Limited sampling models for topotecan pharmacokinetics

BACKGROUND: Limited sampling models for the estimation of the topotecanArea Under the concentration versus time Curve (AUC) and itslactone ring opened form (AUC Tm), from one or more plasma concentrationdeterminations, are desired for further population-kinetic studies. PATIENTS AND METHODS: The models were developed and validated using 34 pharmacokineticcurves in 19 patients who participated in a phase I study. RESULTS: A single point model was selected as optimal: AUC (µmol/L. min) = 499(min) . C_2h(µmol/L) + 0.85(m²/mg . µmol/L. min) . dose(mg/m²), and for topotecan-metabolite (Tm), AUCTm(µmol/L.min) = 55.1 (min) . CTm_2h (µmol/L) / -0.011(m²/mg. µmol/L . min) . dose (mg/m²), where C_2h is the plasmaconcentration (µmol/L) of topotecan at 2 h after the endof a 30-min infusion, and CTm_2h the concentration of the openedform at the same time point. The models are valid for dosagesranging from 0.5 to 1.5 mg/ m²/day and proved to be unbiased(MPE% = –1.8% and –9.3%, respectively) and precise(RMSE% – 17.9% and 22.7%, respectively). From the predictedAUCs, the clearance (Cl = dose (µmol)/AUC(µmol/L. min)) could also reliably be predicted, as well as the totalAUC (AUC + AUC Tm) (RMSE% = 17.1% and MPE% = –0.02%).Half-life values could not be predicted with acceptable precisionand accuracy. CONCLUSION: The limited sampling models presented may be useful for futurestudies focused on pharmacokinetic/ pharmacodynamic relationshipsof topotecan in large populations. AUC, limited sampling model, pharmacokinetics, topotecan     

Limited sampling models for doxorubicin pharmacokinetics

Although doxorubicin is one of the most commonly used antineoplastics, no studies to date have clearly related the area under the concentration-time curve (AUC) to toxicity or response. The limited sampling model has recently been shown to be a feasible method for estimating the AUC to facilitate pharmacodynamic studies. Data from two previous studies of doxorubicin pharmacokinetics were used, including 26 patients with sarcoma and five patients with breast cancer or unknown primary. The former were divided into a training data set of 15 patients and a test datum set of 11 patients, and the latter patients formed a second test data set. The model was developed by stepwise multiple regression on the training data set: AUC (nanogram hour per milliliter) = 17.39 C2 + 163 C48-111.0 [dose/(50 mg/m2)], where C2 and C48 are the concentrations at 2 and 48 hours after bolus dose. The model was subsequently validated on both test data sets: first test data set--mean predictive error (MPE), 4.7%; root mean square error (RMSE), 12.4%; second test data set--MPE, 4.5%, RMSE, 9.2%. An additional model was also generated using a simulated time point to estimate the total AUC for a daily x 3-day schedule: AUC (nanogram hour per milliliter) = 44.79 C2 + 175.65 C48 + 47.25 [dose/(25 mg/m2/d)], where the C48 is obtained just prior to the third dose. We conclude that the AUC of doxorubicin after bolus administration can be adequately estimated from two timed plasma concentrations.     

Clinical Pharmacokinetics of Amonafide (NSC 308847) in 62 Patients

Amonafide (A) demonstrates dose-related increases in area under the curve (AUC) and Cmax values. Total body clearance for A (ranging from 44.2 to 53.8 L/hr/m²) is relatively constant within the dosing range of this study. The dose-related increase of AUC was also observed for the two identified metabolites, acetylamonafide (AA) and noramonafide (NA). A and NA plasma data could be described by a four-compartmental model (two compartments for A, one compartment each for NA and AA). The fitting for NA was poor owing to its low plasma concentration. The terminal half-lives for A, NA, and AA were in the range of 3-6 hr. No cumulative accumulation of parent compound or metabolites was detected after daily administration. The concentrations of A, NA, and AA 24 hr after dosing were either below or very close to the quantitative limits of the assay. Polymorphic disposition of A was confirmed by a frequency distribution of AUC value versus dose plot     

Limited sampling models for simultaneous estimation of the pharmacokinetics of irinotecan and its active metabolite SN-38

Irinotecan (CPT-11) is a novel topoisomerase I inhibitor with clinical activity in human malignancies. The objective of this study was to develop efficient limited sampling models (LSMs) to estimate simultaneously the area under the plasma concentration versus time curves (AUC) for both CPT-11 and its active metabolite SN-38. A total of 64 pharmacokinetic sets (24-h sampling) were obtained in phase I studies at doses ranging from 50 to 750 mg/m² (0.5-h i.v. infusion). The patients were randomly assigned to a training data set (n=32) and a test set (n=32). Multiple linear regression analyses were used to determine the optimal LSMs based on the correlation coefficient (r), bias (MPE%, percentage of mean prediction error), and precision (RMSE%, percentage of root mean squared prediction error). Of these LSMs, the ones including maximal concentrations of CPT-11 (0.5 h, the end of the i.v. infusion) and metabolite SN-38 ( 1 h) were favored along with predictive precision and clinical constraints. Several bivariate models including a 6-h time point as the last sampling time (or 7 h) were found to be highly predictive of either the CPT-11 AUC or the SN-38 AUC. The chosen sampling time points were the ones that allowed the best compromise between the accurate determination of either compound alone with the same sampling times. The simultaneously best prediction of both CPT-11 and SN-38 AUCs was obtained with sampling time points harvested at 0.5, 1, and 6 h (or 7 h). With these sampling time points a trivariate model was selected for the determination of CPT-11 AUC namely, CPT-11 AUC (ng h ml^–1)=0.820×C_0.5h+0.402×C_1h+15.47 ×C_6h+928, and a corresponding model was selected for the determination of metabolite AUC, i.e., SN-38 AUC (ng h ml^–1)=4.05×C_0.5h–0.81×C_1h+23.01×C_6h–69.78, whereC(t) is the concentration in nanograms per milliliter of either compound at a given timet. These models performed well with the test data sets for CPT-11 AUC (r=0.98, MPE%=–1.4, RMSE%=13.9) and for SN-38 AUC (r=0.95, MPE%=–6.5, RMSE%=37.7). In addition to the determination of AUCs (and hence clearance), these models also allow the determination of the maximal concentrations of both compounds, which might be needed for pharmacodynamics studies. Other bi- and trivariate models including other time points are also presented. These LSMs not only will facilitate ongoing and future clinical trials by significantly reducing the number of blood samples needed for pharmacokinetics studies but will hopefully contribute to a better knowledge of pharmacokinetic-pharmacodynamic relationships for both CPT-11 and its active metabolite SN-38.Abbreviations CPT-11 (7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin - SN-38 7-ethyl-10-hydroxy-camptothecin - AUC area under the plasma concentration versus time curve - MPE% percentage of mean prediction error (bias) - RMSE% percentage root mean squared prediction error (precision) - MRT mean residence time - Vdss volume of distribution at steady state - CL total body clearance     

In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia

Benzisoquinolinedione (nafidimide; NSC 308847) is an investigational drug currently in phase I clinical testing. We have studied the antileukemic activity in vitro, the cellular drug transport, and the molecular mechanism of action with DNA of this new compound. By agarose gel electrophoresis, we verified that nafidimide is an intercalating agent, through its alteration of the electrophoretic migration of DNA products produced by the relaxing action of DNA topoisomerase I. Concentrations of up to 100 microM of nafidimide did not produce topoisomerase I-mediated DNA cleavage. Nafidimide produced DNA single-strand breaks (SSB), double-strand breaks, and DNA-protein cross-links in human myeloid leukemia cells (measured with filter elution). The ratio of SSB/DNA-protein cross-links was 1.32 +/- 0.36, a value similar to that produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), suggesting that nafidimide, like m-AMSA, produced protein-associated DNA-strand breaks through a topoisomerase II-mediated reaction. The production of double-strand breaks by nafidimide also suggests the involvement of topoisomerase II in the drug-induced DNA cleavage. The cytotoxic activity of nafidimide was quantified in human myeloid leukemia cell lines differing by a factor of 70 in their cytotoxic sensitivity to m-AMSA. The m-AMSA-resistant line was less than 2-fold resistant to nafidimide. Cellular drug uptake was rapid and reached a steady state level in 30 min at 37 degrees C. At the end of exposure, drug egress was rapid, as was the disappearance of the DNA SSB. Rapid cellular uptake of nafidimide, with low retention at the end of exposure and rapid rejoining of DNA SSB suggest that prolonged cellular exposure may be necessary for optimal antitumor effect. In vitro cloning data suggest that nafidimide may be a therapeutic option for patients with leukemia resistant to m-AMSA.     

Anthracycline pharmacokinetics. Limited sampling model for plasma level monitoring with special reference to epirubicin (Farmorubicin)

A new principle for plasma level monitoring of the anthracyclines doxorubicin and epirubicin is presented. The area under the plasma concentration time curve (AUC) is linearly correlated with the maximum plasma concentration of the drugs at the end of 2 and 4 hours' constant rate infusions. From this relationship it is possible to obtain accurate estimates of the AUC values of the drugs in the individual patients from plasma samples, withdrawn during the last 15 minutes prior to the completion of the infusions. The limited sampling model for drug monitoring of doxorubicin and epirubicin described here is robust and simple to use. It does not require a strict time control for the withdrawing of samples. Measured maximum plasma concentrations of epirubicin during 2 hours' constant rate infusions of 70 mg m-2 to patients with lymphoma (median age: 46.5 years) were within the range 171-404 ng ml-1 (median value: 265 ng ml-1).     

Plasma and cerebrospinal fluid pharmacokinetics of rebeccamycin (NSC 655649) in nonhuman primates

Purpose The rebeccamycins, indolocarbazole topoisomerase I poisons originally discovered in actinomycetes, have shown activity in vitro against a range of adult and pediatric tumors. The derivative NSC 655649 (diethylaminoethyl analog of rebeccamycin, or DEAE rebeccamycin) is currently undergoing early-phase human studies and has shown some signs of antitumor activity. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of NSC 655649 after systemic administration in a nonhuman primate model that is predictive of anticancer drug behavior in humans.Design A dose of 400 mg/m² was infused over 1 h to three rhesus monkeys. Serial blood and CSF samples were collected. Rebeccamycin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis was performed using compartmental and noncompartmental methods.Results A two-compartment or three-compartment model described rebeccamycin pharmacokinetics in plasma adequately. In two animals, the three-compartment model provided a better fit, and in one animal, the two-compartment model was better. The terminal half-life was 730±410 min, the AUC was 3130±425 M min, and the clearance was 190±25 ml/min/m². Rebeccamycin was below the limit of quantitation in all CSF samples. The animals had some nausea and agitation during and shortly after the infusion that responded to treatment with prochlorperazine or diazepam. Otherwise, rebeccamycin was well tolerated with minimal toxicity.Conclusion Rebeccamycin penetrates poorly into the CSF following an intravenous infusion. Therefore, systemically administered rebeccamycin is unlikely to be an important agent for the treatment of leptomeningeal tumors. Because the drug is associated with local irritation at injection sites, it is not an ideal candidate for development as an intrathecal agent. However, the role of rebeccamycin in the treatment of parenchymal brain tumors should be determined in clinical trials.     

Limited sampling models for CPT-11, SN-38, and SN-38 glucuronide

PURPOSE: To determine the ability of WMC26, a prototypic bisimidazoacridone (BIA), to induce apoptosis in sensitive colon adenocarcinoma cells and to advance the hypothesis that cancer cells that are growth-arrested by WMC26 are predisposed to undergo apoptotic death by abrogators of cell cycle checkpoints. METHODS: The antiproliferative activity of WMC26 was examined in detail by a 4-day MTT assay, cell counting, BrdU incorporation and a two-color LIVE/DEAD assay. To detect apoptosis a number of established techniques were used, including gel electrophoresis, flow cytometry, and confocal laser microscopy of treated cells. The activity of senescence-associated beta-galactosidase in treated cells was also analyzed. RESULTS: WMC26, at physiological concentrations, induced complete and longlasting growth arrest of HCT116 cells in culture but did not trigger cell death. The growth-arrested cells (blocked at G1 and G2/M cell cycle checkpoints) did not synthesize DNA but were metabolically active and had intact plasma membranes. Although they resembled the senescence-like phenotype reported to be induced by treatment with some antitumor agents, the cells did not express senescence-associated beta-galactosidase, an indicator of the senescence-like state. Treatment of WMC26 growth-arrested cells with 1 microM UCN-01, an abrogator of the G2/M checkpoint, caused a very rapid (1 h) change in morphology and cell death within 72 h. CONCLUSIONS: BIAs do not induce apoptosis in sensitive colon tumor cells. They are highly cytostatic but only marginally toxic to the cells even at concentrations 100-fold higher than those sufficient for complete growth arrest. In this respect WMC26 differs from some other DNA-interacting antitumor agents that produce cell growth arrest at low concentrations but are toxic at higher doses. The complete growth arrest induced by WMC26 in colon cancer cells sensitized them to apoptotic death induced by UCN-01. This finding suggests that a combination of WMC26 and cyclin-dependent kinase inhibitors may be an attractive treatment method for colon cancer that utilizes the highly tumor-selective activity of WMC26.     

Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.     

Phase I study and pharmacokinetics of menogaril (NSC 269148) in patients with hepatic dysfunction

We performed a phase I study of menogaril to determine if dosage reduction was required in patients with hepatic dysfunction and if the relationship between pharmacokinetics and leukopenia, previously defined in patients with normal hepatic and renal function, was altered. Eighteen patients received 27 courses of menogaril, of which 26 were evaluable for toxicity. Patient characteristics were median age, 63 years (range, 28-80 years), 14 male/4 female, and median Karnofsky performance status 80% (range, 60-100%). Prior therapy included none, five; chemotherapy only, seven; radiotherapy only, two; and chemotherapy and radiotherapy, four. Menogaril was administered as a 2-h.i.v. infusion every 28 days at 62.5 (one patient), 125 (eight patients), 187.5 (seven patients), and 250 mg/m2 (six patients), based on pretreatment serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Patients also had indocyanine green and antipyrine clearances measured before menogaril treatment. Menogaril and metabolites were assayed by high performance liquid chromatography. Dose-limiting toxicity was leukopenia. WBC nadirs occurred between days 8 and 20 (median, 15). Three patients developed platelet nadirs below 100,000/microliters. Other toxicities included grade I nausea and vomiting in three patients and phlebitis at the site of drug infusion in six patients. Correlations were defined between pretreatment indocyanine green clearance and serum concentrations of alkaline phosphatase and total bilirubin. There were no correlations between pretreatment serum concentrations of bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, indocyanine green clearance or antipyrine and menogaril clearances. Menogaril pharmacokinetics in patients with elevated liver function tests was indistinguishable from that described in patients with normal liver function tests. There were excellent correlations between plasma area under the curve of menogaril and the percentage decreases in WBC and neutrophils. These were well described by two models previously used to study the same relationships in patients with normal hepatic and renal function. When compared to previous studies, patients with hepatic and renal dysfunction had a greater percentage decrease in WBC for any given area under the curve than did patients with normal hepatic and renal function. On the other hand, there was no difference in the relationship between percentage decrease in neutrophils and menogaril area under the curve in these two groups of patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

A limited sampling strategy for cyclophosphamide pharmacokinetics

A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.     

Phase I clinical trial and pharmacokinetics of carboplatin (NSC 241240) by single monthly 30-minute infusion

Carboplatin (diammine [1,1-cyclobutanedicarboxylate(2-)-O,o']platinum) is a second generation platinum coordination complex. It has a spectrum of activity that is similar to that of cisplatin and is less nephrotoxic and emetogenic in experimental animals. Fifty-two 30-minute infusions of carboplatin were given to 20 evaluable patients with a variety of solid tumors. Maximum tolerated dose was 440 mg/m2. Thrombocytopenia (less than 100,000/mm3) occurred in six of seven patients; two patients experienced a leukocyte count less than 2000/mm3. Platelet and leukocyte count nadirs occurred on day 21. No nephrotoxicity was seen. Blood urea nitrogen, serum creatine levels, and creatinine clearances remained normal, and no consistent elevation of urinary beta 2-microglobulin, leucine aminopeptidase, or N-acetyl-beta-glucosaminidase occurred. Nausea and vomiting were mild to moderate. A single patient developed mild peripheral neuropathy. No auditory toxicity was noted. The recommended dose for Phase II studies is 400 mg/m2 every 28 days for good risk patients; heavily pretreated patients should receive 320 mg/m2.     

Metabolism and murine pharmacokinetics of the 8-(N,N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451)

The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism. When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolamide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37 degrees C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes. The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.     

Unchanged pharmacokinetics of VP-16-213 (etoposide,NSC 141540) during concomitant administration of doxorubicin and cyclophosphamide

In patients with small-cell lung cancer VP-16-213 is often given in combination with doxorubicin and cyclophosphamide. Little is known about possible interactions between these drugs. Therefore we investigated in 7 patients the pharmacokinetics of VP-16-213, with and without the other two drugs.We found no change in the pharmacokinetics. We also provide evidence that the pharmacokinetics did not change in two sequential administrations of the drug.Pharmacokinetic data are in agreement with previous reports.     

Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1

PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin compound agent that has entered clinical trials. Studies were performed in mice to: (1) define the plasma pharmacokinetics, tissue distribution, and urinary excretion of 17AAG after i.v. delivery; (2) to define the bioavailability of 17AAG after i.p. and oral delivery; and (3) to characterize the concentrations of 17AAG metabolites in plasma and tissue. MATERIALS AND METHODS: All studies were performed in female CD2F1 mice. Preliminary toxicity studies used 17AAG i.v. bolus doses of 20, 40 and 60 mg/kg. Pharmacokinetic studies used i.v. 17AAG doses of 60, 40, and 26.67 mg/kg and i.p. and oral doses of 40 mg/kg. The plasma concentration versus time data were analyzed by compartmental and noncompartmental methods. The concentrations of 17AAG were also determined in brain, heart, lung, liver, kidney, spleen, skeletal muscle, and fat. Urinary drug excretion was calculated until 24 h after treatment. RESULTS: A 60 mg/kg dose of 17AAG, in its initial, microdispersed formulation, caused no changes in appearance, appetite, waste elimination, or survival of treated animals as compared to vehicle-treated controls. Bolus i.v. delivery of 60 mg/kg microdispersed 17AAG produced "peak" plasma 17AAG concentrations between 5.8 and 19.3 micrograms/ml in mice killed 5 min after injection. Sequential reduction of the 17AAG dose to 40 and 26.67 mg/kg resulted in "peak" plasma 17AAG concentrations between 8.9 and 19.0 micrograms/ml, and 4.8 and 6.1 micrograms/ml, respectively. Noncompartmental analysis of the plasma 17AAG concentration versus time data showed an increase in AUC from 402 to 625 and 1738 micrograms/ml.min when the 17AAG dose increased from 26.67 to 40 and 60 mg/kg, respectively. Across the range of doses studied, 17AAG total body clearance varied from 34 to 66 ml/min per kg. Compartmental modeling of the plasma 17AAG concentration versus time data showed that the data were fitted best by a two-compartment, open, linear model. In each study, substantial concentrations of a material, subsequently identified as 17-(amino)-17-demethoxygeldanamycin (17AG), were measured in plasma. A subsequent, lyophilized formulation of 17AAG proved excessively toxic when delivered i.v. at 60 mg/kg. A repeat i.v. study using a 40 mg/kg dose of this new formulation produced peak plasma 17AAG concentrations of 20.2-38.4 micrograms/ml, and a 17AAG AUC of 912 micrograms/ml.min, which was approximately 50% greater than the AUC produced by a 40 mg/kg dose of microdispersed 17AAG. The bioavailabilities of 17AAG after i.p. and oral delivery were 99% and 24%, respectively. Minimal amounts of 17AAG and 17AG were detected in the urine. After i.v. bolus delivery to mice, 17AAG distributed rapidly to all tissues, except the brain. Substantial concentrations of 17AG were measured in each tissue. CONCLUSIONS: 17AAG has excellent bioavailability when given i.p. but only modest bioavailability when given orally and is metabolized to 17AG and other metabolites when given i.v., i.p., or orally. 17AAG is widely distributed to tissues. These pharmacokinetic data generated have proven relevant to the design of recently initiated clinical trials of 17AAG and could be useful in their interpretation.     

A phase III study in lung carcinoma comparing hexamethyl-melamine (NSC 13875) to dibromodulcitol (NSC 104800) 1,2.

A phase III study was designed comparing the effectiveness of Hexamethyl-melamine (NSC 13875) to Dibromodulcitol (NSC 104800) in lung carcinoma. 250 of the 316 patients entered on the study were stratified into groups according to stage of disease and cell type. The results showsed Hexamethylmelamine to be more effective in patients with squamous cell carcinoma and slightly superior to Dibromodulcitol in patients with anaplastic/undifferentiated cell carcinoma, whereas Dibromodulcitol proved to be more effective in patients with adenocarcinoma.