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PubMed2001

Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin.

The urinary excretion of N,N',N"-triethylenethiophosphoramide (thioTEPA), and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA--mercapturate was determined in patients receiving thioTEPA as part of a high-dose combination chemotherapy regimen with cyclophosphamide and carboplatin. The thioTEPA dose was 40 or 60 mg/m(2) in short infusions, twice daily, during 4 days. Urine samples were collected after each voiding on each day of drug administration until 24--48 h after the last thioTEPA infusion. ThioTEPA, TEPA and monochloroTEPA concentrations were determined with gas chromatography and thioTEPA--mercapturate with liquid chromatography--mass spectrometry with direct sample injection. ThioTEPA was present in urine 30 min after infusion and was still excreted 18 h after the last infusion. All metabolites were detected in urine 1 h after infusion. Patients with a creatinine clearance above 140 ml/minl showed higher excretion of TEPA than patients with a creatinine clearance below 140 ml/min (12.8 versus 4.9%, p=0.01). The excretion of monochloroTEPA relative to the excreted amount of TEPA increased at lower pH values of the urine. The excretion of thioTEPA--mercapturate relative to the dose was higher in patients treated with 60 mg/m(2). Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA--mercapturate both accounted for 11.1%.

Acetylcysteine↗
PubMed2000

Stability of thioTEPA and its metabolites, TEPA, monochloroTEPA and thioTEPA-mercapturate, in plasma and urine.

The degradation of N,N',N"-triethylenethiophosphoramide (thioTEPA) and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N, N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA-mercapturate in plasma and urine has been investigated. ThioTEPA, TEPA and monochloroTEPA were analyzed using a gas chromatographic (GC) system with selective nitrogen/phosphorous detection; thioTEPA-mercapturate was analyzed on a liquid chromatography-mass spectrometric (LC-MS) system. The influences of pH and temperature on the stability of thioTEPA and its metabolites were studied. An increase in degradation rate was observed with decreasing pH as measured for all studied metabolites. In urine the rate of degradation at 37 degrees C was approximately 2.5+/-1 times higher than at 22 degrees C. At 37 degrees C thioTEPA and TEPA were more stable in plasma than in urine, with half lives ranging from 9-20 h for urine and 13-34 h for plasma at pH 6. Mono- and dichloro derivatives of thioTEPA were formed in urine and the monochloro derivative was found in plasma. Degradation of TEPA in plasma and urine resulted in the formation of monochloroTEPA. During the degradation of TEPA in plasma also the methoxy derivative of TEPA was formed as a consequence of the applied procedure. The monochloro derivative of thioTEPA-mercapturate was formed in urine, whereas for monochloroTEPA no degradation products could be detected.

Acetylcysteine↗
PubMedDate not supplied

Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.

BACKGROUND: The combination of cyclophosphamide, thioTEPA and carboplatin is used in our Institute for the treatment of breast or germ cell cancer. ThioTEPA inhibits the bioactivation of cyclophosphamide, and platinum drugs are known to interfere with the hepatic metabolism of several anticancer drugs. Of the co-administered drugs to prevent unwanted side effects, some are enzyme inducers, cytochrome P450 inhibitors or substrates. The aim of this study was to investigate the influence of co-medicated drugs on the biotransformation of thioTEPA. METHODS: The possible inhibition of the metabolism of thioTEPA to TEPA was investigated in human microsomes. Influences on the conversion of thioTEPA to monoglutathionylthioTEPA, was studied by the incubation of thioTEPA with glutathione and glutathione S-transferase. RESULTS: No inhibition of the metabolism of thioTEPA to form TEPA was observed for cyclophosphamide and carboplatin, or any other co-medicated drug (ciproflocaxin, amphotericin B, itraconazol, fluconazol, ondansetron, dexamethasone, granisetron, aciclovir, ranitidine, lorazepam). The conversion of thioTEPA to monoglutathionylthioTEPA was inhibited by cyclophosphamide, itraconazol, amphotericin B and ondansetron with IC50 values of 58, 256, 55 and 40 mM, respectively, which are far higher than therapeutic drug levels. CONCLUSION: No clinically relevant drug-drug interactions occur in the CTC regimen as applied in our Institute.

Acetylcysteine↗
PubMed1999

Liquid chromatographic-mass spectrometric determination of the novel, recently identified thioTEPA metabolite, thioTEPA-mercapturate, in urine.

An assay for the quantitative determination of the mercapturic acid conjugate of N,N',N"-triethylenethiophosphoramide (thioTEPA-mercapturate) in human urine has been developed. ThioTEPA-mercapturate, a recently identified metabolite of the alkylating anticancer agent thioTEPA, was analyzed using LC-MS and with direct sample injection. Sulphadiazine was used as internal standard. Linearity was accomplished in the therapeutic relevant range of 1-25 microg/ml; recovery was 84% and both accuracy and precision were less than 20% for the lower limit of quantification (1.0 microg/ml) and less than 10% for the other concentration levels. The stability of thioTEPA-mercapturate proved to be satisfactory over a period of 2 months, when kept at -80 degrees C. ThioTEPA-mercapturate urine concentrations of two patients treated with thioTEPA are presented demonstrating the applicability of the assay for clinical samples.

Acetylcysteine↗
PubMed1988

Human plasma pharmacokinetics of thiotepa following administration of high-dose thiotepa and cyclophosphamide.

Thiotepa is an established alkylating agent whose pharmacokinetics in standard doses are well defined. In order to ascertain whether dose-dependent variations in pharmacokinetics occur, we have undertaken an analysis of plasma thiotepa levels in 16 patients entered on a phase I-II study of bialkylator chemotherapy. High-dose thiotepa (1.8 to 7.0 mg/kg) and cyclophosphamide (2.5 g/m2) were administered intravenously (IV) on days -6, -4, and -2 followed by autologous marrow reinfusion on day 0. Plasma and urinary thiotepa was assayed by gas chromatography. Biexponential plasma decay curves were seen in ten patients, with a t 1/2 alpha of 10.0 +/- 6.4 minutes, a t 1/2 beta of 174 +/- 61 minutes and a total body clearance of 379 +/- 153 mL/h/kg (mean +/- SD). Six patients displayed monoexponential plasma decay curves with a terminal t 1/2 of 137 +/- 83 minutes and a total body clearance of 440 +/- 195 mL/h/kg. Although there was a trend toward reduced plasma clearance in the three patients treated at the highest dose level, the available data suggest that metabolic clearance mechanisms for thiotepa were not saturated with the doses used in this study. By stepwise regression analysis, linear functions using only 15-minute and four-hour postinfusion plasma levels were derived that correlated closely with area under the plasma concentration X time curves (AUC) (P less than .002). We conclude that high-dose thiotepa results in similar pharmacokinetic values to conventional doses with no apparent dose-dependent variation. The value of specific time points to predict AUC and clearance will require prospective evaluation.

Chromatography, Gas↗
PubMed2000

Simultaneous determination of thioTEPA, TEPA and a novel, recently identified thioTEPA metabolite, monochloroTEPA, in urine using capillary gas chromatography.

An assay for the simultaneous quantitative determination of thioTEPA, TEPA and the recently identified metabolite N,N'-diethylene-N"-2-chloroethylphosphoramide (monochloroTEPA) in human urine has been developed. MonochloroTEPA was synthesized by incubation of TEPA with sodium chloride at pH 8. Thus, with this assay monochloroTEPA is quantified as TEPA equivalents. Analysis of the three analytes in urine was performed using gas chromatography with selective nitrogen-phosphorous detection after extraction with a mixture of 1-propanol and chloroform from urine samples. Diphenylamine was used as internal standard. Recoveries ranged between 70 and 100% and both accuracy and precision were less than 15%. Linearity was accomplished in the range of 25-2500 ng/ml for monochloroTEPA and 25-5000 ng/ml for thioTEPA and TEPA. MonochloroTEPA proved to be stable in urine for at least 4 weeks at -80 degrees C. ThioTEPA, TEPA and monochloroTEPA cummulative urinary excretion from two patients treated with thioTEPA are presented demonstrating the applicability of the assay for clinical samples and that the excreted amount of monochloroTEPA exceeded that of thioTEPA on day 2 to 5 of urine collection.

Antineoplastic Agents, Alkylating↗
PubMed1999

A feasibility study of multiple cycle therapy with melphalan, thiotepa, and paclitaxel followed by mitoxantrone, thiotepa, and paclitaxel with autologous hematopoietic cell support for metastatic breast cancer.

Dose-intensive chemotherapy appears to be important in the treatment of patients with recurrent solid tumors. Expanding upon our prior experience, we report the results of our most recent approach to administering dose-intensive therapy using four cycles of moderately high-dose chemotherapy with hematopoietic cell support for patients with metastatic breast cancer. This outpatient therapy includes high-dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone, thiotepa, and paclitaxel for two cycles, with each cycle supported with autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and June 1996, 16 patients with recurrent or refractory breast cancer were enrolled in this prospective study. They had received a median of two previous chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2, followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected by apheresis. Each day's collection was divided into four equal fractions, and each fraction was infused after each cycle of combination therapy. Cycles 1 and 2 consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2. Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and paclitaxel at the same doses as in the first two cycles. The cyclophosphamide infusion was administered in the hospital, whereas all subsequent infusions of chemotherapy and PBPCs were performed on an outpatient basis. The first seven patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment was discontinued for progressive disease (one patient) or morbidity (five patients). Twelve of 16 patients completed at least three cycles of therapy. Nine patients completed all four cycles. One death resulted from fungal sepsis. In 20 cycles delivered to the first seven patients, day +1 G-CSF versus placebo was administered, with a median WBC recovery of 10 versus 13 days, respectively (P = 0.048 in cycle 1). The median duration of response was almost 9 months, and the median survival was 18 months after therapy. With a median follow-up of 1.5 years and longest follow-up of 4.2 years, two patients continue to be without evidence of disease. The 3-year event-free survival, freedom from progression, and overall survival are 19%, 20%, and 31%, respectively. This four-cycle regimen of high-dose combination therapy supported with hematopoietic progenitor cells is feasible, but it is associated with a range of posttransplant complications. The efficacy of such a treatment would have to be substantially superior to that of other currently available therapies, including single autologous transplant procedures, to justify the prolonged period of treatment, multiple episodes of pancytopenia, and associated toxicities, including infectious risks. G-CSF administration after each PBPC infusion appears to accelerate time to neutrophil recovery but does not affect red cell or platelet engraftment.

Adult↗
PubMed1989

Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa.

A Phase I trial of thiotepa (TT) administered as an i.v. bolus was performed in 19 children with refractory malignancies. The starting dose was 25 mg/m2 with escalations to 50, 65, and 75 mg/m2. Seven additional patients were treated with 8-h infusions at 50 or 65 mg/m2. The maximum tolerated bolus dose was 65 mg/m2. Reversible myelosuppression was the dose-limiting toxicity. The plasma and cerebrospinal fluid (CSF) pharmacokinetic parameters of TT and its major active metabolite tepa (TP) were also evaluated. When the bolus or infusion methods of TT administration were compared, there was little difference observed in any pharmacokinetic parameter for either TT or TP. The plasma disappearance of TT was rapid and biphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependent pharmacokinetics was demonstrated by steadily declining plasma clearance with increasing TT dose. Clearance values declined from 28.6 liters/m2/h at the 25-mg/m2 dose to 11.9 liters/m2/h at the 75-mg/m2 dose. The half-life of TP was longer than that of TT and ranged between 4.3 and 5.6 h. There was evidence of the saturation of TP production. TT and TP both exhibited excellent penetration into the CSF, producing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the CSF:plasma area under the (concentration x time) curve ratios for TT and TP were 1.01 and 0.95, respectively. The above data indicate that TT can be safely administered to pediatric patients at doses higher than conventionally used. The favorable CSF penetration of TT and TP suggests that Phase II studies of TT be considered in patients with central nervous system tumors.

Adolescent↗
PubMed1995

The role of human glutathione S-transferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa.

Nonenzymatic and glutathione S-transferase (GST) catalyzed glutathione (GSH) conjugation has been postulated as a mechanism by which alkylating cytostatic drugs can be inactivated intracellularly. In this study, we describe studies on the glutathione-dependent biotransformation of thiotepa (tris(1-aziridinyl)phosphine sulfide), a trifunctional alkylating agent. 31P NMR studies showed that thiotepa is stable in 0.07 M phosphate buffer, pH 7.4 (t1/2 = 3300 min). In the presence of glutathione, the rate of disappearance of thiotepa increased greatly (t1/2 = 282 min). Both monoglutathionyl thiotepa and diglutathionyl thiotepa conjugates were identified by 31P NMR and mass spectrometry. Addition of GST A1-1 (alpha) to an incubation of thiotepa and GSH further increased the rate of disappearance of thiotepa (t1/2 = 100 min) and increased the rate of formation of monoglutathionyl thiotepa. The rate of formation of diglutathionyl thiotepa was not altered, suggesting that the formation of diglutathionyl thiotepa is not catalyzed by GST A1-1. The role of purified human GST on the formation of monoglutathionyl thiotepa was further studied by HPLC. In incubations with 0.2 mM thiotepa, 1 mM GSH, and 40 microM GST, both GST A1-1 and P1-1 enhanced the formation of the monoglutathionyl conjugate 30-35-fold above the nonenzymatic formation, while GST A2-2 and M1a-1a did not catalyze the rate of formation of this conjugate. Kms for the GST A1-1 (alpha) and P1-1 (pi) catalyzed formation of monoglutathionyl thiotepa were in the 5-7 mM range. Since the pH in tumors might be lower than in normal cells, the pH dependency of the GST P1-1 catalyzed formation of monoglutathionyl thiotepa was also studied. At all pHs tested (range, 5.5-8.5), a marked catalytic effect of both GST P1-1 and A1-1 on the formation of monoglutathionyl conjugates was noted. The role of GST on the formation of monoglutathionyl conjugates of tepa (tris(1-aziridinyl)phosphine oxide), the major metabolite formed from thiotepa, was also studied. Both GST A1-1 and P1-1 could enhance the formation of the glutathione conjugate 37-46-fold above the spontaneous levels, while GST M1a-1a and A2-2 again did not increase the rate of formation of this conjugate. The results of these studies show that the aziridine moieties in thiotepa/tepa are substrates for both GST A1-1 and P1-1. Thus, GST catalyzed glutathione conjugation of thiotepa might be an important factor in the development of drug resistance towards thiotepa.

Chromatography, High Pressure Liquid↗
PubMed1990

Cellular transport and accumulation of thiotepa.

Because the transport and accumulation of N,N',N''-triethylenethiophosphoramide (thiotepa) by cells has not been characterized, these processes were investigated with [14C]thiotepa and cultured L1210 or freshly obtained human or avian RBCs. The octanol: phosphate-buffered saline (PBS) partition coefficient of thiotepa was 2.4 +/- 0.1 (n = 8). With this value, the permeability coefficient (Ps) for thiotepa was estimated to be between 2.8 x 10(-4) and 1.81 x 10(-3) cm/sec, and the half-life of accumulation of thiotepa by L1210 cells was estimated to be 0.063 to 0.40 seconds. Thiotepa accumulation by cells was measured after incubation of cells with [14C]thiotepa and subsequent harvesting of cells by centrifugation through silicone fluid. Thiotepa accumulation by L1210 cells was biphasic. The initial phase was rapid and essentially complete by 10 seconds. The amount of cell-associated 14C increased linearly with increasing extracellular concentrations of thiotepa or with increasing size of the cell pellet. The absolute amount of cell-associated 14C was consistent with that expected if the [14C]thiotepa had been evenly distributed in the incubation medium and a volume equal to that of the cell pellet had been sampled and counted. This rapid phase of thiotepa accumulation was not slowed when cells were incubated on ice. The second phase of [14C]thiotepa accumulation occurred at a rate much slower than that of the initial phase. This slower phase of drug accumulation was linear for at least 5 hours. The rate of 14C accumulation increased progressively over a range of extracellular thiotepa concentrations from 5 to 100 nmol/mL and could not be saturated under acceptable tissue culture conditions. The slower rate of 14C accumulation was ablated by incubating cells on ice and was reduced by 30% to 50% in the presence of 1mM of sodium azide or 2,4-dinitrophenol. The slow rate of accumulation of 14C reflected summation of a relatively stable or constant amount of exchangeable 14C and an amount of nonexchangeable 14C that increased linearly from almost undetectable levels at the start of the experiment to amounts equal to 64 +/- 11% of total cellular radioactivity after 5 hours. The initial association of [14C]thiotepa with both human and avian RBCs was also very rapid. Avian RBCs also exhibited a slow rate of 14C accumulation that was linear for at least 5 hours but that was 15% to 20% that of L1210 cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Cellular transport and accumulation of thiotepa in murine, human, and avian cells.

Because the transport and accumulation of thiotepa by cells has not been characterized, these process were investigated with [14C]thiotepa and cultured L1210 or freshly obtained human or avian RBC. The octanol:phosphate buffered saline partition coefficient of thiotepa was 2.4 +/- 0.1 (n = 8). With this value, the permeability coefficient (P) for thiotepa was estimated to be between 2.8 X 10(-4) and 1.81 X 10(-3) cm/s and the half-life of accumulation of thiotepa by L1210 cells was estimated to be 0.063-0.40 s. Thiotepa accumulation by cells was measured after incubation of cell with [14C]thiotepa and subsequent harvesting of cells by centrifugation through silicone fluid. Thiotepa accumulation by L1210 cells was biphasic. The initial phase was rapid essentially complete by 10 s. The amount of cell-associated 14C increased linearly with increasing extracellular concentrations of thiotepa or with increasing size of the cell pellet. The absolute amount of cell-associated 14C was consistent with that expected if the [14C]thiotepa had been evenly distributed in the incubation medium and a volume equal to that of the cell pellet had been sampled and counted. This rapid phase of thiotepa accumulation was not slowed when cells were incubated on ice. The second phase of [14C]thiotepa accumulation occurred at a rate much slower than that of the initial phase. This slower phase of drug accumulation was linear for at least 5 h. The rate of 14C accumulation increased progressively over a range of extracellular thiotepa concentrations between 5 and 100 nmol/ml and could not be saturated under acceptable tissue culture conditions. The slower rate of 14C accumulation was ablated by incubation cells on ice and was reduced by 30-50% in the presence of 1 mM sodium azide or 2,4-dinitrophenol. The slow rate of accumulation of 14C reflected summation of a relatively stable or constant amount of exchangeable 14C an an amount of nonexchangeable 14C which increased linearly from almost undetectable levels at the start of the experiment to amounts approximately equal to those of exchangeable radioactivity after 5 h. The initial association of [14C]thiotepa with both human and avian RBCs was also very rapid. Avian RBCs also exhibited a slow rate of 14C accumulation which was linear for at least 5 h which was 15-20% that of L1210 cells. Human RBCs did not exhibit a slower rate of 14C accumulation and essentially all of the 14C associated with human RBCs was exchangeable for the 5 h duration of the experiment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Dosing of thioTEPA for myeloablative therapy.

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thioTEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean +/- SE plasma concentration of thioTEPA was 124 +/- 63 ng/ml, while that of TEPA was 235 +/- 69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50(s) of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50(s) of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a two-compartment model, the mean thioTEPA Vc was 47.4 +/- 4.7 1/m2, t1/2 alpha 19 +/- 5 min, t1/2 beta 3.7 +/- 0.5 h, and plasma clearance 302 +/- 21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/1 for thioTEPA and 8.9-21.2 mg h/1 for TEPA, while the mean peak concentrations were 0.95-2.08 micrograms/ml for thioTEPA and 0.88-1.90 micrograms/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak > 1.75 micrograms/ml and with combined thioTEPA and TEPA AUC > 30 mg h/1 (5/6 vs 0/9, P = 0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r = 0.74, P = 0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P = 0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.

Adolescent↗
PubMed1990

Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.

In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Human plasma pharmacokinetics and urinary excretion of thiotepa and its metabolites.

Thiotepa has been used clinically for greater than 30 years but its pharmacokinetics remain poorly defined. We determined the plasma pharmacokinetics and urinary excretion of thiotepa and its metabolites in 21 patients with breast cancer who received 25 courses of iv bolus thiotepa (12 mg/m2) as part of combination chemotherapy. Plasma samples were obtained before injection: at 5, 10, 15, 30, 45, 60, 90, and 120 minutes; and, when possible, 180 and 240 minutes after injection. In eight courses, urine was collected as 4-hour aliquots for 24 hours after therapy. All samples were analyzed for thiotepa and tepa by gas-liquid chromatography. Urinary alkylating activity was assessed spectrophotometrically after reaction with 4-(p-nitrobenzyl)-pyridine. Plasma concentrations of thiotepa declined in a biexponential fashion with an alpha-half-life of 7.7 +/- 1.2 minutes and a beta-half-life of 125 +/- 21 minutes. Total-body clearance of thiotepa was 186 +/- 20 ml/minute/m2. The volume of the central compartment was calculated as 0.25 +/- 0.04 L/kg, and the steady-state volume of distribution was calculated as 0.70 +/- 0.11 L/kg. Tepa was detectable in plasma by 5 minutes after the injection of thiotepa. Tepa concentrations increased from 0.093 +/- 0.068 to 0.127 +/- 0.11 micrograms/ml over the 240-minute collection period. By 120 minutes, the concentration of tepa equaled that of thiotepa, and tepa persisted longer in the plasma than did thiotepa. During the first 24 hours after injection, urinary excretion of thiotepa, tepa, and alkylating activity accounted for 1.5%, 4.2%, and 23.5% of the administered dose, respectively. These results extend our laboratory's previous animal studies of thiotepa and argue for metabolism of thiotepa to tepa as a major mechanism of clearance of this compound. Further metabolism or breakdown of both compounds may explain the urinary excretion of alkylating materials other than parent compound and tepa.

Adult↗
PubMed2000

Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens.

PURPOSE: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide thioTEPA carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. METHODS: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1,000 or 1,500 mg/m2 per day), thioTEPA (80 or 120 mg/m2 per day) and carboplatin (265 or 400 mg/m2 per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. RESULTS: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased Cmax (-62%) and AUC (-26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC50 of 23 microM. No inhibition of the formation of TEPA by cyclophosphamide was observed. CONCLUSIONS: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high-dose chemotherapy.

AIMS: To study the population pharmacokinetics of thioTEPA and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of thioTEPA (80-120 mg x m(-2) x day(-1)), cyclophosphamide (1000-1500 mg x m(-2) x day(-1)) and carboplatin (265-400 mg x m(-2) x day(-1)) for 4 days. METHODS: ThioTEPA and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined. RESULTS: A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of thioTEPA (CL) was 34 l x h(-1) with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of thioTEPA was 47 l (IIV = 7.5%; IOV = 19%). The fraction of thioTEPA converted to TEPA divided by the volume of distribution of TEPA was 0.030 l-1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h(-1) (IIV = 27%; IOV = 32%). CL of thioTEPA was correlated with alkaline phosphatase and serum albumin. The volume of distribution of thioTEPA and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. CONCLUSIONS: A model for the description of the pharmacokinetics of thioTEPA and TEPA was developed. Factors involved in the interpatient variability of thioTEPA and TEPA pharmacokinetics were identified. Since, IOV of both thioTEPA and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.

Adolescent↗
PubMed1991

Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid.

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.

Adult↗