Multi-targeted antifolate (MTA): pharmacokinetics of intraperitoneal administration in a rat model.

AIMS: LY 231514 or MTA is a multi-targeted antifolate which has been used as an anticancer drug. It is an analogue of folic acid which has shown antitumour activity against various malignancies, particularly mesothelioma and colon cancer. For cancers with peritoneal surfaces extension, the advantage of intraperitoneal chemotherapy over intravenous chemotherapy administration is the high drug concentration that can be achieved locally. Using a rat model, this study was designed to compare the pharmacokinetics and tissue adsorption of intraperitoneal vs intravenous MTA. METHODS: Sprague-Dawley rats were randomized into three groups according to dose and route of delivery of chemotherapy (10 mg/kg: intravenous; 10 mg/kg: intraperitoneal; 100 mg/kg: intraperitoneal). During the course of the experiment, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the 3 hour procedure the rats were sacrificed, all urine was extracted and selected tissue samples were taken. One additional rat was studied over a 6 hour period for each group. The concentration of MTA in all samples was determined by high performance liquid chromatography (HPLC). RESULTS: When MTA was delivered at 10 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (10 778 microg/mlxmin) compared to intravenous administration (454 microg/mlxmin) (P<0.0001). This represents a 24-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. The AUC ratio (AUC peritoneal fluid/AUC plasma) was 40.8 for intraperitoneal delivery as opposed to 0.014 for intravenous delivery (P=0.0063). The AUC ratio for intraperitoneal MTA at 100 mg/kg was 19.2. The half-life of MTA in the peritoneal fluid after intraperitoneal infusion was approximately 2 hours. There was a significant difference in MTA concentration in the mesenteric nodes and the abdominal wall (P=0. 0036 and 0.0017) and in the kidneys (P=0.0122) when intraperitoneal and intravenous administration were compared. Other tissue samples did not demonstrate any difference in drug concentration. CONCLUSION: These experiments demonstrated that the exposure of peritoneal surfaces to MTA is significantly increased with intraperitoneal MTA administration. Due to the high likelihood of microscopic residual disease after resection of intra-abdominal malignancies, clinical studies to evaluate intraperitoneal MTA may be indicated.     

Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies

BACKGROUND AND OBJECTIVES: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue absorption of intraperitoneal versus intravenous oxaliplatin. METHODS: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups according to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraperitoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplatin (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At the end of each procedure the animals were sacrificed. Selected tissue samples were taken in the second phase only. For all samples, platinum levels were measured by direct current (d-c) plasma emission spectroscopy. RESULTS: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 (+/- 5):1 for intraperitoneal delivery as opposed to 1:5 (+/- 2) for intravenous delivery (P = 0.0059). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 (+/- 8):1. With the exception of the kidneys and the mesenteric nodes, tissue samples in the hyperthermic group exhibited increased oxaliplatin concentrations. These differences were not significant. For both groups colon tissues had the highest oxaliplatin concentrations. CONCLUSIONS: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal administration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxaliplatin for microscopic residual tumor after surgical resection of colon malignancies.     

Dual anti-cancer effects of weekly intraperitoneal docetaxel in treatment of advanced gastric cancer patients with peritoneal carcinomatosis: a feasibility and pharmacokinetic study

This study evaluated the feasibility and pharmacology of intraperitoneal docetaxel (IP docetaxel) when administered weekly for 3 consecutive weeks, followed by 1 week without treatment. A total of 24 patients with peritoneal carcinomatosis of gastric cancer (10 preoperative, 7 postoperative and 7 recurrent) were enrolled in this study. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and was administered in a 1 h dosage of 25, 35, 45 and 60 mg/m(2) to determine the maximum tolerated dose (MTD). To measure the docetaxel concentration, blood and peritoneal fluid samples were collected 0.5, 1, 2, 3, 6 and 24 h after administering the drug to 15 patients. A total of 109 chemotherapy cycles were administered, with a median of four cycles per patient (range 2-9). The MTD of the weekly IP docetaxel was defined at 60 mg/m(2). At a docetaxel dosage of 60 mg/m(2) per week, the dose-limiting events of grade 3 abdominal pain and grade 3 diarrhea, which may be associated with local toxicity, occurred. Peak concentrations of peritoneal fluid ranged from 24.5 to 68.7 microg/ml. The mean ratio of the area under concentration (AUC) in the peritoneal fluid to the plasma concentration was 515. Furthermore, the mean of plasma AUC by IP docetaxel was 5.63 microg h/ml versus that of IV docetaxel at a dose of 60 mg/m(2). The response rate of the preoperative IP docetaxel was 80% (4 CR, 4 PR, 1 NC and 1 PD), which was judged with laparoscopy and peritoneal lavage cytology. Gastrectomy, with D2 lymph node dissection, was performed on all of the patients evaluated as CR. The weekly IP docetaxel demonstrated a low toxicity and high efficacy for peritoneal carcinomatosis with dual anti-cancer effects via the peritoneal surface and capillary blood supply due to its unique pharmacokinetic property.     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

Hyperthermia modifies pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rat model

Background and objectives Peritoneal surface malignancy is a common manifestation of failure of treatment for abdominal cancers. Best results of treatment have been achieved with complete cytoreduction followed by heated intraoperative chemotherapy. Melphalan is a chemotherapeutic agent that shows increased pharmacological activity with heat. But the combination of intraperitoneal administration and heat have never been tested for this drug. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rodent model.Methods Melphalan was given by the intraperitoneal route to 20 Sprague-Dawley rats at a dose of 12 mg/kg over 90 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (33.5°C) melphalan; group HT received hyperthermic (42°C) melphalan. During the course of intraperitoneal chemotherapy, peritoneal fluid and blood were sampled at 5, 15, 30, 60 and 90 min. At the end of procedure, the rats were killed and tissues samples (heart, liver, ileum, jejunum, colon, omentum, and abdominal wall) were collected. Concentrations of melphalan were determined in peritoneal fluid, plasma, and tissues by high-performance liquid chromatography.Results The area under the curve (AUC) of peritoneal fluid melphalan was significantly lower in the HT group than in the NT group (P=0.001), whereas no significant difference in plasma AUC was found. AUC ratios (AUC peritoneal fluid/AUC plasma) were 12.1 for the NT group and 12.3 for the HT group. The mean time to reach the plasma peak was shorter in the HT group than in the NT group (P=0.004). The HT group exhibited increased melphalan concentrations in all intraabdominal tissues. These differences were significant for the ileum (P=0.03) and jejunum (P=0.04).Conclusion Hyperthermia affected the pharmacokinetics of intraperitoneal melphalan by decreasing the AUC of peritoneal fluid melphalan without increasing the plasma AUC. It increased intraabdominal tissue concentrations.Olivier Glehen is supported by a grant from Fondation de France.     

Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions

Background For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel infused intraperitoneally in two isotonic carrier solutions: 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.Methods A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal paclitaxel (40 mg/m²) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.Results Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=0.0079). No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h. Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=0.0079), 12 h (P=0.0079), and 18 h (P=0.0317). The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=0.0079) and 18 h (P=0.0317). There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191). Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium.Conclusions The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity. Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted.     

Measurement of docetaxel concentration in blood and ascites after drip infusion into each vessel and intraperitoneal cavity of gastric cancer

We measured docetaxel (TXT) concentrations in the blood and ascites after drip infusion into each vessel and intraperitoneal cavity of a patient with advanced gastric cancer. The peak concentration was reached immediately (first time 244 ng/ml, second time 215 ng/ml) after the infusion of TXT (25 mg/m2) into the vessels. The concentration of TXT for ascites peaked after 30 min of drip infusion (first time 26 ng/ml, second time 30 ng/ml). AUC ascites/AUC blood was 27.2% and 35.8% respectively. This is the first report demonstrating the concentration of TXT in ascites after drip infusion into vessels. When TXT was administered into the peritoneal cavity, the peak concentration of ascites was reached immediately (54,200 ng/ml). After 240 min, the TXT concentration in the peritoneal cavity was still high (14,200 ng/ml). In blood, the level peaked (64 ng/ml) at 120 min. After 240 min, the TXT level in the blood remained 44 ng/ml. AUC blood/AUC ascites was only 0.25%. These results suggested that the transition rate of TXT from blood to intraperitoneal cavity was excellent, and that TXT was suitable for the treatment of peritoneal dissemination of gastric cancer. Furthermore, infusion of TXT (25 mg/m2) into the peritoneal cavity may directly and systemically provide its antitumor effect. If we prefer the antitumor effect directly, a much lower dose infusion of TXT may be recommended.     

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.     

Id proteins in neural cancer

The effect of intraperitoneal (i.p.) administration of docetaxel was evaluated for preclinical evidence of anticancer activity in athymic mice bearing a gastric cancer cell line, MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice. Nude mice were inoculated i.p. with 10⁷ MKN-45-P cells. On days 2, 5, 9, 12, 16 and 19 after tumor inoculation, mice were treated with i.p. injection of docetaxel. Treatment doses of docetaxel were 8 mg/kg (N=7), 2 mg/kg (N=7) and 0.5 mg/kg (N=7). Intraperitoneal carcinoembryonic antigen (CEA) levels, animal body weight, mortality and survival were determined. All control mice developed ascites and died within 19–40 days. The median survival time in the control group was 32 days, while those of mice treated with 8, 2 and 0.5 mg/kg were 90, 63 and 49.5 days, respectively. One of seven mice treated with 8 mg/kg of docetaxel died of toxicity on day 12. Four mice were tumor-free on day 90, but two had tumors in the abdomen when autopsied on day 90. One mouse treated with 2 mg/kg was ascertained to be tumor-free on day 90. All seven mice treated with 0.5 mg/kg of docetaxel died of peritoneal dissemination within 71 days. The results suggest the potential of intraperitoneal docetaxel administration for the treatment of peritoneal dissemination of gastric cancer.     

Chemotherapy in malignant gynecologic tumors using intraperitoneal catheter with a subcutaneous reservoir

Malignant gynecologic tumors are liable to encourage intraperitoneal dissemination and liver metastasis. Using an implantable reservoir (R), we undertook intraperitoneal (ip) administration of CDDP (P) and etoposide (E). After the ip injection of 150 mg of P, 300 mg of E was diluted with 1,500 ml of saline solution through the R. P and E of the intraperitoneal fluid and blood were measured after the administration, and the therapeutic results were evaluated. The blood concentration of P and E reached peaks at 30-60 minutes and at about 4 hours, respectively, after administration. Detectable levels of both P and E were observed at up to 48 hours after administration. In the first treatment of patients who showed severe peritonitis carcinomatosa and high intraperitoneal levels of proteins, the transfer to blood of P from the peritoneal cavity was slow, but as the treatment progressed (second and third administrations) protein binding P decreased and peritoneal permeability improved. Both maximum blood P concentrations and the concentrations of free P were also increased 48 hours after administrations. The area under the curves (AUC) of the blood free P and E concentrations were 8.0 and 274.0 (microgram/ml x h), respectively, which were higher than those following intravenous administration. The results showed 3 CR and 6 PR. This ip regimen obtained a 64.3% response rate for measurable lesions. A patient in stage IV of ovarian cancer showed marked remission of a liver metastatic focus. Repeated ip administration through R proved to be effective by means of systemic therapy.     

Pharmacokinetics of intraperitoneal gemcitabine in a rat model

BACKGROUND: Gemcitabine (2'-2' difluorodeoxycytidine) has been shown to possess a broad spectrum of antitumor activity against various malignancies, particularly pancreatic carcinoma. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal (i.p.) chemotherapy over intravenous (i.v.) chemotherapy is the high drug concentration that can be achieved locally. In addition, the cytotoxic effect of several anticancer agents can be enhanced by hyperthermia. Using a rat model, this study was designed to compare i.p. vs i.v. gemcitabine and to evaluate the effect of hyperthermia on i.p. gemcitabine. METHODS: In the first phase of this study, 18 Sprague Dawley rats were given a single dose of gemcitabine then randomized into three groups according to dose and route of delivery of chemotherapy (12.5 mg/kg--i.v., 12.5 mg/kg--i.p. or 125 mg/kg--i.p.). In a separate experiment (phase 2), 12 Sprague Dawley rats were given a continuous i.p. perfusion of gemcitabine (12.5 mg/kg in 150 mL total perfusate) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic or hyperthermic). During the course of both experiments, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the procedure the rats were sacrificed and all urine was extracted. Selected tissue samples were taken from rats in the second phase of the study. The concentration of gemcitabine in all samples was determined by high performance liquid chromatography (HPLC). RESULTS: When gemcitabine was delivered at 12.5 mg/kg (phase 1) the area under the curve (AUC) was significantly higher with i.p. administration as compared to i.v. administration (P = 0.001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 12.5+/-3.2 for i.p. delivery as opposed to 0.2+/-0.2 for i.v. delivery (P = 0.0002). The AUC ratio for i.p. gemcitabine at 125 mg/kg was 26.8+/-5.8. Although there was no significant difference in drug concentrations between samples from the normothermic and hyperthermic groups, all tissue samples (except stomach) in the hyperthermic group exhibited increased gemcitabine concentrations. CONCLUSION: These experiments demonstrated that the exposure of peritoneal surfaces to gemcitabine is significantly increased with i.p. gemcitabine. Intraabdominal hyperthermia had no significant effect on the pharmacokinetics of i.p. gemcitabine but there was evidence of increased absorption of gemcitabine in most intraabdominal tissues. Due to the likelihood of a high incidence of microscopic residual disease after resection of a pancreatic carcinoma, clinical studies to evaluate i.p. hyperthermic gemcitabine may be indicated.     

Liver concentration of CPT-11, SN-38 and SN-38 GLU in intraperitoneal and intravenous administration of CPT-11

Our previous mouse experiment showed intraperitoneal administration of CPT-11 was more effective not only for peritoneal seeding but for liver metastases than intravenous administration of CPT-11. We studied tissue concentrations of the liver when CPT-11 was administered intraperitoneally or intravenously for ICR mice. Mice liver was resected at 15 min, 1, 2, 4, 8 and 26 hours after intraperitoneal or intravenous administration of 40 mg/kg CPT-11. CPT-11, SN-38 and SN-38 GLU were measured with HPLC. The liver concentration of CPT-11 at 15 min after intravenous administration was higher than after intraperitoneal administration. A higher liver CPT-11 concentration was prolonged in the intraperitoneal administration group. No differences were demonstrated in the concentrations of SN-38 and SN-38 GLU between i.p. and i.v. groups.     

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion

Over the last few years surgery on patients with abdominal malignancies has become more aggressive but the majority of patients present locoregional recurrence as peritoneal dissemination. Cytoreductive surgery followed by intraperitoneal chemohyperthermic perfusion (ICHP) has been described for treatment and prevention of locoregional cancer spread from various origins. This paper reports our study of the pharmacokinetics of mitomycin C (MMC) administered by intraperitoneal chemohyperthermic perfusion (ICHP) in patients with peritoneal carcinomatosis. 28 patients received MMC 20 mg/m2 intraperitoneally as a perfusion over 60 min. MMC was determined in perfusate, plasma and urine samples with a UV-HPLC method. A compartmental model was used to fit the drug concentrations in plasma and perfusate. Our results showed a mean maximum plasma concentration (Cmax) of 0.14 +/- 0.086 microg/ml with a peak time (Tmax) of 48..7 +/- 5.61 min. The mean area under the curve (AUC) and terminal half-life (t1/2) were 15.8 +/- 9.8 mg x min/L and 83.7 +/- 31.74 min respectively. Clearance (CL) was estimated by fitting the data by a compartmental model and the mean value was 72 +/- 66 L/h. The percent of the dose absorbed was very variable and ranged between 14 and 57% (mean 37 +/- 14%). The mean percentage of dose recovered unchanged in the urine during 24 hours was 7.21 +/- 3.73%. We conclude that ICHP in patients with peritoneal surface malignancies seems to have clinical value since it gives high peritoneal and tumor MMC concentrations with limited systemic exposure and toxicity.     

Comparative pharmacokinetics of weekly and every-three-weeks docetaxel.

PURPOSE: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated. EXPERIMENTAL DESIGN: Forty-six patients received weekly docetaxel (35 mg/m(2)) as a 30-min infusion alone (n = 8) or in combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion at 60 mg/m(2) with doxorubicin (n = 10), 75 mg/m(2) alone (n = 9), or 100 mg/m(2) alone (n = 7). Serial blood samples were obtained immediately before and up to 21 days after the infusion. Plasma concentrations were measured by liquid chromatography-mass spectrometry and analyzed by compartmental modeling. RESULTS: Mean +/- SD docetaxel clearance values were similar with weekly and 3-weekly schedules (25.2 +/- 7.7 versus 23.7 +/- 7.9 liter/h/m(2)); half-lives were also similar with both schedules of administration (16.5 +/- 11.2 versus 17.6 +/- 7.4 h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m(2), the mean +/- SD docetaxel concentration on day 8 was 0.00088 +/- 0.00041 microg/ml (1.08 +/- 0.51 nM) at 75 mg/m(2), concentrations on day 8, 15, and 22 were 0.0014 +/- 0.00043 microg/ml (1.79 +/- 0.53 nM), 0.00067 +/- 0.00025 microg/ml (0.83 +/- 0.31 nM), and 0.00047 +/- 0.00008 microg/ml (0.58 +/- 0.099 nM), respectively. CONCLUSION: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may contribute to the mechanism of action of docetaxel through suppression of microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in combined modality therapy.     

Anti-tumor effect of cisplatin, carboplatin, mitoxantrone, and doxorubicin on peritoneal tumor growth after intraperitoneal and intravenous chemotherapy: a comparative study

Tumor growth was studied in a peritoneal tumor model in the rat after intravenous and intraperitoneal administration of doxorubicin (4 mg/kg), mitoxantrone (2.5 mg/kg) and cisplatin (4 mg/kg) and after intraperitoneal administration of carboplatin (20 mg/kg). All treatments delayed tumor growth and intraperitoneal treatment was more effective initially than intravenous treatment for all drugs tested. Regrowth occurred between 2 and 7 weeks after treatment and was less pronounced after intravenous treatment. Tumor sizes in cisplatin treated rats 7 weeks after treatment were comparable after intraperitoneal and intravenous treatments. Intraperitoneal carboplatin even with a dose 5 times higher than cisplatin resulted in a less tumor growth delay in all stages of the treatment, compared to cisplatin. All cytostatic drugs, except carboplatin, induced loss of body weight. Weight loss was similar for intraperitoneal and intravenous treatment with both cisplatin and mitoxantrone while for doxorubicin the weight loss was significantly higher after intravenous treatment than after intraperitoneal therapy. Considering the "therapeutic index", defined as the ratio of tumor growth delay to weight loss, cisplatin had the highest "therapeutic index", 1.5 (intraperitoneal) and 1.7 (intravenous) compared to 0.3 (intraperitoneal) and 0.6 (intravenous) for Mitoxantrone and 0.4 (intraperitoneal) and 0.5 (intravenous) for doxorubicin. This indicated that cisplatin was the most favorable drug to use in this peritoneal tumor model for both intraperitoneal and intravenous treatment. The tumor growth delay was initially more pronounced after intraperitoneal cisplatin compared with intravenous.     

Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.     

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer

Purpose

The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods

Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75?mg/m² as a 1-h infusion in combination with carboplatin IV over 30?min at a target AUC of 5?mg/ml?min. Cycles were repeated every 21?days for 6 cycles. Midazolam was administered at 2?mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed.

Results

There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125?<10?U/ml (P?=?0.007) and CA-125?<15?U/ml (P?=?0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P?=?0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P?>?0.05).

Conclusions

The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.     

Experimental study on intraperitoneal versus intravenous CPT-11 for peritoneal seeding and liver metastasis

Paclitaxel is an effective antitumor agent that shows ideal pharmacological characteristics for intraperitoneal chemotherapy. Intraperitoneal administration of this agent was compared with intravenous administration in mouse models of peritoneal seeding and liver metastasis. The peritoneal seeding model and liver metastasis model were established by inoculation of Colon 26 tumor cells into the peritoneal cavity and spleen of female BALB/c mice, respectively. Paclitaxel (20 mg/kg) was injected into the peritoneal seeding model intraperitoneally or intravenously on day 2 and 4 after inoculation of tumor cells. Paclitaxel (30 mg/kg) was injected into the liver metastasis model intraperitoneally and intravenously on days 4 and 8 after inoculation of tumor cells. Median survival time for intraperitoneal administration (17.50 +/- 0.86 days) was longer than that for intravenous administration (13.70 +/- 0.47 days) in the peritoneal seeding model experiment. Median survival time for intraperitoneal administration (19.78 +/- 0.74 days) was longer than that for intravenous administration (17.50 +/- 0.54 days) in the liver metastasis model experiment. Intraperitoneal administration of paclitaxel may be a more efficient form of adjuvant chemotherapy for prevention of both peritoneal seeding and liver metastasis in patients with gastrointestinal cancer.     

Pharmacokinetics of carboplatin after intraperitoneal administration

Summary The phamacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i. p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had recived carboplatin (200–500 mg/m²) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24±11. The peritoneal clearance of carboplatin was 8±3 ml/min, which was 12 times less than the plasma clearance (93±32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34%±14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/D_net (D_net=Dose — amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.     

Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the <Superscript>133</Superscript>Xe-clearance technique

Purpose Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The ¹³³Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the ¹³³Xe-clearance technique.Methods The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1×10⁵ syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12–16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the ¹³³Xe-clearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight.Results The basal ¹³³Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in ¹³³Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the ¹³³Xe-clearance the first day after administration of 5-FU.Conclusions Intravenous vasopressin at 0.07 IU/min/kg decreased peritoneal blood flow as measured indirectly with the ¹³³Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin