Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model

Background: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 °C) i.p. doxorubicin; group HT received hyperthermic (43 °C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Conclusion: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder. Received: 14 August 1996 / Accepted: 12 May 1997     

Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan

Background: Peritoneal surface malignancy resulting from local dissemination is a common manifestation of treatment failure of gastrointestinal cancers. Although the management of carcinomatosis has been improved with an aggressive surgical approach of extensive cytoreduction followed by heated intraoperative intraperitoneal chemotherapy, no patients are cured when there is residual disease after surgery. Melphalan (l-phenylalanine mustard) is a well-known antineoplastic alkylating agent which has markedly increased pharmacological activity with heat. The use of heated intraoperative intraperitoneal melphalan may provide a pharmacokinetic and clinical advantage in this group of gastrointestinal cancer patients who cannot be made cancer-free with cytoreductive surgery. Methods: Thirteen patients with residual disease following cytoreductive surgery for peritoneal carcinomatosis were included in this study. After surgical resection and prior to anastomotic reconstruction, patients received intraperitoneal melphalan (70 mg/m²) in 3 l of 1.5% dextrose peritoneal dialysis solution at 41–42°C for 90 min. Concentrations of melphalan were assessed in the peritoneal fluid, blood, urine and tumor nodules using high-performance liquid chromatography. Results: During the 90 min of treatment 87.2±4.3% of the drug was absorbed from the perfusate/peritoneal fluid and 11.9±2.1% was excreted in the urine. The area-under-the-curve ratio of peritoneal fluid to plasma was 33.3±11.8 with an average peak plasma concentration of 0.82±0.24 μg/ml occurring at 28.5±13.1 min. Concentrations of melphalan in tumor nodules on the peritoneal surface were approximately ten times higher than in plasma with an average peak concentration of 7.2±4.2 μg/gm. The grade III/IV morbidity was 38%; there was no mortality. Conclusion: Approximately 90% of the drug was absorbed during the 90-minute procedure with a 30 times greater exposure of drug at the peritoneal surfaces than in the blood. Concentrations of the drug in peritoneal surface tumor nodules were approximately ten times greater than concentrations in the blood. These data demonstrate that heated intraoperative intraperitoneal melphalan could have a significant impact on the treatment of peritoneal surface malignancies.     

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model

PURPOSE: Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged 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 distribution of intraperitoneal versus intravenous docetaxel. METHODS: The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). RESULTS: When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 microg/ml.min) as compared to intravenous administration (0.043 microg/ml.min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 microg/ml.min) as compared to intravenous administration (4.25 microg/ml.min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall ( P=0.0079) and in the stomach and colon ( P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. CONCLUSIONS: The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans.     

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.     

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.     

Effect of hyperthermia on the in vitro hydrolysis of melphalan

The pharmacokinetics of melphalan was investigated at 37°C and 42°C in vitro in canine and porcine plasma to assess heat-induced changes in the in vivo rate of melphalan hydrolysis. Melphalan concentrations were assayed using HPLC. Rate of spontaneous hydrolysis of melphalan at 42°C was increased 1.5-fold in canine and 1.9-fold in porcine plasma. These results should be considered when interpreting in vivo disposition studies.     

Renal function in the elimination of oral melphalan in patients with multiple myeloma

Summary Pharmacokinetic studies in 11 patients with multiple myeloma were undertaken on the first and last days of one course of chemotherapy. The drug was administered PO in single doses of 6–14 mg daily. Melphalan concentrations were determined by high-performance liquid chromatography. The interpatient variability of pharmacokinetic parameters noted by other authors was observed. Regression analysis showed a significant positive correlation between the elimination rate constant for melphalan and renal function (P=0.003). The form of the line which describes the overall elimination rate constant for melphalan is given by the equation: K_el=5.67×10^-3+[4.90×10^-5xGFR]. There was also a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve (P=0.006). In vitro stability studies of melphalan in plasma at 37°C and pharmacokinetic data suggest that hydrolysis and renal clearance are the major mechanisms of melphalan elimination. This work shows quantitatively the relationship between renal function and drug elimination and how the data may be used in predicting melphalan half-life from creatinine clearance.The work described in this paper was supported by the Northern Ireland Leukaemia Research Fund     

Pharmacokinetics of intraperitoneal hyperthermic perfusion with mitoxantrone in ovarian cancer

Purpose: Theoretical data and experimental assumptions indicate that intraperitoneal hyperthermic chemotherapy may play a role in the treatment of peritoneal carcinomatosis. The feasibility, tolerability and pharmacokinetics of intraperitoneal hyperthermic perfusion with mitoxantrone were studied in patients with pretreated ovarian cancer. Methods: After cytoreductive surgery, 11 patients underwent intraperitoneal hyperthermic perfusion with mitoxantrone. A heated (42–43 °C) solution of the drug (28 mg/m²) was recycled through a perfusion apparatus into the abdominal cavity for 90 min. Treatment was repeated every month for two to four cycles. In six patients blood and peritoneal perfusate samples were collected at 0.5, 1, 1.5, 2, 4, 8, 16 and 24 h after drug administration and mitoxantrone was assayed by an HPLC method. Results: Although treatment was generally well tolerated, all patients developed transient intestinal subocclusion. Maximal mitoxantrone plasma concentrations (C_max), times to C_max (T_peak) and area under the curves (AUC) were highly variable between subjects (C_max 14–337 ng/ml; T_peak 0.5–8 h; AUC 222–4130 ng · ml⁻¹ · h). The plasma to peritoneal fluid AUC ratio was significantly higher during the second (0.177) than during the first cycle (0.066), suggesting a cycle-dependent increase in systemic bioavailability. Furthermore, when comparing present data with those reported previously, hyperthermic perfusion may have lowered the mitoxantrone levels in the peritoneal fluid without greatly influencing plasma levels. Conclusions: Intraperitoneal mitoxantrone administered under hyperthermia to advanced ovarian cancer patients is feasible and well tolerated. Mitoxantrone pharmacokinetics may be altered by repeated intraperitoneal administration (increased bioavailability) and by hyperthermic perfusion (possibly, increased peritoneal tissue uptake). Received: 6 September 1999 / Accepted: 11 January 2000     

Pharmacokinetic changes induced by the volume of chemotherapy solution in patients treated with hyperthermic intraperitoneal mitomycin C

Background: The rationale supporting the use of intraperitoneal chemotherapy in peritoneal surface malignancy relates to a large local–regional effect and low systemic toxicity. While optimizing the use of this treatment strategy, little information regarding the effect of volume of chemotherapy solution is available. Objective: The goal of this study was to provide data regarding the effect of volume of chemotherapy solution on the pharmacokinetics of intraperitoneal chemotherapy. Data by which to optimally adjust this parameter during intraperitoneal chemotherapy treatments were sought. Methods: Forty-eight patients with peritoneal surface malignancy were treated with hyperthermic intraperitoneal mitomycin C chemotherapy after a complete cytoreduction to remove all visible evidence of mucinous tumor. The dose of mitomycin C was always 12.5 mg/m² in males and 10 mg/m² in females. The first 12 patients were treated with 6 l of 1.5% dextrose peritoneal dialysis solution. The next 14 patients were treated with 4 l of fluid and then ten patients were treated with 2 l. In the last 12 patients the volume of fluid was 1.5 l/m² . Blood, peritoneal fluid, and urine samples were obtained every 15 min for 90 min; additional blood and urine samples were obtained at 120 min. Mitomycin C concentrations, urine volumes, and final intraperitoneal fluid volume were obtained. Results: The intraperitoneal and the plasma concentrations were highest in the 2-l group, less in the 4-l group, and least in the 6-l group. All differences were statistically significant. Also, the percent of mitomycin C absorbed decreased significantly from 2, to 4, to 6 l of fluid. The area under the curve (AUC) ratio of intraperitoneal concentration times time to intravenous concentration times time was 27.01±4.92 for 2 l, 22.22±7.95 for 4 l, and 24.01±8.46 for 6 l. These differences were not statistically significant. If both the volume of chemotherapy solution and the total dose of mitomycin C were determined from the body surface area, the pharmacokinetics of intraperitoneal mitomycin C were more consistent. Conclusions: In order to prescribe a uniform treatment for patients receiving hyperthermic intraperitoneal mitomycin C, the total dose of the drug and the total volume of chemotherapy solution should be determined from the body surface area. If the volume of chemotherapy solution is not based on patient body surface area, predictions regarding toxicity are less precise.     

Pharmacokinetics of high-dose melphalan in children and adults

Summary Melphalan pharmacokinetics were studied in 20 children with stage IV neuroblastomas or Ewing's sarcomas and in 10 adults with AML, ALL, or small cell lung carcinomas, after IV administration of high doses (140 mg/m² with furosemide-induced diuresis and 180 mg/m² without induced diuresis) and high fluid intake (3000 ml/m²/day).Unchanged melphalan was assayed in plasma and cereorospinal fluid by means of a high-performance liquid chromatographic procedure. The elimination half-life (t_1/280 min) allows autologous bone marrow transplantation 24 h after the drug administration. In some children we were able to detect melphalan in cerebrospinal fluid samples.     

Hyaluronidase pretreatment produces selective melphalan enrichment in malignant melanoma implanted in nude mice

 Preclinical and clinical observations suggest that the administration of hyaluronidase (Hyase) shortly before that of chemotherapy increases the access and, thus, the effectiveness of aniticancer drugs in tumors. To examine this hypothesis as well as the selectivity of such a therapeutic approach potentially beneficial in isolated limb perfusion, the Hyase-induced distribution of melphalan was measured in tumor-bearing nude mice with respect to the mode of drug administration using RP-18 ion-pair high-performance liquid chromatography (HPLC) with fluorimetric detection. Melphalan alone (50 μmol/kg) or a combination of melphalan (50 μmol/kg) and Hyase (100,000 IU/kg) was injected either i.p. or s.c. in the vicinity of the tumors. The s.c. melphalan injection caused a 4-fold rise in melphalan concentration (59 μM) in the tumors as compared with i.p. application (15 μM). Only minor effects were observed with respect to the route of melphalan application on its distribution in other tissues (ca. 13 μM in plasma, 15 μM in muscle, 30 μM in the liver, 26 μM in the kidney, and 21 μM in the testicle). Irrespective of the route of Hyase coadministration, the enzyme increased the concentration of i.p. injected melphalan in all tissues to ca. 20 μM in the tumor, 15 μM in plasma, 27 μM in muscle, 40 μM in the liver, 29 μM in the kidney, and 28 μM in the testicle. In contrast, s.c. injected melphalan was selectively accumulated by the tumors after both s.c. and i.p. Hyase administration (462 and 388 μM, respectively). Melphalan enrichment in the tumors was higher (16- to 32-fold higher than in the other tissues) after i.p. administration of Hyase since, in contrast to s.c. injection of the enzyme, its i.p. administration caused a decrease in the concentration of the cytostatic in all other tissues as compared with the s.c. administration of melphalan alone. Received: 8 May 1995/Accepted: 5 September 1995     

Population pharmacokinetics of melphalan,infused over a 24-hour period,in patients with advanced malignancies

Purpose The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies.Methods Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity.Results Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3±4.5 l/h per m²) than in female patients (12.3±4.5 l/h per m²). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m²). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels.Conclusion The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.     

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.     

Study of Lymphotropic Targeting and Macrofilaricidal Activity of a Melphalan Prodrug on the Molinema dessetae Model

Summary

Thia Mudv deals with the design of a new macrofilaricidal drug derived from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Melphalan was linked to a ligand leading to a prodrug called 1,3-dp-melphalan which has structural analogy to triglycerides. The Molinema dessetae / Proechimys oris model was used for antiparasitic evaluation. Melphalan was macrofilaricidal in vitro against Molinema dessetae at 1 mM, inactive in vivo after an oral single dose at 164 μmol/kg while the prodrug 1,3-dp-melphalan was active against adult worms after a single dose at 82 μmol/kg. After an oral administration of the prodrug to rats, the maximum concentration and the cumulated quantities of melphalan in lymph were about 45-fold higher than those observed with the free drug under the same conditions. Moreover, the plasma concentration of melphalan was 2-fold higher than those observed after the administration of the free drug. These results are in favor of lymphotropic targeting as a novel approach to develop new orally active macrofilaricides.     

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.     

Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is increasingly used in the treatment of colorectal peritoneal carcinomatosis (PC). However, the additional benefit of hyperthermia remains clinically unproven, while it may aggravate postoperative morbidity. Here, we report the correlation of perfusion temperature with postoperative morbidity during clinical HIPEC with OX.Patients and methodsPatients who underwent hyperthermic (41 °C, HT) or normothermic (37 °C, NT) chemoperfusion with OX for colorectal PC were identified from a prospectively kept database of HIPEC cases and matched for baseline characteristics using propensity score (PS) analysis. The groups were compared to assess the impact of perfusion temperature on morbidity. Morbidity was graded using the Clavien-Dindo (CD) classification and the Comprehensive Complication Index (CCI).ResultsOut of 612 patients, 146 patients met the inclusion criteria and from these patients, 45 HT patients were matched with 45 NT patients. Baseline variables were comparable between the PS matched groups. Overall mortality was 0.7% and major morbidity (CD ≥ 3) occurred in 35,6% of patients. There were no significant differences between the HT and NT cohorts in mortality, major morbidity (RR 1.33, 95% CI 0.71 to 2.49, p = 0.36), anastomotic leakage (13.8% versus 11.1%, p = 1.0), hemorrhagic complications, or systemic toxicity. A trend of increased wound infections was observed in the hyperthermia group (13.3% versus 4.4%, P = 0.27).ConclusionsCompared to NT, the use of HT during HIPEC with OX does not aggravate postoperative mortality or morbidity in a high-volume center.     

The effect of food on oral melphalan absorption

Summary Fifteen patients receiving oral melphalan (4.2–5.3 mg/m²) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m²) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95–336) ng · h · ml^-1, and when taken with food, 122 (47–227) ng · h · ml^-1, the median reduction being 39% (P0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38–71) was no different from its oral half-life [55 (27–104) min fasting; 55 (30–72) min with food] (P>0.1). In these patients bioavailability was 85% (26–96)% when the drug was taken fasting and 58% (7–99)% when taken with food (P0.025). Median clearance following IV administration was 362 ml/min/m² (range 104–694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (r_s=0.915, P0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.     

A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin

Purpose  A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality. Methods  Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC). Results  Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid. Conclusions  Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.     

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.