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Biomedical subjects

M J Ratain

Publications and source records attributed to M J Ratain.

At least 163 records · Page 9Linked to original sources
PubMed1990

Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration.

The clinical formulation of leucovorin calcium (leucovorin, LV) is a mixture of stereoisomers [(6R,S)-5-formyltetrahydrofolate], which have been shown to differ significantly in plasma clearance and route of elimination after intravenous administration; the (6S) isomer is rapidly converted to 5-CH3 tetrahydrofolate (5-CH3 THF), and the (6R) isomer is slowly eliminated by renal excretion. The relative importance of (6S) LV and 5-CH3 THF in expanding reduced folate pools in tumor cells is unknown, but it is known that high concentrations of (6R) LV can support growth of folate-depleted cells and thus have the potential to interfere with the biological activity of the (6S) isomer. To examine the pharmacokinetics of the LV isomers and metabolites, we administered 1,000 mg of LV to five normal subjects as a 2-hour intravenous infusion and in divided oral 100-mg doses given over 24 hours. Plasma and urine samples were analyzed by reverse phase followed by chiral high-performance liquid chromatography. Following intravenous administration, peak plasma concentrations of (6R) LV, (6S) LV, and 5-CH3 THF were 148 +/- 32, 59.1 +/- 22, and 17.8 +/- 17 microM, respectively. During oral administration of LV, virtually no (6S) LV appeared in the plasma. Steady-state plasma concentrations of (6R) LV and 5-CH3 THF were approximately 1.5 +/- 0.23 and 2.8 +/- 0.41 microM, respectively. Intravenous administration of LV resulted in an area under the curve (AUC) for (6R) LV that was more than four times that of the biologically active (6S) folates, whereas oral administration produced an AUC for (6S) reduced folates [(6S) LV and 5-CH3 THF] that was approximately twice that of (6R) LV. After administration of high doses of LV intravenously, conversion of (6S) LV to 5-CH3 THF was saturable, as indicated by the prolonged (6S) LV half-life of 58 minutes and the slow (6S) LV clearance of 119.2 +/- 38 mL/min, compared with previously reported data for administration of low doses. This study illustrates that intravenous administration of LV produces equivalent AUCs of (6S) LV and 5-CH3 THF but a substantially higher AUC for (6R) LV. Oral administration over 24 hours results in an AUC of 5-CH3 THF equivalent to that obtained after intravenous dosing in the presence of only small amounts of (6R) LV. The optimal route of LV administration will ultimately be determined by ongoing studies of the cellular pharmacology of LV that will determine if high concentrations of (6R) LV interfere with the biological activity of the (6S) reduced folates.

Administration, Oral↗
PubMed1990

Pharmacodynamics in cancer therapy.

Our understanding of anticancer pharmacodynamics, and the relationships between pharmacologic measurements and clinical effects, has grown markedly in recent years due to advances in analytical and computational technology. Although methotrexate plasma levels have been empirically used to guide leucovorin dosing during high-dose methotrexate therapy, there has been no other standard use of therapeutic drug monitoring in oncology. More recently, investigators have attempted to titrate precisely the dose of antineoplastic agents based on previously derived models and real-time analysis of plasma drug or tissue concentrations. Studies have been completed or are in progress using hexamethylene bisacetamide, etoposide, teniposide, fluorouracil (FUra), and cytarabine (ara-C). Future studies will focus on optimal sampling strategies, analysis of intermediate biochemical end points, combination chemotherapy, modulation by colony-stimulating factors, and more sophisticated pharmacodynamic models.

Antineoplastic Agents↗
PubMed1990

Hairy cell leukemia. Current management.

The long-term outlook for patients with HCL has brightened over the last 5 years with the development of two highly effective systemic therapies, pentostatin and alpha-interferon. Pentostatin can induce complete responses in over 75 per cent of patients and may offer cure in this disease. Splenectomy continues to have a role as first-line therapy in selected patients in whom it may offer a median remission duration of over 5 years. Alpha-interferon is the treatment of choice for patients requiring initial systemic therapy and can be used intermittently to re-induce remission in patients with disease progression off therapy. Outside of clinical trials pentostatin should be utilized only in appropriately selected patients refractory to interferon therapy.

Bone Marrow↗
PubMed1989

Low-dose interferon alfa-2b in the treatment of hairy cell leukemia.

Twenty-two patients with hairy cell leukemia were treated with low-dose interferon alfa-2b (0.2 X 10(6) U/m2 given three times weekly) for 6-12 months. The overall response rate was 54%, with only 18% complete plus partial responses. The therapy had to be terminated early in five of these patients because their progressive disease led to severe cytopenia. Although the toxic effects with this regimen were minimal, the significantly lower response rate and the poorer quality of the responses prohibit its use as initial therapy in hairy cell leukemia.

Adult↗
PubMed1989

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.

Cyclophosphamide↗
PubMed1989

Plasma pharmacokinetics of high-dose oral melphalan in patients treated with trialkylator chemotherapy and autologous bone marrow reinfusion.

The pharmacokinetics of melphalan following high-dose p.o. administration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days -7, -6, and -5, melphalan was given p.o. and the dose was escalated on each cohort consisting of at least 3 patients (beginning at 0.75 mg/kg). On days -6, -4, and -2, cyclophosphamide at 2.5 g/m2 and thiotepa at 225 mg/m2 were given i.v. On day -7 the peak melphalan concentration was 1.64 +/- 0.89 (SD) microM with a terminal half-life of 1.56 +/- 0.86 h. The area under the plasma concentration time curve (AUC) and oral clearance were 217.9 +/- 115.1 microM/min and 30.2 +/- 14.2 ml/min/kg. There was only a moderate correlation between the melphalan dose and both the peak concentration (r = 0.50, P less than 0.05) and AUC (r = 0.64, P less than 0.01) over the dosage range of 0.75-2.5 mg/kg. There was a trend towards greater interpatient variability in peak concentration, AUC, and oral clearance observed at the higher doses of melphalan. Analysis of intrapatient pharmacokinetic variability in 8 patients showed a significant difference between the doses given on days -7 and -5 in the peak concentration (2.09 versus 1.07 microM, P = 0.02), AUC (264.9 versus 134.8 microM/min, P = 0.01), and oral clearance (25.1 versus 53.1 ml/min/kg, P = 0.05) but no significant difference in the time to peak and terminal half-life. We conclude that there is marked interpatient and intrapatient variability in melphalan pharmacokinetics following high-dose p.o. administration. The data are consistent with saturable absorptive pathways for melphalan, which might be especially sensitive to concurrent high-dose chemotherapy.

Absorption↗
PubMed1989

A randomized study of inpatient versus outpatient continuous infusion chemotherapy for patients with locally advanced head and neck cancer.

This study was designed to evaluate the safety, reliability, and patient acceptance of outpatient continuous intravenous infusion (CVI) chemotherapy. Twenty-two patients with locally advanced head and neck cancer received induction chemotherapy with methotrexate, cisplatin and a 5-day CVI of 5-fluorouracil (5-FU). Patients were randomized to receive the 5-FU portion of cycle 1 either by a standard inpatient CVI chemotherapy delivery device (standard pump) or by the Infusor (Baxter Healthcare Corporation, Deerfield, IL), a portable chemotherapy delivery system that provides a constant flow of drug over a period of 24 hours. For cycle 2, patients crossed over to the alternative drug delivery method. Patients receiving chemotherapy via the Infusor could choose to be either inpatients or outpatients. Daily plasma concentrations of 5-FU were determined during the first two cycles of chemotherapy. There was no significant difference in the mean steady state plasma 5-FU levels achieved with either drug delivery method (329.7 +/- 95.8 ng/ml for infusor cycles vs. 352.8 +/- 114.9 ng/ml for standard pump cycles). Clinical toxicities consisted primarily of mucositis for both methods of drug delivery. Eight patients declined to receive CVI chemotherapy as outpatients citing as reasons fear of malfunction of the device, inconvenience of the frequent clinic visits necessitated by daily monitoring of plasma 5-FU concentrations, and restrictions in daily home activities. Eleven patients underwent CVI chemotherapy via Infusor as outpatients. All reported outpatient CVI chemotherapy as convenient and effective and, when eligible, chose it again in subsequent cycles. A comparison of estimated costs revealed reductions in daily costs of +366.00 (+2,200.00 per cycle) for outpatient chemotherapy. Outpatient CVI chemotherapy is a reliable drug delivery method that was accepted by a majority of patients in this study. These factors may help to establish outpatient CVI chemotherapy as a viable alternative to hospitalization.

Ambulatory Care↗
PubMed1989

Conservative management of primary cervical lymphoma using combination chemotherapy: a case report.

A 22-year-old nulligravida presented with a stage IE/IIIB primary malignant lymphoma of the cervix which measured 8 cm in diameter. In order to preserve reproductive potential, a 12-week course of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin was administered. One month later a 4-cm-diameter left parametrial mass was excised at laparotomy; no tumor was detected in the specimens obtained. Menses resumed after an additional 6 months. The patient was clinically disease-free at the 33-month follow-up.

Adult↗
PubMed1989

Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability.

We sought to use a previously derived pharmacodynamic model for 72-hour etoposide infusions to adaptively control administration of this agent and to demonstrate that more predictable toxicity could be obtained with this dosing scheme. A randomized crossover study design was used to compare "standard" dosing (125 mg/m2/day) to adaptive control, with dose adjustment at 28 hours based on the 24-hour plasma level. A total of 31 patients received 86 cycles of chemotherapy, 36 by standard dosing and 50 by adaptive control. However, there was no demonstrable advantage to the adaptive control scheme, because of apparent bias of the previous model. A new model was proposed that also included serum albumin, performance status, and prior RBC transfusions as measures of interpatient pharmacodynamic variability. We conclude that adaptive control dosing of etoposide is feasible but that the therapy must be individualized for both pharmacokinetic and pharmacodynamic variability.

Algorithms↗
PubMed1989

Pharmacokinetics and pharmacodynamics of long-term continuous-infusion doxorubicin.

Steady-state plasma levels of doxorubicin and doxorubicinol were analyzed in 32 patients with advanced cancer, each of whom was given doxorubicin by long-term continuous infusion at progressively increasing infusion rates. Patients received doxorubicin for 2 to 50 weeks at rates of 0.2 to 6.1 mg/m2/day. Dose-limiting stomatitis and leukopenia were observed. The mean maximum steady-state doxorubicin concentration was 6.04 ng/ml at a mean maximum infusion rate of 3.92 mg/m2/day. Clearance mechanisms did not appear to be saturated at the durations or infusion rates used in this study. The maximum steady-state doxorubicin level and the ln (initial WBC) were significant correlates of the ln (nadir WBC) (p = 0.002 and 0.02, respectively). A model was constructed according to these two parameters that significantly describes ln (nadir WBC) (p = 0.001). Neither age, infusion rate, nor doxorubicinol level correlated with nadir WBC. Stomatitis did not correlate with any of these parameters. The demonstration of this pharmacodynamic relationship highlights the potential importance of pharmacologic data collection in ongoing attempts to predict the clinical effects of anticancer drugs.

Adult↗
PubMed1988

Prognostic variables in hairy cell leukemia after splenectomy as initial therapy.

Splenectomy has been used as initial therapy in hairy cell leukemia (HCL) for many years and usually causes rapid improvement in peripheral blood counts. However, most patients eventually require further therapy. We have analyzed the case histories of 194 patients with HCL who had splenectomy as initial therapy. The median time to failure (second therapy or death) was 18.8 months. Univariate analysis of prognostic variables demonstrated that age, hemoglobin level, platelet count, bone marrow cellularity, bone marrow hairy cells, and hairy cell index (HCI) were statistically significant predictors of failure-free survival (FFS). However, only the bone marrow cellularity and platelet count were significant independent prognostic variables by Cox analysis. The patients were divided into the following three subsets by prognosis after splenectomy: (1) low risk of failure (cellularity less than 85% and platelet count greater than or equal to 60,000/microliters), (2) intermediate risk (cellularity less than 85% and platelet count less than 60,000/microliters), and (3) high risk (cellularity greater than or equal to 85%). The median FFS for each of these subsets was 56.5 months, 11.7 months, and 5.4 months, respectively. The median overall survival after splenectomy has not been reached with follow-up of up to 22 years. Patients diagnosed since 1982 have a better overall prognosis than those diagnosed earlier, with 4-year survivals of 88% and 68%, respectively (P less than 0.01). We conclude that splenectomy should continue to be the standard initial therapy in HCL. However, patients with bone marrow cellularity of 85% or greater have a short duration of response to splenectomy, and thus, may be considered for initial systemic therapy.

Adult↗
PubMed1988

Hydroxyurea and etoposide: in vitro synergy and phase I clinical trial.

L1210 murine leukemia cells were treated with hydroxyurea (10-200 microM) for 24 hours and/or etoposide (0.17-3.4 microM) for 2 hours. Combination treatments used a fixed molar hydroxyurea:etoposide ratio of 58.9:1, and drug-drug interactions were quantitated according to the median effect principle. Hydroxyurea and etoposide were antagonistic at low doses at which the survival fraction was greater than 0.5 and synergistic at higher doses at which the survival fraction was less than 0.25. In a phase I clinical trial, 19 patients were treated with the two drugs at one of three dose levels. The dose-limiting toxic effect was myelosuppression. Doses of 100 mg of etoposide/m2 per day by continuous infusion and 500 mg of hydroxyurea orally every 4 hours, both for 3 days, are recommended for phase II trials.

Adult↗
PubMed1988

Limited sampling models for amonafide (NSC 308847) pharmacokinetics.

The limited sampling model (LSM) offers a means of estimating the area under the concentration-time curve (AUC) from only two timed plasma concentrations. In this study, pharmacokinetic profiles were simulated for 23 patients treated with amonafide, using each patient's individual pharmacokinetic parameters. Data were simulated for a dose of 250 mg/m2 administered over 1 h. The initial 15 patients formed the training data set. Based on the training data set, five different LSMs were generated, with the multiple r ranging from 0.92 to 0.98. A single model was selected as optimal: AUC (micrograms min/ml) = 292.9 (min) C45 (micrograms/ml) + 3262 (min) C1440 (micrograms/ml) + 21.8 (micrograms min/ml) dose (mg/m2)/250 mg/m2 where C45 = 45-min plasma concentration and C1440 = 24-h plasma concentration. This model was revalidated on a second test data set of seven patients actually treated with a 1-h infusion. The relative root mean square predictive error was 15.8%, acceptable for most clinical uses. We conclude that the LSM is a powerful tool for estimation of the AUC in a large patient population. The LSM may facilitate population pharmacodynamic studies in conjunction with Phase II trials.

Adenine↗
PubMed1988

Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia.

Several previous studies have demonstrated that both partially purified and recombinant alpha-interferons (alpha-IFNs) have high response rates in advanced hairy cell leukemia. However, the optimal dose and duration of therapy have not yet been defined. In this study, 90 patients were randomized after 12 months of IFN alfa-2b therapy with a standard dose of 2 X 10(6) U/m2 sc three times weekly to either no further therapy or an additional 6 months of therapy (18 mo total). There was no significant difference in the peripheral blood cell counts between the two groups (when analyzed) dating from the end of IFN therapy rather than from the time of randomization. Eighteen evaluable patients relapsed and were re-treated with IFN: 11 in the no-further-therapy group and 7 in the treated group. No patient was resistant to re-treatment with IFN. There was a significantly greater incidence of fatigue in the treated group (44% vs. 21%; P = .02) during the first 6 postrandomization months. We conclude that the duration of IFN therapy does not influence the clinical course after therapy is discontinued, but responses are maintained while patients receive therapy. However, because of a high incidence of fatigue with prolonged therapy and the ability to reinduce a second response, we recommend that IFN therapy be discontinued after 12 months in asymptomatic patients.

Clinical Trials as Topic↗