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M J Ratain

Publications and source records attributed to M J Ratain.

At least 91 records · Page 5Linked to original sources
PubMed1996

Mineralocorticoid insufficiency due to suramin therapy.

BACKGROUND: During a Phase I trial of suramin, a novel antineoplastic agent with activity against hormone-refractory prostate carcinoma, the authors observed two patients with clinical mineralocorticoid insufficiency in spite of hydrocortisone replacement therapy. METHODS: The authors retrospectively assessed adrenal cortical function in 20 such patients via adrenocorticotropic stimulation testing, measuring both cortisol and aldosterone responses, either at the time or treatment of immediately after discontinuation of treatment. RESULTS: Two of 9 patients (22%) treated at relatively low dose levels (< or = 1200 mg/m2 on Day 1) demonstrated adrenal cortical insufficiency, as compared with 9 of 11 patients (32%) treated with relatively high doses (> 1200 mg/m2 on Day 1) (P = 0.03 by 1-tailed Fisher's exact test). There appeared to be a cumulative dose-response relationship to the development of glucocorticoid insufficiency, with no instances being observed at doses < 4.8 g/m2 and uniform toxicity occurring at doses > 7.6 g/m2. Long term glucocorticoid insufficiency was present in 1 of 5 patients (20%) tested at an interval of > 90 days after discontinuation of suramin treatment. All instances of glucocorticoid insufficiency were associated with mineralocorticoid insufficiency. Suramin did not affect the absorption or excretion of exogenously administered glucocorticoid in one patient. CONCLUSIONS: Suramin causes both primary mineralocorticoid and primary glucocorticoid insufficiency. This may occur in a dose-dependent manner. Long term glucocorticoid insufficiency appears to occur in a minority of patients treated with low doses of suramin. Patients receiving high doses of suramin for treatment of advanced carcinoma should receive at least physiologic replacement doses of both mineralocorticoid and glucocorticoid. Higher doses of glucocorticoid may be required in selected patients.

Addison Disease↗
PubMed1996

Phase I study of escalating doses of mitoxantrone and paclitaxel with granulocyte-macrophage colony stimulating factor support.

BACKGROUND: Both paclitaxel and mitoxantrone demonstrate significant antineoplastic activity in breast cancer patients. Colony stimulating factor support allows significant dose escalation of each of these drugs when administered as a single agent. METHODS: We performed a Phase I study employing escalating doses of paclitaxel and mitoxantrone with granulocyte-macrophage colony stimulating factor (GM-CSF) support. Initially the paclitaxel dose was fixed at 175 mg/m2 and an attempt was made to escalate mitoxantrone from the starting dose of 14 mg/m2. Subsequently, the dose of mitoxantrone was fixed at 14 mg/m2 and the dose of paclitaxel was increased. Treatments were given every three weeks. RESULTS: In neither case could we safely escalate beyond a combination of paclitaxel 175 mg/m2 and mitoxantrone 14 mg/m2 which is, therefore, the recommended Phase II dose. The dose limiting toxicity was neutropenia. No unexpected toxicities were observed, although two patients were removed from the study because of chest pain possibly related to GM-CSF. There were no complete or partial remissions. CONCLUSIONS: We conclude that GM-CSF does not allow significant dose escalation of this combination of agents.

Adult↗
PubMed1996

Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A.

The focus of this investigation was to modulate the pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G, by possibly reducing biliary excretion, which in turn could lower irinotecan toxicity. We determined the effect of a known cholestatic agent, cyclosporin A (CsA), which is transported across the bile canalicular membrane by P-glycoprotein, on the biliary excretion of irinotecan and its metabolites. Wistar rats were pretreated with 60 mg/kg CsA 5 min before an i.v. dose of irinotecan at dose levels of 6, 10, and 20 mg/kg. The control groups received irinotecan only. CsA pretreatment resulted in an average increase of 339, 361, and 192% in the area under the plasma concentration-time curve of irinotecan, SN-38, and SN-38G, respectively. Analysis of clearance (CL) of irinotecan indicated a 55 and 81% reduction in the average renal and nonrenal CLs, respectively, in the pretreated groups. The nonrenal CL, which is the primary component of irinotecan CL, includes protein and tissue binding as well as the metabolic and biliary CL of irinotecan. There was no change in the volume of distribution at steady state (indicative of unchanged binding) and in the metabolic conversion of irinotecan to SN-38 due to pretreatment. Therefore, the significant reduction in the systemic CL of irinotecan due to CsA pretreatment was primarily due to lowered biliary excretion. Studies using a photoaffinity analogue of verapamil, [125I]NAS-VP, and membrane vesicles from the multidrug-resistant cell line, MCF-7/Adr, revealed that irinotecan and metabolites had moderate interaction with P-glycoprotein. Further studies are required to determine the mechanism of inhibitory effect of CsA on the biliary excretion of irinotecan and its metabolites.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Pharmacodynamic modeling of prolonged administration of etoposide.

PURPOSE: A refined pharmacodynamic model for toxicity is necessary for successful adaptive control of the administration of an anticancer drug to avoid toxicity. We sought to establish a pharmacodynamic model of leukopenia in a 14-day administration of etoposide. METHODS: Pharmacokinetic data of 32 patients treated with etoposide infused over 14 days in a phase I study (20 patients) or in an adaptive control study (12 patients) were used to develop a model for the prediction of a leukocyte nadir count. The concentrations of both estimated unbound and total etoposide at steady state, as well as patient demographic factors, were included in linear and nonlinear models. The unbound fraction of etoposide was estimated using an equation based on serum albumin and total bilirubin. The efficacy of the models was evaluated in terms of correlation coefficient (r), mean predictive error (MPE) and root mean square error (RMSE). RESULTS: For both total and unbound drug concentration, a nonlinear model predicted leukopenia more precisely and with less bias than a linear model, and unbound drug explained more variability of leukopenia than total drug concentration in both linear and nonlinear models. The best model was a nonlinear model with three variables of unbound concentration, pretreatment leukocyte count and prior treatment (r = 0.76, MPE +/- SEM = 0.07 +/- 0.17 x 10(3)/microl, RMSE = 0.95 x 10(3) microl), which was better than the best linear model. CONCLUSIONS: The nonlinear model using unbound etoposide concentration explained the interpatient variability of leukocyte nadir count to a fairly large extent. Although the model provided useful information on the pharmacodynamics of etoposide, it was still imprecise and a more refined model is necessary for application to an adaptive control study.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Etoposide combined with interferon alfa-2b: novel exploitation of established etoposide pharmacokinetics and pharmacodynamics.

PURPOSE: To construct an efficient pilot study design to determine whether interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of continuous-infusion etoposide. PATIENTS AND METHODS: A two-stage randomized 2 X 2 factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10 MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide. RESULTS: Based on 29 patients, dose-normalized 24-hour total and estimated free etoposide concentrations did not differ with interferon alfa-2b dose or schedule. Patients treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545 +/- 225 cells microliter lower than that predicted by a pharmacodynamic model for etoposide alone. An optimal nonlinear model for leukopenia was defined by interferon alfa-2b schedule in addition to 24-hour etoposide concentration. CONCLUSION: A novel study design and statistical analysis provided an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation of a previously validated pharmacodynamic model allowed evaluation of interferon alfa-2b effect and eliminated the need for an etoposide-alone control arm. The pharmacokinetics of continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be unchanged by interferon alfa-2b at the doses and schedules tested and the combination appears to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a higher dose of interferon alfa-2b.

Adult↗
PubMed1996

Promising new agents in oncologic treatment.

Over the past year, several new anticancer agents have entered the clinic and are undergoing further phase II clinical development at the time of this writing. There has been a sudden influx of rationally designed drugs with novel therapeutic effects ranging from direct cellular toxicity to inhibition of blood vessel formation and of metastases. This review focuses only on cytotoxic drugs that have been in clinical development for the past 5 years; however, only recently have these drugs found a "niche" in the clinic. These drugs include novel taxanes (eg, docetaxel), the camptothecin analogues (eg, irinotecan [CPT-11]), the newer generation of thymidylate synthase inhibitors (eg, raltitrexed [ZD 1694, Tomudex]), nucleoside analogues (eg, gemcitabine), and oral alternatives to intravenous 5-fluorouracil. Most of these agents have completed or have entered phase II or III testing, and the results of these trials will be available to us over the next few years.

Animals↗
PubMed1996

Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.

Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.

Acetylation↗
PubMed1996

Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies.

PURPOSE: The optimal dose and schedule for cladribine (2CdA) therapy of malignant hematologic diseases have not been determined. This dose-escalation study was designed to assess toxicity when 2CdA is given using five daily 1-hour intravenous infusions. PATIENTS AND METHODS: Forty-two adults with advanced hematologic malignancies were treated in one of nine cohorts, starting at 2.5 mg/m2/d for 5 days. Plasma drug concentrations were measured by high-performance liquid chromatography. Responses were assessed by bone marrow biopsy on day 15 of the first course and by clinical measurements after each course. Patients received one to four courses each. RESULTS: Nonhematologic toxicity was mild, and dose-limiting nonhematologic toxicity was not observed, even at the highest dose level of 21.5 mg/m2/d. In particular, neurotoxicity was not observed. The maximum-tolerated dose (MTD) was not identified. However, prolonged cytopenias and severe infections were more common in the higher 2CdA dose cohorts. Logistic regression analysis suggested that severe hematologic toxicity was associated with pretreatment platelet count and performance status (PS). Good-risk patients were identified as having a PS of 0 and platelet count > or = 80,000/microL, PS of 1 and platelet count > or = 120,000/microL, or PS of 2 and platelet count > or = 160,000/microL. Sustained complete responses (CRs) and partial responses (PRs) were observed in eight patients. CONCLUSION: 2CdA can be administered using five daily 1-hour infusions at 21.5 mg/m2/d without dose-limiting nonhematologic toxicity. Unlike continuous intravenous infusions, neurotoxicity was not observed using this schedule. Further dose escalation may be possible in good PS patients with adequate platelet counts.

Adult↗
PubMed1996

Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.

PURPOSE AND METHODS: To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells. RESULTS: Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found. CONCLUSION: L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.

Adolescent↗
PubMed1996

Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity.

PURPOSE: To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures. MATERIALS AND METHODS: The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT-11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15). RESULTS: LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN-38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005). CONCLUSION: These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Limited sampling model for area under the concentration time curve of total topotecan.

Antitumor activity of topotecan, a new derivative of camptothecin, has been documented in many tumors. The active lactone form of topotecan is in equilibrium with the inactive hydroxyacid form. However, dose-limiting toxicity, neutropenia, is correlated to the area under the concentration time curve (AUC) of not only the lactone form but also total (lactone + hydroxyacid) topotecan. Because the determination of the total topotecan plasma concentration is technically much easier than the lactone, we sought to establish a limited sampling model for the AUC of total topotecan. Thirty-four pharmacokinetic profiles were obtained in 19 patients in a Phase I study of topotecan, which was infused over 30 min for 5 days. Multiple regression models predicting the AUC were developed using 17 profiles and validated using the rest of the data. The best model was: AUCpred (ng x h/ml) = 1.75 x C15m (ng/ml) + 11.2 x C6h (ng/ml) + 7.90 x dose (mg/m2), where AUCpred was the AUC predicted by the model, and C15m and C6h were the measured concentrations of total topotecan at 15 min and 6 h after the end of infusion, respectively. When this model was validated, it was unbiased (percentage of mean predicted error +/- SE, -1.0 +/- 3.3%) and precise (percentage of root mean square error, 11%). Because this model requires only two concentrations of total topotecan to estimate the AUC, it will be useful for further pharmacodynamic evaluation of topotecan in multi-institutional studies.

Antineoplastic Agents↗
PubMed1995

Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies.

Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies. Hepsulfam was administered as a 30-min or 2-h intravenous infusion to 21 patients with advanced leukemia or multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous hepsulfam was severe encephalopathy. The single patient treated at 800 mg/m2 became comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter encephalopathy. When hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of hepsulfam so that the drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory leukemia. The dose-limiting toxicity is CNS toxicity with increasingly severe encephalopathy at doses > or = 640 mg/m2. It would be reasonable to investigate further dose escalation of hepsulfam in a divided dose schedule to minimize the peak concentrations which may be related to the encephalopathy. EEG monitoring is recommended for early detection of slowing of alpha rhythm waves. Hematopoietic stem cell support will probably be required at total doses exceeding 800 mg/m2.

Adult↗
PubMed1995

A population model for the leukopenic effect of etoposide.

We present a new model-dependent approach to quantify hematologic toxicity in a patient population after anticancer therapy. The population model consists of three submodels that are simultaneously fit to the data: (1) a cubic spline function describing the average response of the population versus time ("structural model"), (2) a covariate model, which relates parameters of the structural model to measured demographic or therapeutic variables that are found to be of predictive value (in this study: white blood cell (WBC) count baseline, drug concentration, serum albumin, and serum bilirubin concentration), and (3) a variance model, which estimates the contribution to the response from random variability between patients and from variability within patients, both between courses and within courses, between days. To demonstrate the approach, previously reported data from 118 courses of etoposide therapy in 71 patients with cancer were used to model the decrease in WBC count after 3-day continuous infusions of drug. The estimated typical response profile is characterized by (1) a lag-time of 4 1/2 days before any WBC count decline is observed, (2) a duration of time below baseline of 22 days, and (3) half-maximal effect (i.e., decrease to 50% of baseline WBC count) after exposure to C50 = 3 mg/L etoposide (mean) over 3 days. Lower serum albumin concentrations, higher bilirubin concentrations, or both are associated with greater effects at a given etoposide exposure. Large variability in the estimated response was found between individuals and within individuals, between courses. The total variabilities (SD) in lag-time, duration of the decrease, and C50 were 1 day, 6 days, and 1.8 mg/L, respectively. The population model can also be used to predict the consequence of as-yet untested therapy and sampling strategies, as well as to relate acceptable risks of toxicity to target drug exposure.

Adult↗
PubMed1995

Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.

PURPOSE: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS: The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P < or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION: The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.

Acetylation↗