Pharmacokinetics Of Cisplatin Research Articles

Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer

To evaluate the pharmacokinetics (PK) of capecitabine and cisplatin, administered in combination with or without trastuzumab, in Japanese patients with HER2-positive advanced gastric cancer (AGC). Patients eligible for this PK study (study JP19959), which was carried out during treatment Cycle 1 of the ToGA study, received either capecitabine and cisplatin (XP arm) or trastuzumab plus capecitabine and cisplatin (HXP arm). All patients received capecitabine (1,000 mg/m(2) orally, twice daily for 14 days) and cisplatin (80 mg/m(2) intravenous infusion on Day 1). Patients in the HXP arm also received trastuzumab (8 mg/kg intravenous infusion on Day 1), concurrently with capecitabine. No further study medication was administered during study JP19959. Serial plasma samples for PK analysis were obtained at intervals before and after the administration of capecitabine and cisplatin on Day 1. Twenty-two patients were enrolled in this PK study: eight in the HXP arm and 14 in the XP arm. All blood samples were available for PK analysis. Co-administration of trastuzumab resulted in no statistically or clinically significant changes in the PK profiles of capecitabine or its metabolites, or of cisplatin (total or unbound platinum). Variability in the AUC(last) and C (max) values for the capecitabine was consistent with the known PK profile of capecitabine and fell within established limits. Concurrent trastuzumab therapy is unlikely to alter the PK or safety profile of capecitabine or cisplatin in Japanese patients with HER2-positive AGC.

Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non-small-cell lung cancer patients receiving cisplatin/gemcitabine

This study quantified the impact of drug pathway-associated genetic variants on the pharmacokinetics (PK) of gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). Thirty-seven patients with advanced NSCLC were sampled for plasma concentrations of gemcitabine, difluoro-deoxy uridine (dFdU), intracellular gemcitabine triphosphates (dFdCTP), and unbound platinum concentrations after gemcitabine 1,250mg/m(2) i.v. followed by cisplatin 75mg/m(2). We analyzed 13 germline single nucleotide polymorphisms and one deletion-glutathione S-transferase (GST) M1-within six drug pathway-associated genes (GSTM1, GSTP1, cytidine deaminase (CDA), solute carrier (SLC) 28A1, SLC28A2, and deoxycytidine kinase). PK models were fitted to the data using nonlinear mixed-effects modeling, and genetic data were tested on drug PK and hematological toxicity. Patients carrying the nonsynonymous CDA SNP 79A >C (CDA*2) had a 21% lower gemcitabine clearance as compared to wild-type patients (outcomes and complications.0.0009), but the risk for chemotherapy-associated neutropenia (61% vs. 32%, P=0.07) and severe neutropenia (17% vs. 5%, P=0.26) was not significantly higher. Other gene polymorphisms were not associated with drug PK parameters or hematological toxicity. The known functional mutant variant CDA*3 was not found in any of the patients. Although the mutant CDA*2 allele results in an increased exposure to gemcitabine in Caucasian patients, this study gives no definite conclusion on the clinical relevance of this finding. Further studies should look into the relationship between CDA genotypes, plasmatic CDA activity, and clinical outcome in patients receiving gemcitabine-based chemotherapy.

Effect of Stoichiometry of Cisplatin—Alginate Complex on the Pharmacokinetics of Cisplatin

It was previously reported that alginate forms a complex with cisplatin, increasing plasma levels of cisplatin and reducing nephrotoxicity but without decreasing in-vitro antitumour activity. We examined three kinds of cisplatin—alginate complexes with various stoichiometrics (molar ratios of uronic acid of two-, four- and tenfold to cisplatin) to clarify the effect of alginate on the pharmacokinetics of cisplatin-alginate complex. Plasma levels of cisplatin were maintained at high levels dependent upon the content of alginate. Tissue-plasma partitioning values of cisplatin (Kp) in several tissues, especially the kidney, at 48 h after administration were repressed by complexation. However, the addition of alginate at molar ratios of uronic acid residue to cisplatin of more than four-fold had no further effect on plasma level or tissue accumulation of cisplatin. Urinary excretion of cisplatin was accelerated by alginate content up to a ratio of four uronic residues to each cisplatin molecule, while a uronic acid molar ratio of ten showed no further effect. Thus, the effect of alginate on pharmacokinetics of cisplatin is dependent on the amount of alginate, and the optimal content of alginate was around a molar ratio of four, uronic acid to cisplatin.

Effect of figitumumab (CP-751871) on the pharmacokinetics of cisplatin and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC).

e18046 Background: Figitumumab is a fully human IgG2 monoclonal antibody targeting the IGF-1 receptor (IGF-1R). The combination of figitumumab with cisplatin and pemetrexed was evaluated in a phase I trial in patients with advanced non-small cell lung cancer (NSCLC). The effect of figitumumab on the pharmacokinetics (PK) of cisplatin and pemetrexed was determined as part of the phase I trial. Methods: A total of 13 patients with NSCLC were administered 20 mg/kg of figitumumab, 75 mg/m2 of cisplatin, and 500 mg/m2 of pemetrexed via intravenous infusion in cycles of every 3 weeks. Patients received the combination therapy for a maximum of 6 cycles, with the option to continue treatment with single agent figitumumab upon chemotherapy discontinuation. Plasma PK of total cisplatin and pemetrexed were evaluated over a 24-hour period before figitumumab dosing in cycle 1 and after concomitant figitumumab dosing in cycle 2. The concentration–time data were analyzed by noncompartmental methods to determine PK parameters. Results: Figitumumab at the dose level evaluated was well tolerated when given in combination with cisplatin and pemetrexed. For cisplatin, although mean values for Cmax and AUC0-24hr in cycle 2 (in the presence of figitumumab) were respectively, 23% and 26% higher than for cycle 1 (in the absence of figitumumab), individual Cmax and AUC0-24hr values from both cycles were in a similar range. Based on preliminary pemetrexed PK data available from 10 of the 13 patients, the mean Cmax and AUC0-24hr in cycle 2 were approximately 16% and 21% higher than corresponding mean values from cycle 1, respectively. These findings should be viewed in the context of the high inter-patient variability (CV% up to 44%) for cisplatin and pemetrexed PK parameters. Conclusions: Concomitant administration of figitumumab with cisplatin and pemetrexed appeared to result in slight increases in systemic exposures of cisplatin and pemetrexed. The high inter-patient variability in cisplatin and pemetrexed PK parameters and the overall tolerability of the tested combination suggest that adjustment of the starting dose for the chemotherapeutics may not be necessary. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer

Effect of buthionine sulphoximine, glutathione and methimazole on the renal disposition of cisplatin and on cisplatin-induced nephrotoxicity in rats: pharmacokinetic-toxicodynamic analysis.

The aim of this study was to classify the protective mechanisms of DL-buthionine-(S,-R)-sulphoximine, glutathione and methimazole on cisplatin-induced nephrotoxicity in rats. An Emax model was used to study the effect of these compounds on the pharmacokinetics of cisplatin, especially renal handling and intra-renal biotransformation. Cisplatin (5 mg kg(-1)) was administered as an intravenous bolus to rats treated with either 0.9% NaCl (control), buthionine sulphoximine, glutathione or methimazole. The blood urea nitrogen level was monitored to estimate cisplatin-induced nephrotoxicity. To estimate renal handling of cisplatin, cisplatin was infused intravenously to rats treated with 0.9% NaCl, buthionine sulphoximine, glutathione or methimazole. The concentrations of unchanged cisplatin in plasma, urine and kidney were determined by a post-column derivatization HPLC method. The relationship between the pharmacokinetics and toxicodynamics of cisplatin was analysed using a sigmoid Emax model. All compounds studied ameliorated significantly the nephrotoxicity of cisplatin. The renal accumulation of cisplatin was reduced significantly by pretreatment with buthionine sulphoximine but not by either glutathione or methimazole. Although glutathione treatment did not affect the renal accumulation of cisplatin, it significantly decreased the binding of cisplatin to the intrarenal organelle and the decreased binding was well correlated to the decrease of the blood urea nitrogen level. In summary, pharmacokinetic-toxicodynamic analysis will be useful for classifying the protective mechanism of cisplatin-induced nephrotoxicity.

Cisplatin pharmacokinetics in a child receiving peritoneal dialysis

Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumors in children, but there is currently no information to guide dosing in children requiring dialysis. Here, we present the case of a 2-year-old boy with end-stage renal disease managed with peritoneal dialysis and requiring cisplatin for a newly diagnosed hepatoblastoma. A pharmacokinetic study was performed to personalize the cisplatin dose with the goal of providing adequate cisplatin exposure and avoiding excessive exposure and toxicity. Accordingly, 25% of the standard cisplatin dose was infused intravenously over 4 h. Serial blood and peritoneal fluid samples were obtained, and free cisplatin levels were subjected to noncompartmental pharmacokinetic analysis. The disposition of free cisplatin was significantly altered as compared to that of normal children. Despite a 75% dose reduction, our patient showed a fourfold increase in free cisplatin exposure (AUC = 64.1 h mcg/mL) compared with the AUC observed in children with normal kidney (15 + or - 9 h mcg/mL) function. When a subsequent dose was decreased to 8.7% of the standard dose, the free cisplatin AUC measured 29.7 h mcg/mL and more closely approximated the exposure observed in children with normal kidney function.

Population pharmacokinetics of cisplatin in Asian Indian cancer patients

The aim of this study was to describe population pharmacokinetics of cisplatin in an Indian cancer population. Dosage adjustment based on individual pharmacokinetic parameters is of considerable importance for effective and safe use of drugs. Extensive work on cisplatin and other was carried out in different cancer patient populations, but no data are available in Indian cancer patients. In the present study 154 steady state concentrations of cisplatin were analyzed from 46 patients. Pharmacostatistical work was done by using NONMEM. The covariates evaluated in this study were age, body weight, height, sex, and creatinine clearance. The model found to best describe the data following the FO and FOCE method was: Clearance (CL) = θ1*(CLCR/74.92) *EXP (η1) and Volume (V) = {θ2 *(AGE/52.3) + θ3*(BSA/1.55)}*EXP (η2). The final model estimates of CL and V estimated by FO method were 3.02 L/h and 2.72 L, respectively, and by FOCE method were 3.39 L/h and 4.48 L, respectively. These parameters are utilized for in...

Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration

Background: Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics. Patients and methods: Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM®) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods. Results: Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described. Conclusion: The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.

Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration

Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics. Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods. Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of distribution in the Uf Pt model, and both IP and serum protein concentrations for the clearance from the central compartment in the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described. The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.

Pharmacokinetics of cisplatin and methotrexate after M‐VAC chemotherapy for advanced urothelial cancer in hemodialysis patients

Pharmacokinetics of cisplatin and methotrexate after M‐VAC chemotherapy for advanced urothelial cancer in hemodialysis patients

Phase I and pharmacokinetic study of NC-6004, a new platinum entity of cisplatin-conjugated polymer forming micelles

2573 Background: NC-6004 contains cisplatin derivatives in micellar nanoparticles. Preclinical activity was seen in platinum resistant cell lines. We report a phase I trial of NC-6004 with doses from 10–120mg/m2 cisplatin equivalent. Methods: NC-6004 dose was escalated in patients with refractory solid tumors according to toxicity with 1 patient per dose level until grade 2 toxicity observed then 3–6 evaluable patients per dose level. Eligible patients had adequate bone marrow, hepatic and renal function. NC-6004 was administered as a 1 hour intravenous infusion on day 1 of a 21 day cycle (C). Patients were monitored for usual dose-limiting toxicities (DLT) and renal function assessed by EDTA GFR. Pharmacokinetics (PK) of cisplatin were characterized by atomic absorption spectrometry for total platinum, micellar component by gel-filtration, inductively-coupled plasma mass spectrometry for free platinum species. Patients were restaged every 2 cycles and treatment continued if clinical benefit and acceptabl...

Oncological and Functional Outcome of Radical Cystectomy in Patients With Bladder Cancer and Obstructive Uropathy

We present our experience with the perioperative, functional and oncological outcomes of radical cystectomy in patients with bladder cancer and obstructive uremia. From 1998 to June 2006, 58 patients with bladder cancer, and concomitant obstructive uropathy and azotemia presented to our institution. Mean +/- SD serum creatinine at presentation was 9.2 +/- 4.5 mg% (range 2.4 to 16.5). Radical cystectomy, bilateral pelvic lymphadenectomy and urinary diversion were performed after stabilizing renal function with and without percutaneous nephrostomy in 28 and 8 patients, respectively. Various preoperative variables were evaluated for predicting long-term treatment failure and renal deterioration. Mean followup was 34 months. Mean serum creatinine at surgery was 1.85 mg%. An ileal conduit was used in 32 patients and cutaneous ureterostomy was used in 4. One patient died of chest infection in the perioperative period. All patients had muscle invasive disease, while 15 had positive lymph nodes. At the mean followup 15 patients (41.6%) were free of disease and 21 had treatment failure. Of the factors evaluated pathological tumor stage, grade and lymph node involvement predicted the long-term oncological outcome, while serum creatinine greater than 2.5 mg% at surgery and ileal conduit diversion predicted long-term renal deterioration. Patients with bladder cancer who have obstructive uremia usually present with locally advanced disease. Radical cystectomy is not associated with additional morbidity, provided that patients are adequately prepared before surgery by optimizing renal function. An adequate number of these patients achieve long-term disease-free survival after radical cystectomy. As the urinary diversion of choice, an ileal conduit appears to be safe in patients with serum creatinine less than 2.5 mg% at surgery.

A Parallel Dose-Escalation Study of Weekly and Twice-Weekly Bortezomib in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced Solid Tumors

To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors. Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m(2) days 1 and 8 and cisplatin 70 mg/m(2) day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD. Thirty-four patients were enrolled of whom 27 had non-small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m(2) in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m(2) as well. Most common > or =grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade > or =3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule. Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.

Relationship Between Cisplatin Administration and the Development of Ototoxicity

To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2. Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 weeks.

Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat

Cisplatin is an effective anticancer drug, but has its severe adverse effects, especially nephrotoxicity. The molecular mechanism of cisplatin-induced nephrotoxicity is still not clear. In the present study, we examined the role of rat (r)OCT2, an organic cation transporter predominantly expressed in the kidney, in the tubular toxicity of cisplatin. Using HEK293 cells stably expressing rOCT2 (HEK-rOCT2), we evaluated the cisplatin-induced release of lactate dehydrogenase and the uptake of cisplatin. The release of lactate dehydrogenase and the accumulation of platinum were greater in HEK-rOCT2 cells treated with cisplatin than in mock-transfected cells. Moreover, cimetidine and corticosterone, OCT2 inhibitors, inhibited the cytotoxicity and the transport of cisplatin in HEK-rOCT2 cells. Pharmacokinetics of cisplatin was investigated in male and female rats because the renal expression level of rOCT2 was higher in male than female rats. The renal uptake clearance of cisplatin was greater in male than female rats, while the hepatic uptake clearance was similar between the sexes. In addition, glomerular filtration rate and liver function were unchanged, but N-acetyl-β- d-glucosaminidase activity in the bladder urine and the urine volume were markedly increased 2 days after the administration of 2 mg/kg of cisplatin in male rats. Moreover, cisplatin did not induce the elevation of urinary N-acetyl-β- d-glucosaminidase activity in the castrated male rats whose renal rOCT2 level was lower than that of the sham-operated rats. In conclusion, the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity.

Phase I clinical and pharmacologic study of a 2-weekly administration of cisplatin and gemcitabine in patients with advanced non-small cell lung cancer

Our objective was to study the feasibility of schedule- and dose-intensive cisplatin plus gemcitabine in patients with non-small cell lung cancer (NSCLC) when given on 1 day in four 2-weekly cycles. Cisplatin was administered as a 3 h i.v. infusion followed by gemcitabine as a 30-min i.v. infusion on the same day, every 2 weeks. An interval of 1 h between the two infusions was applied. Patients received four courses without any break. An interpatient dose-escalation scheme was used. The starting dose was 87.5 mg/m of cisplatin and 1350 mg/m of gemcitabine. The pharmacokinetics of cisplatin and gemcitabine were determined in plasma and white blood cells. In total, 23 patients were included in the study. Median age of the patients was 56 years (range 27-76) and most patients were in good clinical condition. Thirteen patients received all planned courses. Dose-limiting toxicity was Common Toxicity Criteria grade 2 ototoxicity. The maximum tolerated dose was established at cisplatin 90 mg/m in combination with gemcitabine 1500 mg/m. This short induction schedule is practical and convenient for the patient. We conclude that the combination of cisplatin at a dose intensity of 51 mg/m/week followed by gemcitabine (1500 mg/m) on the same day is clinically feasible in NSCLC patients when given as a 2-weekly cycle.

Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding

Intraperitoneal (i.p.) chemotherapy is a promising therapeutic method to improve the effectiveness of cisplatin in patients with ovarian cancer and peritoneum involvement. Intraperitoneal treatment can be intraoperatively performed just after a complete surgical resection of peritoneal tumor nodules. However, little is known regarding the pharmacokinetics of platinum during intraoperative i.p. chemotherapy (IIC). Serum and i.p. measurements of total and ultrafilterable platinum were performed to determined pharmacokinetic parameters in 11 consecutive patients who received a 2-h IIC with 50 mg/m cisplatin. Protein concentrations were determined in serum and peritoneal liquid at the same times. The cisplatin concentration required to kill OVCAR-3 human ovarian cancer cells and evaluation of cisplatin binding to proteins were determined in vitro. Platinum i.p. concentration decreased rapidly and quickly came under the cytotoxicity threshold (10 mg for 2 h). About 85% of i.p. and serum cisplatin was ultrafilterable during IIC. Platinum concentrations were closely related to protein concentrations. Due to the very low level of serum protein (almost 25 g/l), serum cisplatin binding during chemotherapy was very low (almost 25%), but increased with protein concentration recovery. These pharmacokinetic data show that a sufficient concentration to kill human ovarian cancer is not reached with a single i.p. bath containing 50 mg/m cisplatin for 2 h. A new protocol with a renewed bath and a higher cisplatin concentration is under investigation.

A high-performance liquid chromatographic assay for determination of cisplatin in plasma, cancer cell, and tumor samples

A method for determination of cis-diaminedichloroplatinum (II) (cisplatin) in ultrafiltered plasma, cell, and tumour samples is described. Cisplatin separation was carried out on a reversed-phase column using methanol–acetonitrile–water as the mobile phase. The flow rate was maintained constant at 1.6 mL/min and analysis was performed at 23 °C. Detection was carried out by absorbance at 254 nm. The method was linear in the range of 0.2–10 μg/mL, and the coefficients of variation were < 10%. Using this technique, we measured the intracellular accumulation of cisplatin in cancer cells and in tumours of mice receiving treatment with cisplatin and evaluated the pharmacokinetics of cisplatin in nu/nu mice after intraperitoneal (i.p.) administration. The method proved to be adequate for measuring cisplatin both in vitro and in vivo and could be suitable for studies of cisplatin pharmacokinetics in animal models.

Hyperthermic isolated regional perfusion with CDDP for bone and soft-tissue sarcoma of the lower limb: pharmacokinetics, thermal dose, toxicity, and feasibility

The objectives of this study were to investigate the pharmacokinetics of cisplatin (CDDP) and the thermal dose, toxicity, and feasibility of hyperthermic isolated regional perfusion (HIRP) with CDDP for bone and soft-tissue sarcomas of the lower limb. A total of 43 patients were treated with HIRP using CDDP. The dose of CDDP administered was 62.9+/-11.8 mg/limb (20 mg/m(2) +20 approximately 30 mg). The mean highest CDDP concentration was 56.9 microg/ml as total platinum (tPt) and 49.0 microg/ml as free platinum (fPt). The tPt concentration remained higher than 10 microg/ml. The highest temperature within tumor was 42.3+/-1.4 degrees C on average. The complications of HIRP were grade II toxicity in 30 patients, grade III in 9, and grade IV in 4. The mean necrotic ratio in the resected specimen was 84.5%, and the effect was grade IV (no viable tumor cells) in 13 patients, grade III(>90% necrosis) in 12, grade II (50 to <90%) in 9, and grade I (<50%) in 4. We obtained favorable levels of platinum concentration of the perfusate using a lower CDDP dosage compared with previous studies of HIRP. Considering our results of the pharmacokinetics of CDDP and clinical efficacy, we propose a lower dosage of CDDP for HIRP in the treatment of osteosarcoma. Multimodality treatment of HIRP with preoperative chemotherapy and surgery is a relatively safe and reliable therapeutic option for patients with limb sarcomas, and our method offers excellent local control.

High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics.

Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin. Prospective study of 15 patients with stage IV malignant melanoma. Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry. Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis. Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment.