100 mg/m²) was given in 3% saline as a 3-h infusion on days 1 and 8 of each 28-day cycle; IL-2(2-4×10⁶ units/m²) was given as an i.v. bolus on days 15–19 in a dose escalation trial. Peak total and ultrafiltrate plasma platinum concentrations were 1.15 and 0.172 g/ml for cycle 1 and 1.2 and 0.124 g/ml for cycle 3, respectively. The AUCs for total and ultrafiltrate plasma platinum were 7.33 and 0.965 g/ml per hour for cycle 1 and 8.48 and 0.924 g/ml per hour for cycle 3, respectively. Total body clearances for total and ultrafiltrate platinum were 0.051 and 0.525 ml/h for cycle 1 and 0.042 and 0.443 ml/h for cycle 3, respectively. These data demonstrate no significant effects of IL-2 on the plasma pharmacokinetics of cisplatin in the dose schedule given and support the feasibility of this combined modality therapy.Supported in part by Cetus Corporation, Emeryville, California     

Combination treatment of cis- and carboplatin in cancers restricted to the peritoneal cavity in the rat

In the present study, cisplatin (cDDP) and carboplatin (CBDCA) were combined in different in vitro and in vivo assays to determine whether combined cDDP and CBDCA treatment would eventually lead to a better antitumor response. Co-incubation of CC531 cells with cDDP and CBDCA led to higher intracellular Pt concentrations (30.5±3.4 ng Pt/10⁶ cells) than did cDDP (16.9±9.4 ng Pt/10⁶ cells) or CBDCA (1.28±0.72 ng Pt/10⁶ cells) incubation alone. In survival assays an additive cell kill was seen after combined treatment with cDDP and CBDCA. DNA binding experiments using isolated salmon-sperm DNA exposed to the drugs separately or in combination were in agreement with the survival studies (for cDDP a binding of 12.42 g Pt/mg DNA; for CBDCA, 0.49 g Pt/mg DNA at 76 h). Toxicity studies in rats treated with cDDP plus CBDCA required a dose reduction for cDDP amounting to 20% of the MTD, whereas the CBDCA dose could be maintained. Pharmacokinetics studies showed higher AUCs andt _1/2 in plasma as well as the peritoneal cavity after combined treatment with cDDP and CBDCA (both given i.p.) or following cDDP given i.p. and CBDCA given i.v. Pt concentrations in peritoneal tumors corresponded with these observations, with higher Pt concentrations following combined treatment than after single-agent injection. In addition, combined adminstration of cDDP i.p. and CBDCA i.v. led to higher Pt concentrations in peritoneal tumors than did administration of both drugs i.p. (3.93±0.9 vs 2.76±0.2 mg Pt/g tissue). The higher Pt concentrations in the peritoneal tumors after combined treatment was associated with a significantly better antitumor response in comparison with that observed after single-agent treatment (a growth delay of 30.2±5.6 days for cDDP i.p. plus CBDCA i.v. vs 16.1±5.4 days for cDDP alone and 10.8±4.2 days for CBDCA alone).     

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     

Pharmacokinetics of (glycolato-0,0′)-diammine platinum (II), a new platinum derivative,in comparison with cisplatin and carboplatin

Summary The pharmacokinetics of (glycolato-0,0)-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m², respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 g/ml and 959 g/min per ml for 254-S, 3.09 g/ml and 208 g/min per ml for cisplatin, and 19.90 g/ml and 3446 g/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.     

Human pharmacokinetics of marcellomycin

Summary In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m². Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40–50 mg/m², the peak MCM concentration in plasma was 1.67±0.61 M; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 Mxh; plasma clearance of MCM was 1.50±0.88 l/min/m². Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m², fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40–50 mg/m², and to 7.0%±2.3% at 27.5 mg/m². No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.This work was presented in part at the Annual Meeting of the American Society of Clinical Oncology, San Diego, CA, May 1983     

A model for ultrafilterable plasma platinum disposition in patients treated with cisplatin

Summary A model incorporating recent information regarding the specificity of a high-performance liquid chromatographic assay for active platinum in plasma ultrafiltrate, and the concept of mobile and fixed metabolites, was developed for cancer patients treated with cisplatin. Model parameters were determined using plasma and urinary platinum data obtained in 20 patients. It was assumed in the model that parent drug accounted for essentially all the platinum measured in plasma ultrafiltrate in the 2 h period immediately post infusion. At times greater than 4 h post infusion, platinum concentrations in plasma ultrafiltrate were assumed to be due entirely to reactive, mobile metabolites with possible cytotoxicity. The model accurately simulated platinum concentrations in plasma ultrafiltrate over a 24-h period following a 2-h infusion of 80 mg/m² of cisplatin to seven patients, 100 mg/m² to ten patients and 120 mg/m² to three patients.This work was supported by a grant-in-aid from the Anti-Cancer Foundation of the Universities of South Australia.     

Short-termcis-diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells

Summary We examined the short-term accumulation of cisplatin (DDP) in sensitive 2008 human ovarian carcinoma cells and in a 2- to 3-fold DDP-resistant and accumulation-deficient variant. During the 1st min of exposure to 500 M DDP, sensitive cells accumulated platinum at a rate of 187±63 pmol/mg protein per min, whereas resistant cells accumulated platinum at 123±85 pmol/mg protein per min, a rate that was 66% that of sensitive cells. From 2–10 min of exposure, sensitive and resistant cells accumulated the drug at rates of 51.4±21.5 and 34.0±9.70 pmol/mg protein per min, respectively. In resistant cells, this rate again represented 66% that of sensitive cells. For each cell line, the DDP accumulation was 3.6 times faster during the 1st min that it was over 2–10 min. Initial DDP accumulation was linear with drug concentration in each cell line. Efflux measurements were made over a 50-min period after a 10-min load in 500 M DDP. The loss of platinum was biphasic in each cell line, with an initial, rapidly effluxing component being lost within 10 min in each cell line. The rate constant for loss of platinum from this rapidly effluxing pool, measured after a 10-min loading period in 500 M DDP, was 0.67±0.09 s^–1 in sensitive cells and 1.03±0.15 s^–1 (a 53% increase) in resistant cells. Between 5 and 50 min of an accumulation time course in 500 M DDP, the size of the rapidly effluxing platinum pool remained relatively constant in each cell line, with the major contribution to the increase in total platinum over time coming from growth of the slowly effluxing platinum pool. We conclude that diminished retention of platinum in the rapidly effluxing pool of resistant cells in a major determinant of decreased DDP accumulation in these cells.Abbreviations DDP cis-diamminedichloroplatinum(II) - DEP cis-dichloro(ethylenediamine)platinum(II) - RPMI Roswell Park Memorial Institute - PBS phosphate-buffered saline, consisting of (per liter) 8 g NaCl, 0.2 g KCl, 1.15 g Na₂HPO₄, and 0.2 g KH₂PO₄ Supported by a grant from Bristol-Myers Co., grants CA-35309 and CA-23100 from the National Institutes of Health, and grants CH-368 and CH-417 from the American Cancer Society. This work was conducted in part by the Clayton Foundation for Research, California Division. Drs. Mann, Andrews, and Howell are Clayton Foundation investigators     

Pharmacokinetics of cisplatin given at a daily low dose as a radiosensitiser

Summary A total of 25 patients with inoperable cervical cancer were treated by daily radiotherapy (2 Gy); sensitisation was obtained by administration of 5 mg cisplatin 30 min before each irradiation session. The total cumulative dose of cisplatin varied between 50 and 150 mg. A complete kinetic profile (0–24 h) of platinum (Pt) was established after the first dose and at the end of treatment for 22 patients. Pt was quantified by atomic absorption spectrophotometry using Zeeman-effect background correction for trace analysis. The total Pt AUC_{0–24 h} increased from 1.53±0.77 to 7±3.55 g·h·ml^–1 between the start and the end of treatment (P<0.001). Ultrafilterable Pt (Pt UF) rose from 0.079±0.038 to 0.138±0.095 g·h·ml^–1 (P<0.01). Elimination half-lives were unchanged for total Pt but rose for Pt UF; these kinetic modifications in Pt UF did not correlate with any significant change in individual serum creatinine levels. No clear correlation was found between the cumulative cisplatin dose and tumor levels measured in 13 patients, and the tumor cisplatin dose did not correlate with response to treatment. Patients with hematological toxicity were characterised by an increase in their residual Pt UF level during treatment. Overall, our findings strengthen the notion of Pt UF kinetic variability during repeated treatment.     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

Pentetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy

Summary Platinum distribution was studied in rat peritoneal tumors after i.p. treatment with equimolar doses of carboplatin and cisplatin. Low platinum concentrations (4 ppm) were detected in the periphery of the tumor after carboplatin treatment, whereas no platinum was detected 0.5 mm in from the periphery. In contrast, after cisplatin treatment, high platinum concentrations (29 ppm) were measured in the periphery of the tumor and moderate concentrations (14 ppm) were measured in the center. Only following increased carboplatin doses were low platinum concentrations detectable in the tumor. The total platinum concentration in the tumors was determined after equimolar administration of both drugs. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumors. When single cells were incubated with equimolar concentrations of carboplatin and cisplatin, 6–7 times more platinum was found in cells treated with cisplatin. However, pharmacokinetic studies favored i.p. administration of carboplatin because the clearance of this compound from the peritoneal cavity, expressed ast _1/2, was lower than that of cisplatin (239 vs 78 min), resulting in an AUC in the peritoneal cavity for both total and ultrafiltered drug that was almost 3 times higher for carboplatin than cisplatin. The AUC for ultrafiltered carboplatin in plasma was 2-fold that for cisplatin (2,801±210 vs 1,334±431 M m). The present study demonstrated that in spite of the pharmacological advantages of carboplatin, its capacity to penetrate into peritoneal tumors and tumor cells is far lower than that of cisplatin.This work was supported by grant NKI 86-5 from the Dutch Cancer Society     

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m² of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 μg/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m²) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P < 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.     

High-dose cisplatin with diethyldithiocarbamate (DDTC) rescue therapy: preliminary pharmacologic observations

Summary Diethyldithiocarbamate (DDTC), a chelating agent that is a major metabolite of disulfuram, has been proposed as a potential rescue agent to reduce toxicity following high-dose cisplatin (HDCP) therapy. In the present study, we examined the pharmcologic interaction of HDCP and DDTC given as rescue therapy. Total plasma platinum and ultrafiltrate platinum pharmacokinetics and DDTC levels were determined in six patients with advanced malignancies who received a total of 11 cycles of HDCP with DDTC rescue. HDCP therapy (200 mg/m² per cycle) consisted of 100 mg/m² reconstituted in 250 cc 3% saline and infused over 3 h on days 1 and 8 of each 28-day cycle. DDTC rescue at a dose of 4 gm/m² was given by an i.v. infusion (duration 1.5–3.5 h), beginning 45 min after the completion fo cisplatin infusion. Peak total and ultrafiltrate levels and cisplatin pharmacokinetics in this study were indistinguishable from those of previous studies using the same HDCP regimen without DDTC rescue. Ultrafiltrate or unbound plasma platinum was<10% of total plasma platinum concentrations and demonstrated a biphasic pattern of elimination. Levels of DDTC predicted to be chemoprotective (>400 M) were achieved with the dose and schedule used in this study. These data demonstrate that DDTC can be targeted to protective plasma concentrations without significantly altering plasma cisplatin pharmacokinetics and support the potential usefulness of DDTC as a rescue agent following HDCP therapy.Supported in part by grant No. CA-34620, the Merieux Institute, the Louis R. Lurie Foundation, the Randy Lynn Baruh Foundation, and the United States Veterans Administration     

Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cancer

Summary Tumor-tissue platinum levels and major pharmacokinetic parameters were determined in 11 patients with head and neck squamous cancer (HNSC) who were given cisplatin (50 mg/m² daily x 2 days) and 5-fluorouracil (5-FU; 1000 mg/m², continuous infusion x 5 days) either i.a. or i.v. The plasma peak platinum concentrations (c _max) and the areas under the curve for total platinum concentration versus time (AUC) during i.a. infusions were lower than the i.v.c _max (mean, 1.92±0.28 and 4.08±2.80 mg/l, for i.a. and i.v. infusions, respectively) and AUC values (mean, 22.55±4.96 and 40.66±10.71 mg h^–1 l^–1 for i.a. and i.v. treatment, respectively), suggesting a first-passage extraction of the drug by the tumor mass during i.a. infusion. However, no statistically significant difference was found in platinum tumor concentrations after i.a. administration versus i.v. infusion. The lack of a difference in tumor platinum concentrations between the i.a. and the i.v. administration routes might be explained either by a relatively high blood supply to the tumor area, enabling efflux of the surplus free platinum from the tissue, or by the delay between drug infusion and biopsy. After three cycles of i.a. treatment good tumor remission was obtained with minimal local toxicity. Larger clinical studies testing the advantages of the i.a. administration route over i.v. infusion appear to be necessary.Abbreviations HNSC head and neck squamous cancer - AUC area under the total platinum concentration versus time curve - OS overall survival - 5-FU 5-fluorouracil - DFS disease-free survival - CR complete response - PR partial response - SD stable disease - PRO progression This study was supported by grants from the AIRC (Italian Association for Cancer Research) and by grant from the Regione Veneto. One of the Authors (P.A.) is the recipient of an MPI 40% grant     

Clinical pharmacology of high-dose cisplatin

Summary Although nephrotoxicity has frequently limited conventional treatment with cisplatin to doses of 100–120 mg/m² per cycle, vigorous chloruresis can permit the administration of high-dose cisplatin (200 mg/m² per cycle) with minimal nephrotoxicity. Systemic toxicities are worsened, but therapeutic response seems to be enhanced. The pharmacokinetics of cisplatin in plasma and urine were examined to assess the causes of these effects. Plasma disappearance of ultrafiltrable platinum was well-described by a single exponential for each patient. The mean t_1/2 was 50% longer for patients receiving high-dose cisplatin than for patients receiving conventional doses. The total systemic exposure was three times greater in the high-dose group, which tends to explain the systemic toxicity and improved tumor efficacy, but not the lack of nephrotoxicity. It is suggested that the kidneys of patients in the high-dose group were relatively protected by dilution of active Pt species in the urine in the tubule lumen as well as by high chloride ion concentrations in the urine.     

In vitro evaluation of a novel chemotherapeutic agent,adozelesin, in gynecologic-cancer cell lines

Summary Adozelesin is a derivative of an extremely cytotoxic compound, CC1065. This entirely new class of drug binds preferentially to DNA and facilitates alkylation reaction. In the present study, we used the adenosine triphosphate (ATP) chemosensitivity assay to compare the cytotoxic potency of Adozelesin with that of common chemotherapeutic agents in ten gynecologic-cancer cell lines. Flow cytometry was also used to study its effects on cell-cycle kinetics. The mean drug concentrations required to produce a 50% reduction in ATP levels as compared with controls [IC₅₀] were: Adriamycin, 0.17±0.06 m; 4OH-Cytoxan, 18±3 m; cisplatin, 17±7 m; 5-fluorouracil, 183±116 m; and Adozelesin, 11.0±5.4pm. Thus, Adozelesin was 10⁴–10⁷ times more potent than Adriamycin, cisplatin, 5-fluorouracil, and Cytoxan. Cell kinetics studies revealed significant S and G2 blocks such as those previously reported for other alkylating agents.Supported in part by an American Cancer Society Clinical Oncology Fellowship and an American Cancer Society/Florida Division Startup Grant (both awarded to H. N. N.)     

Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.