Plasma Concentrations Of Paclitaxel Research Articles

Pharmacokinetic study of paclitaxel in malignant ascites from advanced gastric cancer patients

To examine the paclitaxel concentrations in plasma and ascites after its intravenous administration in patients with ascites due to peritonitis carcinomatosa resulting from advanced gastric cancer. Two patients with ascites due to peritonitis carcinomatosa resulting from gastric cancer were included in this study. The paclitaxel concentrations in plasma and ascites were investigated for 72 h in case 1 and 168 h in case 2 after intravenous administration. The paclitaxel concentration in plasma peaked immediately after administration, followed by rapid decrease below the threshold value of 0.1 micromol (85 ng/mL) within 24 h. In contrast,the paclitaxel concentration in ascites increased gradually for 24 h after administration to a level consistent with the level found in plasma. After 24 h the level of paclitaxel in ascites and plasma became similar, with the optimal level being maintained up to 72 h following administration. The concentration of paclitaxel in ascites is maintained within the optimal level for the treatment of cancer cells for up to 72 h after intravenous administration. Paclitaxel is a promising drug for the treatment of malignant ascites of gastric cancer.

Thoracic radiation therapy and concomitant low-dose daily paclitaxel in non-small cell lung cancer: A phase I study

The primary objective of the current study was to determine the maximum tolerated dose of paclitaxel (PTX) that could be added daily to radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC). The secondary objective was to achieve a plasma concentration of PTX estimated to exert a radiosensitizing effect. Eighteen patients with locally advanced NSCLC were treated. 60 Gy of RT were given in 2 Gy fractions, 5 days per week. A daily dose of PTX was delivered by 4-h i.v. infusion before RT. The initial dose level of PTX was 9 mg/m2/day, escalated by 1 mg at each additional patient triplet. Two out of 6 patients experienced acute dose limiting toxicity (DLT) at the 12 mg/m2/day PTX dose level. PTX continuously greater than 10 nM, the estimated radiosensitizing condition, was achieved at the PTX dose level of 12 mg/m2/day. PTX at doses up to 11 mg/m2/day may be safely added to a conventional conformal RT course. Both DLT and the estimated radiosensitizing plasma exposure to PTX were encountered at the 12 mg/m(2)/day dose level.

Phase I and Pharmacokinetic Study of S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer

Objective: A dose-escalation study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the dose-limiting toxicities (DLTs) in advanced gastric cancer. Patients and Methods: Twelve patients were enrolled. S-1 was given orally at a fixed dosage of 40 mg/m² b.i.d. for 14 consecutive days, followed by a 1-week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8 at a dose of 50, 60, 70 or 80 mg/m², depending on the DLTs. Treatment was repeated every 3 weeks. A pharmacokinetic study was conducted in an additional 5 patients on days 7 and 8 during the first course given at the RD. Results: The MTD of paclitaxel was presumed to be 60 mg/m², because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). DLT was observed in 1 out of 8 patients at a dose of 50 mg/m². Therefore, the RD of paclitaxel was estimated to be 50 mg/m². The preliminary response rate was 62.5% (5/8) at the RD. There were no significant pharmacokinetic interactions between S-1 and paclitaxel. An adequate plasma paclitaxel concentration for an antineoplastic effect was achieved with weekly doses of 50 mg/m². Conclusion: Weekly paclitaxel combined with S-1 was demonstrated to exhibit a tolerable toxicity profile with therapeutic plasma concentration at the dose of 50 mg/m². This regimen could represent a novel and low toxic combination for advanced gastric cancer.

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

Disposition of paclitaxel (Taxol®) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Hercpetin®)

Monoclonal antibodies are capable of modulating drug metabolising enzymes resulting in unexpected plasma concentrations of a drug when given concomitantly. Therefore plasma concentration of paclitaxel (PTX) and its metabolites has been monitored in 10 patients with advanced breast cancer during treatment with PTX alone or combined with trastuzumab (TMAB, paired cross over design). Compared to the MONO regimen PTX peak plasma concentrations were about 25% lower in the TMAB schedule: cmax = 3294 +/- 1174 ng/ml (MONO: 4368 +/- 1887 ng/ml). TMAB also caused lower peak plasma concentration of the main metabolite 6-hydroxy PTX (248 +/- 89 ng/ml) compared to the MONO schedule (194 +/- 82 ng/ml). Cmax of the minor metabolites was distinctly below 100 ng/ml and consequently differed negligible in both schedules. The similar apparent formation rate of the metabolites in both schedules (range from 30 to 50 min) as well as identical tmax values (range 170-190 min) suggested that TMAB had no influence on PTX metabolism. In accordance to plasma concentrations, AUClast of PTX was lower in the MONO schedule (733 +/- 197 microg/ml*min, AUClast = 669 +/- 248 microg/ml*min for TMAB) but without significance. In summary no indices for an altered plasma disposition of PTX and its metabolites could be found when TMAB was given concomitantly.

No pharmacokinetic drug???drug interaction between nevirapine and paclitaxel

We have investigated the pharmacokinetics of nevirapine and paclitaxel in a patient who used both drugs concomitantly, as there are strong theoretical indications for a potential pharmacokinetic drug-drug interaction. Plasma concentrations of nevirapine (dose: 200 mg twice daily orally) and paclitaxel (dose: 100 mg/m(2) 3-h i.v. infusion) were determined in a HIV-1-infected patient with Kaposi's sarcoma. Since both drugs are metabolized via the same cytochrome P450 isoenzymes, investigation of a drug-drug interaction was considered important. We found that the plasma concentrations of nevirapine given together with paclitaxel were similar to those given without paclitaxel. The exposures to paclitaxel (AUC(0-infinity) = 3787 h.ng/ml) and its hydroxy metabolites when co-administered with nevirapine were comparable to the mean exposure to paclitaxel and its metabolites from eight historical controls (AUC(0-infinity) = 3614 h.ng/ml) treated with the same dose. No pharmacokinetic drug-drug interaction between nevirapine and paclitaxel could be demonstrated in our HIV-1-infected patient.

Enhanced bioavailability of paclitaxel by bamboo concentrate administration

The purpose of this study was to investigate the effect of a cotreatment of bamboo concentrates (Jukcho solution; 0.75, 1.5, and 3.0 mL/kg) with the chemotherapeutic agent paclitaxel on the bioavailability of orally administered paclitaxel (50 mg/kg) in rats. The effect of a pretreatment of bamboo concentrates (1.5 and 3.0 mL/kg for 1.0 h or a consecutive 3 day) was also examined. The paclitaxel plasma concentrations of rats orally administered paclitaxel plus bamboo concentrates (coadministration, 3.0 mL/kg and pretreatment, 1.5 and 3.0 mL/kg) were significantly higher than those of rats treated with paclitaxel alone. Plasma concentrations of paclitaxel in groups pretreated with bamboo concentrates for 3 day were markedly higher than those of a paclitaxel control group at the measured time points. The areas under plasma concentration-time curves (AUCs) of paclitaxel in groups pretreated with bamboo concentrates were elevated and the absolute bioavailability (AB%) and relative bioavailability (RB%) of paclitaxel were also significantly higher than those in the control group. The peak concentration (Cmax), half-life (t1/2), and the elimination rate constant (Kel) of paclitaxel after 3 day of pretreatment with bamboo concentrates were also significantly higher than those in the control, but the time required to reach the maximum plasma concentration (Tmax) of paclitaxel was unaffected by the bamboo concentrates. Western blot analyses demonstrated that the level of CYP3A4 was increased in the livers of rats treated orally with paclitaxel, but this was reversed by pretreating with bamboo concentrates. These results show that bamboo concentrates enhance the bioavailability of orally administered paclitaxel and this effect may be associated with a diminished expression of CYP3A4 in the liver.

Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats

The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of paclitaxel after oral administration of paclitaxel or its prodrug coadministered with naringin to rats. Paclitaxel (40 mg/kg) and prodrug (280, 40 mg/kg paclitaxel equivalent) were coadministered orally to rats with naringin (1, 3, 10 and 20 mg/kg). The plasma concentrations of paclitaxel coadministered with naringin increased significantly ( p < 0.01 at paclitaxel, p < 0.05 at prodrug) compared to the control. The areas under the plasma concentration–time curve (AUC) and the peak concentrations ( C max) of paclitaxel with naringin significantly higher ( p < 0.01) than the control. The half-life ( t 1/2) was significantly ( p < 0.05) longer than the control. The absolute bioavailability (AB, %) of paclitaxel with naringin was significantly higher (3.5–6.8%, p < 0.01) than the control (2.2%). Absorption rate constant ( K a) of paclitaxel with naringin increased, but not significantly. The AUC of paclitaxel after coadministration of prodrug with naringin to rats was significantly ( p < 0.05) higher than the prodrug control. The relative bioavailability (RB, %) of paclitaxel after coadministration of prodrug with naringin was 1.35–1.69-fold higher than prodrug control. The absolute bioavailability (AB, %) of paclitaxel after coadministration of prodrug with naringin increased significantly ( p < 0.05) from 6.6 to 9.0% and 11.2%. The bioavailability of paclitaxel coadministered as a prodrug with or without naringin was remarkably higher than the control. Paclitaxel prodrug, a water-soluble compound concerning with its physicochemical properties, passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. Oral paclitaxel preparations which is more convenient than the IV dosage forms could be developed with a prodrug form with naringin.

In Vivo Pharmacokinetic and Tissue Distribution Studies in Mice of Alternative Formulations for Local and Systemic Delivery of Paclitaxel: Gel, Film, Prodrug, Liposomes and Micelles

The aim of this study was to increase the understanding on the pharmacokinetic and tissue distribution of paclitaxel as influenced by formulation approach. For this purpose, various formulations investigated in Swiss mice included liposomes, poloxamer 407 gel and chitosan film for subcutaneous route; and water-soluble methacrylate prodrug, liposomes and poloxamer micelles for systemic administration. During this study, the currently marketed formulation of Cremophor EL of paclitaxel was used as the reference. A highest plasma concentration following intravenous administration of paclitaxel was observed for rigid and 'Stealth((R))' liposomes containing the prodrug while, least was for covalently incorporated paclitaxel micelles. Further, poloxamer micelles demonstrated both the highest mean residence time of 7.34 h and volume of distribution (VSS=4.82 and VZ=5.87 L/kg) for paclitaxel. This was followed by prodrug loaded 'Stealth' liposomes, which showed a mean residence time of 4.96 h but were least distributed into apparent physiological volume (VSS=2.12 and VZ=3.16 L/kg). These results clearly signify the role of formulation/excipient in drug disposition and possible interactions. Importantly, due to decrease in the clearance rate of drug, the area under curve values of paclitaxel increased by 1.64- and 2.5-fold for micellar and prodrug loaded 'Stealth' liposomal formulations, respectively over reference formulation. While thermoreversible gels served to decrease plasma concentration of paclitaxel (8-fold) after subcutaneous administration, systemic levels were totally absent after implantation of films. In tissue distribution studies, maximum percent of paclitaxel was observed in liver for reference formulation, conventional liposomes and micelles whereas highest levels of prodrug and 'Stealth((R))' liposomes were in kidney and spleen, respectively. The novel formulations significantly altered tissue accumulation profiles of paclitaxel relative to the reference formulation, for example, reduction in uptake by heart from liposomes and micelles, as well as the major recognition mechanism for elimination. It is proposed that a combination therapy with liposomes and micelles of paclitaxel for systemic delivery along with implantation of chitosan film for local delivery, may serve not only to improve patient compliance by obliterating the need to administer Cremophor EL, but also increase patient survival.

Prospective Evaluation of Body Surface Area as a Determinant of Paclitaxel Pharmacokinetics and Pharmacodynamics in Women with Solid Tumors

To study a fixed dose (360 mg) of paclitaxel given i.v. over 3 hours to female patients, and to evaluate prospectively the relationships between the following: body surface area and toxicity; body surface area and pharmacokinetics; and pharmacokinetics and toxicity. The eligibility criteria included the following: female sex; solid tumors; no more than one prior chemotherapy regimen; no prior paclitaxel; performance status of 0 to 2; and normal organ function. Paclitaxel plasma concentrations were quantified by high-performance liquid chromatography. The area under the curve, total body clearance, and hours above 0.05 micromol/L (T > 0.05) were calculated. Thirty-two patients were enrolled, and 29 patients received the correct dose and regimen. For statistical analyses, 26 patients had complete follow-up blood counts, 23 patients had complete data to correlate blood counts and area under the curve, and 25 patients had data to correlate blood counts and T > 0.05. The main toxicity was neutropenia of grade 3 and 4 severity in 21% and 25% of patients, respectively, in cycle 1. The worst grade of any toxicity, nadir WBC and absolute neutrophil count, and survival fractions were assessed; no significant relationship was found between body surface area and any measure of toxicity. Body surface area correlated inversely with area under the curve (r = -0.67; P < 0.001) and correlated with total body clearance (r = 0.69; P < 0.001), but body surface area did not correlate with T > 0.05. Neither area under the curve nor total body clearance were correlated with nadir absolute neutrophil count or survival fractions, but a significant correlation was found between T > 0.05 and log(nadir absolute neutrophil count; r = -0.41; P = 0.04). These results suggest that fixed dosing of paclitaxel is feasible in women, which would simplify the administration of this drug.

ENHANCED ORAL BIOAVAILABILITY OF PACLITAXEL BY RECOMBINANT INTERLEUKIN-2 IN MICE WITH MURINE LEWIS LUNG CARCINOMA

The effect of recombinant interleukin-2 (rIL-2) pretreatment on the pharmacokinetics of paclitaxel was investigated in the murine Lewis lung carcinoma model in C57B1/6 mice. Paclitaxel 15 mg/kg was administrated orally to mice, either alone or after 3 days pretreatment with twice daily dose of 16.5 microg rIL-2. Plasma concentrations of paclitaxel were estimated by reversed phase HPLC. Pharmacokinetic parameters were determined using MicroPharm software. Using Bailer's method, a significant difference was observed in the AUCs of paclitaxel administrated alone and with rIL-2 pretreatment (928.2 +/- 136.8 vs 2549.6 +/- 131.3 ng.h.ml(-1), p <0.0001). Pretreatment with rIL-2 resulted in a 3-fold increase in the oral bioavailability of paclitaxel without altering its elimination half-life (0.798 vs 0.747 h). This could be due to the inhibition of P-glycoprotein (P-gp) mediated transport, thus enhancing paclitaxel intestinal absorption. The combination of these two drugs could be of interest in clinical practice due to their activity in pulmonary cancer.

Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats

The purpose of this study was to investigate the effect of flavone on the bioavailability of paclitaxel orally coadministered in rats. Paclitaxel (40 mg/kg) and flavone (2, 10, 20 mg/kg) were orally administered to rats orally. The plasma concentration of paclitaxel with flavone increased significantly ( P<0.01) compared to that of paclitaxel control. Area under the plasma concentration–time curve (AUC) of paclitaxel with the dose of 2–20 mg/kg flavone was significantly ( P<0.05 at 10 mg/kg, P<0.01 at 20 mg/kg) higher than that of control. AUCs of paclitaxel were increased dose-dependently in the dose range of flavone. The absorption rate constant ( K a) of paclitaxel with the dose of 10–20 mg/kg flavone was significantly increased ( P<0.05 at 10 mg/kg, P<0.01 at 20 mg/kg) compared to that of control. Peak concentration ( C max) of paclitaxel with the dose of 10–20 mg/kg flavone were significantly increased ( P<0.05 at 10 mg/kg, P<0.01 at 20 mg/kg) compared to that of control. Half-life ( t 1/2) of paclitaxel with the dose of 10–20 mg/kg flavone was significantly prolonged ( P<0.05 at 10 mg/kg, P<0.01 at 20 mg/kg) compared to that of control. The relative bioavailability increased significantly by about 2.38- or 3.10-fold ( P<0.05 at 10 mg/kg, P<0.01 at 20 mg/kg) compared to that of paclitaxel control. Based on these results, It might be considered that the bioavailability of paclitaxel coadministered with flavone was significantly enhanced by the both inhibition of cytochrome P-450 and the P-gp efflux pump in the intestinal mucosa. It could be possible to administer paclitaxel orally besides the established IV route.

Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin

The aim of this study was to investigate the effect of quercetin on the bioavailability of paclitaxel after the oral administration of paclitaxel or a prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280 mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel pretreated with quercetin were increased significantly ( P<0.01, for paclitaxel; P<0.05, for prodrug) compared to the control. The areas under the plasma concentration–time curve (AUC) and the peak concentrations ( C max) of paclitaxel pretreated with quercetin were significantly higher ( P<0.01) than the control. The half-life ( t 1/2) and mean residence times were significantly ( P<0.05) longer compared to the control. The absolute bioavailability (AB%) of paclitaxel pretreated with quercetin was significantly higher ( P<0.01) than the control. The AUC of paclitaxel after administration of the prodrug to rats pretreated with quercetin was significantly ( P<0.05) higher than the prodrug control. The relative bioavailability of paclitaxel after administration of the prodrug to rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug control. The AB% of paclitaxel was increased significantly ( P<0.05) by quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel administered as a prodrug with or without pretreatment of quercetin was remarkably higher than the control. AUC, AB% and C max of paclitaxel after administration of the paclitaxel or prodrug pretreated with quercetin for 3 days were much higher than those administered after 20 min. It might have resulted from the physicochemical properties of the prodrug, which is a water-soluble compound and passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. It seems that the development of oral paclitaxel preparations as a prodrug or with quercetin is feasible, which is more convenient than the i.v. dosage forms.

딜티아젬과 파크리탁셀의 약물동태학적 상호작용

The purpose of this study was to investigate the effect of coadministration (2.5, 10, 20 mg/kg) and 3 or 7 days-pretreatment (10 mg/kg) of diltiazem on the pharmacokinetic parameters of paclitaxel (50 mg/kg) given orally in rats. The plasma concentrations of paclitaxel coadministered or pretreated with diltiazem were significantly (p of paclitaxel with diltiazem were significantly (p of paclitaxel with diltiazem were significantly (p and mean residence time (MRT) of paclitaxel with diltiazem was significantly (p and P-glycoprotein, which are respectively engaged in paclitaxel absorption and metabolism in liver and gastrointestinal mucosa.

The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice.

We determined the effect of zosuquidar.3HCl, an inhibitor of P-gp, on the penetration of the anticancer drug paclitaxel into the brain. Zosuquidar.3HCl was administered orally at 25 and 80 mg/kg 1 h before i.v. paclitaxel and i.v. at 20 mg/kg 10 min and 1 h before paclitaxel. The concentrations of paclitaxel in plasma and tissues and of zosuquidar.3HCl in plasma were quantified by high-performance liquid chromatography. The results revealed 3.5-fold and 5-fold higher paclitaxel levels in the brain of wild-type mice treated orally with 25 and 80 mg/kg zosuquidar.3HCl, respectively. However, complete inhibition as in P-gp knockout mice (11-fold increase) was not achieved. Zosuquidar.3HCl also increased the paclitaxel concentrations in plasma and tissues to levels similar to those observed in P-gp knockout mice, suggesting selective P-gp inhibition of zosuquidar.3HCl. When zosuquidar.3HCl was administered i.v. 10 min before paclitaxel, the paclitaxel levels in the brain of wild-type mice increased by 5.6-fold, whereas the increase was only 2.1-fold when zosuquidar.3HCl was administered 1 h before paclitaxel. This suggests that the inhibition of P-gp at the blood-brain barrier by zosuquidar.3HCl is rapidly reversible and that the concentrations of zosuquidar.3HCl in the plasma have already declined to levels insufficient to inhibit P-gp at the blood-brain barrier. In conclusion, zosuquidar.3HCl is only moderately active as an inhibitor of P-gp at the blood-brain barrier.

Determination of paclitaxel in mouse plasma and brain tissue by liquid chromatography–mass spectrometry

Paclitaxel is an anticancer agent extracted from the bark of the yew tree and is widely used in chemotherapy for solid tumors, including non-small cell lung cancer and ovarian carcinoma. Most assays to measure paclitaxel in plasma require a large amount of sample (0.4–1 ml) to achieve the necessary sensitivity, and are not suitable when only small sample sizes are available. To circumvent this latter limitation, we developed a sensitive liquid chromatography–mass spectrometry (LC–MS) method for the determination of paclitaxel in plasma based on the use of small sample volumes (50 μl plasma). A solid phase extraction procedure was employed that enabled the eluent to be directly injected onto a reversed phase chromatographic HPLC system using positive electrospray ionization followed by mass spectrometric detection. The extraction recoveries of paclitaxel were 98 and 83% from plasma and brain tissues, respectively. The mobile phase consisted of 50% acetonitrile in 0.1% formic acid that was pumped at 0.2 ml/min to yield a retention time for paclitaxel of 6.2 and 5.4 min for cephalomannine, the internal standard. The method has been validated at paclitaxel plasma concentrations from 0.036 to 9.9 μg/ml, and from 0.054 to 1.96 μg/ml in brain homogenates. A sensitive and specific assay for paclitaxel has been developed that has the advantages of using small sample sizes, and a single extraction step without solvent evaporation.

케토코나졸과 파크리탁셀과의 약물상호작용

The purpose of this study was to investigate the effect of ketoconazole (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with ketoconazole was significantly (p of paclitaxel pretreated with ketoconazole were significantly (p of paclitaxel pretreated with ketoconazole were significantly (p of paclitaxel pretreated with ketoconazole was significantly (p

Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions

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. 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. 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. 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.

Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients

The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol®; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112–233 mg/m2). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m2 typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 μM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.

Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction. Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)<paclitaxel. The interaction with paclitaxel (31.6 micro mol/kg) was striking, with coadministration of DMXAA extending the median tumour growth delay from 0.3 to 80 days with three of seven animals cured. The interaction showed a broad timing of the optimum with similar activity when paclitaxel was administered 4 h before to 1 h after DMXAA: No therapeutic synergy was obtained when paclitaxel was combined with the antivascular agent combretastatin A4 phosphate (227 micro mol/kg), which induced only transient blood flow inhibition in this tumour, measured using the H33342 perfusion marker. Paclitaxel did not enhance the antivascular activity of DMXAA: Plasma and tumour concentrations of paclitaxel (and carboplatin), measured by LC-MS and ICP-MS respectively, were not elevated by combination with DMXAA: There was a dramatic therapeutic interaction between DMXAA and standard chemotherapy drugs, particularly paclitaxel, against the MDAH-MCa-4 tumour, which was not due to a pharmacokinetic interaction or potentiation of antivascular activity. It is suggested that the major mechanism of synergy is killing of cells by DMXAA in poorly perfused regions of tumours that are inaccessible to chemotherapy drugs.