Disposition of temozolomide in a patient with glioblastoma multiforme after gastric bypass surgery

Temozolomide, used for anaplastic gliomas and glioblastoma multiforme, is an oral drug that is stable under acidic, but labile under neutral and basic conditions. Although the bioavailability of temozolomide is approximately 100%, pathology or anatomical changes of the gastrointestinal tract may adversely affect absorption, and consequently therapeutic response. HPLC-UV was used to evaluate temozolomide plasma pharmacokinetics in a patient with unresponsive glioblastoma multiforme who had previously undergone gastric bypass as part of a weight-loss strategy. Temozolomide plasma pharmacokinetics were comparable to values reported for patients with normal gastrointestinal anatomy. These data imply that progression of disease in this patient was not due to inadequate temozolomide concentrations. Physicians need to become aware of the rapidly increasing population of patients who have had a gastric bypass and require oral therapy, of which our case is representative. The effect of gastric bypass on pharmacokinetics will need to be evaluated on a drug-by-drug basis.     

Tolerance,safety, and kinetics of the new antineoplastic compound dexniguldipine-HCl after oral administration: a phase I dose-escalation trial

Dexniguldipine-HCl is a new dihydropyridine compound that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. The purpose of this trial was to determine the toxicity and pharmacokinetics of dexniguldipine and to establish a recommended dose for phase II trials. A total of 37 patients with cancer were treated with oral dexniguldipine in increasing doses for up to 7 days. The main parameters evaluated were subjective tolerance and laboratory and cardiovascular parameters (blood pressure and ECG). Blood samples were drawn for analysis of the drug's pharmacokinetics. Dizziness and nausea were the major adverse events observed in seven patients, but episodes were generally mild and not clearly dose-related. Vomiting occurred in one patient. Hypotensive effects and orthostatic dysregulation were observed in some patients but were not considered to be dose-limiting. Therefore, no dose-limiting toxicity was found and the maximally tolerable dose could not be determined. Pharmacokinetic data showed wide interindividual variation and a dose-dependent increase in steady-state serum concentrations at doses of up to 1,000 mg daily, with no clear further increase being observed at higher doses. Consistently high concentrations were achieved with the 2,500-mg dose. Despite the lack of dose-limiting toxicity, higher doses of dexniguldipine do not appear to be useful for clinical evaluation because of the pharmacokinetics properties of the compound; therefore, 2,500 mg/day is recommended as the daily dose for phase II trials.This work was sponsored by Byk Gulden Pharmaceuticals, Konstanz, Germany     

Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC

Purpose To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children.Methods LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145–200 mg/m² per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations.Results The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (–8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [–1.0% (–12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1±6.1% and –0.8±6.5%), and the highest accuracy (4.5±4.1% and 5.0±4.3%) for temozolomide clearance and MTIC apparent clearance, respectively.Conclusions Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.This work was presented at AACR 2002 Annual Meeting.     

Metabolism, excretion and pharmacokinetics of a single dose of [14C]-raltitrexed in cancer patients

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase and has recently been licensed in Europe for use in the treatment of advanced colorectal carcinoma. This study evaluated the metabolism, excretion and pharmacokinetics after a single dose of 3.0 mg/m² [¹⁴C]-raltitrexed in patients with advanced solid malignancies not amenable to curative therapy. From April 1994 to July 1995, nine patients (six men and three women) were recruited into the study. Pharmacokinetics analysis was performed during the first cycle of treatment in all patients and, in two patients, limited sampling was done prior to and during the second cycle of treatment. The mean observed peak plasma concentration (C_max) was 700.6 ng/ml and the median time (t _max) to reach maximal raltitrexed concentrations was 15 min after the initiation of the infusion. After reaching C_max the drug declined in a triexponential manner with a terminal half-life of 257 h. The AUC_0–∞ as predicted by the pharmacokinetic model was 2341.7 ng h ml⁻¹. Clearance was 41.3 ml/min, of which renal clearance accounted for 50–60%. Urinary collection for the measurement of radiolabeled drug revealed that renal excretion extrapolated to infinity accounted for 40% of the total radioactive dose. Faecal excretion accounted for only 3% of the dose when samples were collected to day 5 in the first six patients. Collection was extended to 10 days in the last three patients and faecal elimination accounted for 14% in these patients. Raltitrexed measurements prior to subsequent doses suggest that there was no accumulation of the drug with repeated administration. Low levels of radioactivity measured in the red cell pellets on days 15, 22 and 29 are likely to represent drug retained by newly forming red cells at the time of dosing. Examination of the urine revealed that the drug was excreted unchanged. The toxicities seen were in line with those encountered in previous studies. Grade 3 and 4 thrombocytopenia occurred in three patients and grade 3 neutropenia occurred in two patients. Received: 29 July 1997 / Accepted: 23 October 1997     

Phase I study of the combination of docetaxel, temozolomide and cisplatin in patients with metastatic melanoma

Purpose  In a search for more effective combination chemotherapy for the treatment of metastatic melanoma, we conducted a phase I trial of a novel combination of docetaxel, temozolomide, and cisplatin. Methods  Patients with inoperable or recurrent metastatic melanoma with a Zubrod performance status of 2 or less and adequate organ function were eligible. The dose of docetaxel was escalated between cohorts of patients, and the doses of temozolomide and cisplatin were fixed. A standard 3 + 3 dose escalation design was used to determine the maximum tolerated dose (MTD). Results  Among 23 patients who were enrolled, 21 were evaluable for toxicity. Eighteen patients (78%) had stage IV-M1c disease. The dose-limiting toxicities were myelosuppression and pulmonary embolism. The MTD was 30 mg/m² docetaxel on days 1, 8, and 15 when given with 150 mg/m² temozolomide on days 1–5, and 20 mg/m² cisplatin on days 1–4, repeating every 4 weeks. Among 19 patients evaluated for response, 6 (32%) had partial responses and 5 (26%) had stable disease. Among 14 chemo-naive patients, 6 (43%) had a partial response and 4 (29%) had stable disease. Nine patients developed brain metastases by the time of the last follow-up evaluation, and the median time to brain metastases for all 19 evaluable patients has not been reached. Conclusions  This combination was well tolerated and appears to be a promising treatment for patient with metastatic melanoma. This study was supported by Sanofi-Aventis.     

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors

Purpose To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors.Methods We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m² per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling.Results The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C_max 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 g/ml·h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C_max (P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies.Conclusions This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.This work was supported in part by USPHS awards CA 23099, Cancer Center CORE grant CA21765, the Schering Plough Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

Clinical and pharmacology study of chloroquinoxaline sulfonamide given on a weekly schedule

The in vitro human tumor colony-forming assay identified chloroquinoxaline sulfonamide (CQS) as an active agent at human plasma concentrations of >100 g/ml. In the initial phase I trial of CQS given every 28 days, peak plasma concentrations >500 g/ml were associated with reversible dose-limiting hypoglycemia and occasional cardiac arrhythmias. Therefore, we evaluated whether a weekly schedule of treatment might minimize the drug-associated toxicity while maintaining potential therapeutic concentrations. CQS was given intravenously over 1 h once per week for 4 weeks to 12 patients, beginning at a dose of 2,000 mg/m². All patients underwent monitoring for cardiac arrhythmias and hypoglycemia. Plasma drug levels were measured following each dose. Mild hypoglycemia was the most common adverse effect. A median nadir plasma glucose concentration of 56 mg/dl was observed at a weekly dose of 2,500 mg/m². Two patients experienced cardiac dysrhthmia while on study. Continuous electrocardiographic monitoring failed to identify any significant infusion-related arrhythmia. The median CQS plasma concentration measured 24 h following a 2,000-mg/m² dose of CQS was >100 g/ml, and the cumulative area under the concentration x time curve (AUC) determined at concentrations of 100 g/ml was similar to that observed with the every-28-day schedule. The weekly schedule described herein appears to maximize the plasma AUC with an acceptable margin of safety. The recommended phase II dose and schedule for CQS is 2,000 mg/m² given once per week. Although severe hypoglycemia is unlikely, glucose monitoring is appropriate for 6 h following CQS administration.Presented in part at the Annual Meeting of the American Association for Cancer Research,Orlando, Florida, May 20, 1993. This work was supported in part by grant CA-05826 from the National Cancer Institute, DHHS.     

Pharmacokinetics of temozolomide in association with fotemustine in malignant melanoma and malignant glioma patients: comparison of oral, intravenous, and hepatic intra-arterial administration

Purpose: Depletion of the DNA repair enzyme O⁶-alkylguanine-DNA alkyltransferase (AT) has been shown to increase tumor sensitivity to chloroethylnitrosoureas. Temozolomide (TMZ), an analogue of dacarbazine, can deplete AT, suggesting that it may be used to sensitize tumors to chloroethylnitrosoureas. However, the influence of nitrosoureas on the pharmacokinetics of TMZ is unknown, and a pilot study was performed to assess the pharmacokinetics of TMZ given via, various routes to 29 patients (27 malignant melanomas, 2 gliomas) with or without sequential administration of i.v. fotemustine. Methods: On day 1, TMZ was given intravenously (i.v.), orally (p.o.), or by intrahepatic arterial infusion (h.i.a.) at four ascending dose levels (150 to 350 mg/m² per day). On day 2 the same dose of TMZ was given by the same route (or by another route in six patients for determination of its bioavailability), followed 4 h later by fotemustine infusion at 100 mg/m². Plasma and urinary levels of TMZ were determined on days 1 and 2 by high-performance liquid chromatography after solid-phase extraction. Results: The pharmacokinetics of i.v. TMZ appeared linear, with the area under the curve (AUC) increasing in proportion to the dose expressed in milligrams per square meter (r = 0.86 and 0.91 for days 1 and 2, respectively). The clearance after i.v. administration was 220 ± 48 and 241 ± 39 ml/min on days 1 and 2, respectively. The apparent clearance after p.o. and h.i.a. administration was 290 ± 86 and 344 ± 77 ml/min, respectively. The volume of distribution of TMZ after i.v., p.o., and h.i.a. administration was 0.4, 0.6, and 0.6 l/kg on day 1 and 0.5, 0.5, and 0.6 l/kg on day 2, respectively. The absolute bioavailability of TMZ was 0.96 ± 0.1, regardless of the sequence of the i.v.-p.o. or p.o.-i.v. administration, confirming that TMZ is not subject to a marked first-pass effect. A comparison of TMZ pharmacokinetics after i.v. and h.i.a. treatment at the same infusion rate revealed little evidence of hepatic extraction of TMZ. However, the systemic exposure to TMZ (AUC) appeared to decrease at a lower infusion rate. TMZ excreted unchanged in the urine accounted for 5.9 ± 3.4% of the dose, with low within-patient and high interpatient variability. TMZ crosses the blood-brain barrier and the concentration detected in CSF amounted to 9%, 28%, and 29% of the corresponding plasma levels (three patients). The equilibrium between plasma and ascitic fluid was reached after 2 h (assessed in one patient). Conclusion: The sequential administration of fotemustine at 4 h after TMZ treatment had no clinically relevant influence on the pharmacokinetics of TMZ. The potential clinical effect of TMZ given by h.i.a. or by locoregional administration has yet to be established, as has the impact of the infusion duration on patients' tolerance and response rate. Received: 9 March 1998 / Accepted: 2 June 1998     

Phase I trial of chloroguinoxaline sulfonamide,with correlation of its pharmacokinetics and pharmacodynamics

To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m². The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m² dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m² Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m². Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of >1,000 mg/m². The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of 1,000 mg/m², and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of 1,000 mg/m². These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged <5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak) ^H/(peak ₅₀)^H+(peak)^H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak ₅₀ is the peak total [CQS] at whichE is half-maximal (326 mg/l), andH is the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of –0.06. The recommended phase II dose of CQS is 1,000 mg/m². Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of 1,000 mg/m² would probably be tolerated better than single large doses of equivalent intensity.Abbreviations CQS Chloroquinoxaline sulfonamide - AUC area under the plasma concentration x time curve - CLTB total body clearance - MAE mean absolute error - ME mean error - DNA deoxyribonucleic acid - BCNU carmustine [N, N-bis(2-chloroethyl)-N-nitrosourea] - ECOG Eastern Cooperative Oncology Group - WBC white blood cell count - PLT platelet count - ALT alanine aminotransferase - AST aspartate aminotransferase - PT prothrombin time - PTT partial thromboplastin time - EKG electrocardiogram - D5W 5% dextrose in water - HPLC high-performance liquid chromatography - BEE basal energy expenditure This work was supported in part by contract N-01-CM-07303 awarded by the National Cancer Institute, Department of Health and Human Services. One of the authors (B.A.C.) is the recipient of American Cancer Society Clinical Oncology Career Development Award 90-127     

Leptomeningeal carcinomatosis from gastric cancer successfully treated by the intrathecal methotrexate plus temozolomide and simultaneous radiotherapy: Case report and literatures review

Leptomeningeal carcinomatosis (LMC) from gastrointestinal cancer is rare. A 56-year-old man with complaint of upper abdominal pain exhibited adenocarcinoma upon histopathologic examination of biopsy specimens. At the end of adjuvant chemotherapy, the patient was affected by hearing loss. Malignant cells were observed by cerebrospinal fluid (CSF) cytology. Therefore, the patient received intrathecal methotrexate and oral temozolomide chemotherapy and radiotherapy. The progress-free survival was approximately 11 months. To our knowledge, such cases of LMC from gastric cancer are very rare. Here, we describe the case of a patient with LMC from gastric cancer and review the literature associated with treatment. We hope that the present report may be helpful when considering how to improve treatment of LMC in gastric cancer patients and offer some tips for the adjuvant treatment modality.     

Phase I and pharmacology study of flavone acetic acid administered two or three times weekly without alkalinization

Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we performed a phase I and pharmacology study with frequent administration and no hyperhydration or alkalinization. Sixteen patients (9 men, 7 women) were given FAA as 6-h i.v. infusions 2 or 3 times a week (10 and 6 patients, respectively), at doses ranging from 2.5 to 8.1 g/m². A total of 130 doses were administered during this study. Sedation, arterial hypotension, vomiting and diarrhea were the predominant toxicities observed at the highest dose (8.1 g/m²). One patient developed severe but reversible multiple organ failure. No treatment-related deaths occurred. Pharmacokinetics was linear for the doses studied, with peak plasma levels ranging from 39 to 449 g/ml and a mean terminal half-life of 3.1 h. No drug accumulation was observed with this frequent-administration schedule. No objective response was observed. Three FAA infusions per week at 8.1 g/m² could be recommended as an optimal and tolerable schedule.Dedicated to the memory of Dr. Marcel de Forni (deceased on 10 May 1994)     

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule

Background Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.Methods Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m², respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay.Results A total of 35 patients were treated. The MTD was docetaxel 30 mg/m² plus irinotecan 65 mg/m². Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease.Conclusions The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.     

Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients

Purpose To characterize and compare pharmacokinetic parameters in children and adults treated with temozolomide (TMZ) administered for 5 days in three doses daily, and to evaluate the possible relationship between AUC values and hematologic toxicity.Methods TMZ pharmacokinetic parameters were characterized in pediatric and adult patients with primary central nervous system tumors treated with doses ranging from 120 to 200 mg/m² per day, divided into three doses daily for 5 days. Plasma levels were measured over 8 h following oral administration in a fasting state. A total of 40 courses were studied in 22 children (mean age 10 years, range 3–16 years) and in 8 adults (mean age 30 years, range 19–54 years).Results In all patients, a linear relationship was found between systemic exposure (AUC) and increasing doses of TMZ. Time to peak concentration, elimination half-life, apparent clearance and volume of distribution were not related to TMZ dose. No differences were seen among TMZ C_max, t_1/2, V_d or CL/F in children compared with adults. Intra- and interpatient variability of systemic exposure were limited in both children and adults. No statistically significant differences were found between the AUCs of children who experienced grade 4 hematologic toxicity and children who did not.Conclusions No difference appears to exist between pharmacokinetic parameters in adults and children when TMZ is administered in three doses daily. Hematologic toxicity was not related to TMZ AUC. AUC measurement does not appear to be of any use in optimizing TMZ treatment.     

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Purpose The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated. Patients and methods A dose of 40 mg/m² of S-1 was administered orally twice daily for 7 days (80 mg/m²/day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre- and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined. Results At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 ± 304 ng h/ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 ± 331, 1,070 ± 403, and 946 ± 226 ng h/ml, respectively. No significant differences for plasma 5-FU were observed between pre- and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 ± 83 ng/g around 4.5 h and 91.7 ± 37.0 ng/g around 20 h after the final administration, respectively. Conclusion Gastrectomy does not affect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.     

Pharmacokinetic study of temozolomide on a daily-for-5-days schedule in Japanese patients with relapsed malignant gliomas: first study in Asians

Background Temozolomide (TMZ) is widely used in Europe and the United States. For the safe use of TMZ in the Japanese, as representative of Asians, the pharmacokinetics of TMZ was investigated in Japanese patients and compared to that in Caucasians. Methods The pharmacokinetics and safety of TMZ following oral administration of 150 and 200 mg/m² per day for the first 5 days of a 28-day treatment cycle were investigated in six Japanese patients with relapsed gliomas. Results The time-to-maximum plasma concentration (tmax) of TMZ was about 1 h and the elimination half-life of terminal excretion phase (t_1/2λz) was about 2 h. A dose-dependent increase was observed in maximum plasma concentration (Cmax) and AUC, while values for t_1/2λz, apparent total body clearance (CL/F), and apparent distribution volume (Vz/F) were independent of dose. After administration for 5 days, changes in pharmacokinetics and accumulation were not observed. The plasma 5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide (MTIC) concentration changed in parallel with the TMZ plasma concentration, and the Cmax and AUC of MTIC were about 2% of those of TMZ. The pharmacokinetic parameters of TMZ and MTIC in Japanese patients in this study were comparable to those previously determined in Caucasian subjects. Adverse events occurred in all patients, but toxicities were mostly mild or moderate, and continuation of administration was possible by adjusting the dose and by delaying the start of the next treatment cycle. Conclusion The pharmacokinetic and safety profile of TMZ in Japanese patients was comparable to that in Caucasians. The treatment regimen used in Europe and the United States will be suitable for Asian patients, including Japanese.     

Preclinical pharmacokinetics and oral bioavailability of BMS-310705, a novel epothilone B analog

Purpose BMS-310705, a novel semisynthetic derivative of epothilone B, is a tubulin-polymerization agent currently in phase I clinical trials for anticancer therapy. The in vitro and in vivo pharmacokinetics and oral bioavailability of BMS-310705 were investigated in mice, rats, and dogs. In addition, comparison of the pharmacokinetics of BMS-310705 using various formulations was conducted in rats.Methods The permeability of BMS-310705 was evaluated in Caco-2 cells, an in vitro model of the human intestinal epithelium. Human liver microsomes were used to determine the cytochrome P450 enzymes involved in the metabolism of BMS-310705. Plasma protein binding of BMS-310705 was determined in mouse, rat, dog, and humans. BMS-310705 was administered to female nude mice as single doses of 5 mg/kg intravenously or 15 mg/kg orally. Male Sprague-Dawley rats were treated with single doses of BMS-310705 either intraarterially (2 mg/kg) or orally (8 mg/kg). The effect of Cremophor on the pharmacokinetics of BMS-310705 was evaluated in rats using various formulations with and without Cremophor. Male dogs were treated with 0.5 mg/kg intravenously or 1 mg/kg orally in a crossover study design.Results Systemic clearance of BMS-310705 was high in mice (152 ml/min/kg), rats (39 ml/min/kg), and dogs (25.7 ml/min/kg). The volume of distribution (Vss) in mice, rats, and dogs was 38, 54, and 4.7 l/kg, respectively, and greater than total body water. BMS-310705 showed moderate binding to plasma proteins in all four species tested. The clearance in humans may be intermediate to high based on both allometric scaling using parameters obtained from three species, and in vitro human liver microsomal stability data. In rats, the presence of Cremophor in the formulation resulted in a significant increase in exposure compared to buffered vehicles not containing Cremophor. Inhibition of p-glycoprotein and/or CYP3A4 by Cremophor may be responsible for this phenomenon, and studies in Caco-2 cells and human liver microsomes suggested that BMS-310705 may be a substrate for both p-glycoprotein and CYP3A4. The oral bioavailability of BMS-310705 in pH buffered formulations was 21% in mice, 34% in rats and 40% in dogs.Conclusion In summary, BMS-310705 is cleared rapidly and distributes extensively in mice, rats, and dogs. The presence of Cremophor in the formulation could significantly increase exposure in rats, possibly due to interactions with p-glycoprotein and/or CYP3A4. Oral bioavailability using formulations not containing Cremophor were found to be adequate, suggesting potential for development of BMS-310705 as an oral anticancer drug.     

Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule

Purpose: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. Methods: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m² per day to 74.7 mg/m² per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. Results: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m² dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 C_max values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and C_max values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. Conclusions: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted. Received: 24 August 1998 / Accepted: 17 December 1998     

A phase I trial of high-dose oral tamoxifen and CHOPE

Drug resistance is a common phenomenon in clinical oncology. In vitro, tamoxifen has been shown to be an effective inhibitor of P-glycoprotein and a modulator of the multidrug resistance phenotype. We have previously shown that vinblastine can be given safely in combination with tamoxifen at doses that may modulate P-glycoprotein activity. In this phase I trial, tamoxifen (150 mg/m² twice a day) was given with CHOPE (cyclophosphamide/doxorubicin/vincristine/prednisone/etoposide) in order to assess the toxicities of the combination. Resistance to three of these cytotoxic agents (doxorubicin, vincristine, and etoposide) may be mediated by P-glycoprotein. A total of 13 patients were evaluable on this trial, which showed that the maximum tolerated doses of cyclophosphamide and etoposide were 750 and 80 mg/m², respectively. The dose-limiting toxicity was myelosuppression with 50% of the patients (3/6) treated at this dose level developing febrile neutropenia and 85% (6/7) developing grade 4 neutropenia. Tamoxifen at a dose of 150 mg/m² twice a day can be given safely with the lymphoma regimen CHOPE at standard doses, but his combination may result in increased myelosuppression.Supported in part by grants 5T32-CA-09307 and P30-A-14236-18 from the National Institutes of Healthand the National Cancer Institute, the P. B. Cohen Memorial Fund, and ICI Pharmaceuticals, Inc.