Search PubMed⌕ Search

Biomedical subjects

J H Rodman

Publications and source records attributed to J H Rodman.

At least 37 records · Page 2Linked to original sources
PubMed1993

Targeting the systemic exposure of teniposide in the population and the individual using a stochastic therapeutic objective.

A stochastic control approach for dose regimen design is developed and applied to the problem of targeting the systemic exposure, defined as the area under the blood concentration-time curve (AUC), of the anticancer drug teniposide in both the population and individual patients. The control objective involves maximizing the probability that AUC is within a selected target interval given either the population distribution for the kinetic model parameters (a priori control) or the posterior distribution for an individual patient (feedback control). Results of a detailed simulation study are presented, illustrating the feasibility of applying stochastic control principles to the design of dose regimens. The predictive ability of the calculated distributions of AUC for the population and for individuals is evaluated in part by determining the percentage coverage of the computed 95% uncertainty intervals using the simulation results. For the a priori control phase, 94% of the simulated subjects had values of systemic exposure within the computed 95% uncertainty interval, while 93.4% of the simulated subjects had feedback control phase systemic exposure values within their computed 95% uncertainty intervals. Similar evaluation of the uncertainty intervals calculated for plasma concentrations further document the ability of the proposed stochastic control method to predict the uncertainty associated with future therapy.

Drug Monitoring↗
PubMed1993

Pharmacokinetics and acute renal effects of continuously infused carboplatin.

Carboplatin was given as a 24-hour infusion at high doses to pediatric patients with cancer (n = 11) and pharmacokinetic parameters and renal effects were determined. Median carboplatin clearance for course 1 (151 ml/min per 1.73 m2;) was not significantly different from clearance for course 2 (144 ml/min per 1.73 m2; p = 0.33). The median glomerular filtration rate measured before (159 ml/min per 1.73 m2) and after course 1 (161 ml/min per 1.73 m2) did not differ significantly (p = 0.4). Binding was time dependent but modest with a median free fraction at the end of infusion of 0.82. Pharmacokinetic parameters for continuous-infusion carboplatin are similar to those reported for short infusions, but the median dose of 817 mg/m2 required to achieve an acceptable systemic exposure in these patients was 45% greater than the previously suggested maximum tolerated dosage. Continuous infusion carboplatin did not alter carboplatin clearance or adversely effect glomerular filtration rate during a second course, showing the feasibility of this alternative dosage strategy to enhance therapeutic effects.

Adolescent↗
PubMed1993

Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients.

PURPOSE: The primary objective for this study was to determine whether controlling pharmacokinetic variability, by designing patient-specific dosage regimens for teniposide using a Bayesian estimation control strategy, would permit an increase in dose intensity without increased toxicity. PATIENTS AND METHODS: Twenty patients with relapsed acute lymphocytic leukemia were given teniposide as part of their induction and maintenance therapy. Before beginning reinduction therapy, an intensive pharmacokinetic study was performed based on 12 measured teniposide plasma concentrations. Doses were determined to achieve a targeted systemic exposure defined by an area under the plasma concentration time curve (AUC) beginning at an AUC consistent with that predicted for a patient with average pharmacokinetic parameters receiving the currently accepted maximal-tolerated dose. The targeted systemic exposure was then escalated in increments of 25% in cohorts of at least three patients until unacceptable toxicity occurred. In 36 follow-up studies, when teniposide was administered during maintenance therapy, a Bayesian strategy based on only three or five measured drug concentrations was evaluated for precision and bias for achieving the targeted systemic exposure against the full pharmacokinetic study. RESULTS: Teniposide clearance varied over a fivefold range (3.7 to 21.6 mL/min/m2). With the use of the patient-specific dosage regimens, the intensity of systemic exposure was increased 50% (1,656 mumol.h v 1,060 mumol/L.h) over that previously possible with standard fixed doses, with no increase in acute, nonhematologic toxicity. Teniposide concentrations (n = 265) were well predicted (R2 = .82) with as few as three measured values from the initial study. CONCLUSION: Targeting systemic exposure is clinically feasible, precise, and allows increased dose intensity for teniposide without increased risk of acute, nonhematologic toxicity, when compared with fixed-dose regimens.

Adolescent↗
PubMed1993

Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children.

Pharmacokinetic variability in children with cancer is substantial and confounds drawing conclusions regarding optimal therapy based only on dose-response relationships. Careful pharmacokinetic studies performed during drug development in conjunction with an assessment of patient characteristics, such as age, renal and hepatic function, and concomitant therapy, is essential for defining those factors that may alter drug disposition. By integrating pharmacokinetic studies with measures of efficacy and toxicity, a pharmacodynamic framework can be established for guiding therapy to minimize differences in systemic exposure among subpopulations of patients (eg, impaired renal function and neonates). In selected instances when pharmacokinetic variability cannot be predicted by patient covariates, the potential for individualizing dosages based on patient-specific pharmacokinetic parameters is now a clinically feasible option. The need for and benefits of incorporating such strategies into routine therapy represents an exciting area for further clinical research.

Adult↗
PubMed1992

Pharmacokinetics of subcutaneous recombinant human granulocyte colony-stimulating factor in children.

Fifteen children (age 1.2 to 9.4 years) with advanced neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide, cisplatin, doxorubicin) followed by 5 (n = 5), 10 (n = 5), or 15 (n = 5) micrograms/kg recombinant granulocyte colony-stimulating factor (rG-CSF) subcutaneously (SC) once daily for 10 days, starting the day after chemotherapy. Serial serum samples obtained on days 1 and 10 were analyzed for G-CSF activity by a specific proliferation assay using NFS-60 cells. G-CSF serum concentration-time data were best described by a one-compartment model, with zero-order absorption and first-order elimination. After SC injection, absorption was prolonged, with peak concentrations of G-CSF (3 to 117 ng/mL) being reached after 4 to 12 hours. The relatively slow absorption, with a mean elimination half-life of 5.8 hours on day 1 and 4.5 hours on day 10, provided measurable G-CSF concentrations for the entire 24-hour dosing interval in all patients at each dosage level. The median apparent clearance of G-CSF on day 10 was significantly higher than on day 1 (0.57 v 0.31 mL/min/kg, P = .02), and was positively correlated with the absolute neutrophil count (ANC) (r2 = .33, P = .003). Systemic exposure to G-CSF was dose-related, but interpatient pharmacokinetic variability yielded overlap in area under the concentration-time curve (AUC) at all three dosage levels. Stepwise regression analysis showed that G-CSF AUC could be predicted by a model that includes rG-CSF dosage and ANC on the day of administration (r2 = .82, P = .0001).

Absorption↗
PubMed1992

The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer.

Carboplatin disposition was studied in 18 pediatric patients with cancer over a dosage range of 400 to 700 mg/m2 given on an alternate-day schedule (total doses of 1200 to 2100 mg/m2) with high-dose etoposide. Median age was 7.7 years, hepatic functions were normal, and serum creatinine levels were less than or equal to 1.0 mg/dl. Carboplatin pharmacokinetics were determined by atomic absorption spectroscopy. Median pharmacokinetic parameters for ultrafilterable platinum were as follows: clearance 45.8 ml/min/m2 (range, 25.5 to 65.3 ml/min/m2) and a terminal half-life of 3.6 hours (range, 2.1 to 14.2 hours). Carboplatin clearance (CL) values and volume of distribution (VC) were highly correlated to body size (CL = 55 x Body surface area in [BSA, in square meters] - 6.7, r2 = 0.73; VC = 5 x BSA [in square meters] + 0.26, r2 = 0.69). However, carboplatin doses normalized to BSA still resulted in twofold to threefold variability in area under the concentration-time curve. Carboplatin CL was significantly lower in those subjects (n = 9) who had previously received cumulative cisplatin doses of greater than or equal to 960 mg/m2 (p less than 0.05) but was not influenced by age, gender, or diagnosis.

Adolescent↗
PubMed1992

Increased teniposide clearance with concomitant anticonvulsant therapy.

PURPOSE: A possible pharmacokinetic interaction between teniposide and anticonvulsant medications was evaluated in pediatric patients. PATIENTS AND METHODS: The systemic clearance of teniposide was determined in six pediatric patients with acute lymphocytic leukemia receiving concomitant therapy with anticonvulsants. Clearance was then compared with a control group of patients treated with the same protocol therapy and matched for age at diagnosis, sex, and race but not receiving anticonvulsants or other agents known to induce hepatic metabolism or alter protein binding of drugs. Eight blood samples were obtained during and after 4-hour infusions of teniposide, and plasma concentrations were measured by a specific high-performance liquid chromatography (HPLC) assay. A two-compartment model was fitted to each subject's data. RESULTS: The mean systemic clearance (range) for the six anticonvulsant-treated patients studied during 22 courses of therapy was 32 mL/min/m2 (range, 21 to 54 mL/min/m2), significantly higher (P less than .001) than the mean value of 13 mL/min/m2 (range, 7 to 17 mL/min/m2) for the control patients studied during 26 courses of therapy. Clearance estimates for control patients were similar to previously published values for pediatric patients. CONCLUSION: These data indicate that the systemic clearance of teniposide is consistently increased two- to three-fold by concomitant phenobarbital or phenytoin therapy. The consequent substantial reduction in systemic exposure may reduce teniposide's efficacy.

Adolescent↗
PubMed1992

Disposition of antineoplastic agents in the very young child.

Maturation of physiologic process which govern the disposition of pharmacologic agents can yield significant changes in absorption, distribution, metabolism, and elimination of drugs in neonates, infants and children. However, there are very little data concerning the disposition of anticancer drugs in young children. Pharmacokinetic data for six anticancer agents were compared in infants less than 1 year of age and children greater than 1 year of age treated at St Jude Children's Research Hospital. No pharmacokinetic data were available for infants less than 2 months of age. Median methotrexate clearance tended to be lower in four infants (0.26-0.99 years) vs 108 children (1-19 years): 80 vs 103 ml min-1 m-2, respectively (P = 0.01). There was no difference in the median 42 h methotrexate concentration. Teniposide systemic clearance and terminal half-life and cytarabine systemic clearance were not different between the two groups. There was no significant difference in etoposide systemic clearance when normalised to body surface area (ml min-1 m-2), however a significantly lower systemic clearance relative to body weight (ml min-1 kg-1) was observed in two infants, 0.5 to 1 year of age, vs 23 children, 3-18 years of age. Doxorubicin systemic clearance was not significantly different between the two groups when systemic clearance was expressed in ml min-1 kg-1. However, there was a trend toward a lower rate of systemic clearance in ml min-1 m-2 in infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1992

Variability in teniposide plasma protein binding is correlated with serum albumin concentrations.

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (greater than 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p less than 0.014), and decreased further during intensive postremission therapy containing L-asparaginase (mean = 3.2; p less than 0.05). For all 18 patients, a significant negative correlation (r2 = 0.667; p less than 0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.

Adolescent↗
PubMed1992

Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia.

Teniposide, a widely used investigational anticancer drug, is extensively bound to plasma proteins (greater than 95%). The present study evaluated the clearance and pharmacodynamics of total and unbound teniposide in patients with acute lymphocytic leukemia who were either in first complete remission or who had relapsed and achieved a subsequent complete remission. When compared to values of patients in first remission, the mean total systemic clearance of teniposide in relapsed patients was significantly lower at the time remission reinduction therapy was initiated, but increased to values greater than first remission patients after a subsequent remission was achieved. However, the mean clearance of unbound teniposide (ml/min/m2) was 3-fold lower in relapsed patients during reinduction therapy (1224 vs. 4261, P less than .0001), and improved but remained low after these patients achieved a subsequent remission (1965, P = .025). Changes in plasma protein binding accounted for the increase in total clearance when unbound clearance decreased. Continuous therapy with L-asparaginase was the major treatment difference in those patients with hypoalbuminemia and lower clearance of unbound teniposide. In 15 evaluable patients in complete remission, there was a statistically significant (P = .039) linear correlation between the percentage decrease in white blood cell count and the systemic exposure (AUC) to unbound teniposide, with higher exposure associated with a greater decrease in white blood cell count. There was not a significant correlation between the percent decrease in white blood cell count and the dosage given or the systemic exposure to total teniposide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia.

The incidence, clinical characteristics, and outcome of hypersensitivity reactions to teniposide (VM-26), etoposide (VP-16), or both were determined in 108 children with acute lymphoblastic leukemia (ALL) treated with a contemporary regimen of intensive multiagent chemotherapy. Fifty (46%) of the 108 patients had one or more hypersensitivity reactions. The risk of any child having an initial reaction over the cumulative dose range studied was 52% (95% confidence limits, 41% and 63%) for VM-26, compared with 34% (95% confidence limits, 24% and 44%) for VP-16. The risk of having an initial reaction to VM-26 or VP-16 was clearly related to the cumulative dose. This risk peaked at 1500 to 2000 mg/m2 for VM-26 and at 2000-3000 mg/m2 for VP-16. All reactions were Type 1 reactions according to the Gell and Coombs classification, characterized by urticaria, angioedema, flushing, rashes, or hypotension, and 86% of reactions were of Grade 1 or 2 severity according to standard criteria. There was no evidence of increasing clinical severity on repeated rechallenge with premedication, and no deaths occurred. The findings suggested that hypersensitivity reactions to epipodophyllotoxins in children with ALL are more common than previously reported, but only rarely constitute dose-limiting toxicity.

Adolescent↗
PubMed1991

Concept of maximum tolerated systemic exposure and its application to phase I-II studies of anticancer drugs.

The traditional approach to conducting Phase I studies of anticancer drugs is to select a starting dosage for humans based on preclinical data (e.g., mg equivalent of 1/10 LD10 in mice), then empirically escalate dosages in cohorts of patients until the maximum tolerated dosage (MTD) is established. More recently, NCl and EORTC investigators have advocated the use of pharmacokinetic data from preclinical studies to facilitate more rapid dose escalation (e.g., double the dose until the area under the concentration-time curve [AUC] in humans equals the AUC in mice at the LD10). The present paper describes a strategy which builds on the above approach, by extending the application of pharmacokinetic principles to systematically escalate systemic exposure (AUC) instead of dosage in Phase I trials. Human trials are initiated at whatever patient-specific dosage is required to achieve an AUC equal to 1/10 the AUC in mice at the LD10, such that three patients at the first treatment level might receive three different dosages. If no dose-limiting toxicity is observed, the next cohort of patients receives whatever dosage is required to achieve 2 x AUC of the first dosage level, with AUC escalation continuing until the maximum tolerate systemic exposure (MTSE) is reached. By escalating systemic exposure instead of dosage, one adjusts for interpatient pharmacokinetic variability. This strategy will permit more rapid and precise dosage escalations and, more importantly, it should more precisely establish the maximum level of treatment intensity for future Phase II trials.

Antineoplastic Agents↗
PubMed1991

Somnolence, hypotension, and metabolic acidosis following high-dose teniposide treatment in children with leukemia.

This report describes an unexpected adverse effect in three children receiving teniposide at 3-5 times the conventional dosage (i.e. 200 mg/m2) plus cytarabine as part of continuation therapy for acute lymphocytic leukemia. Pharmacokinetic studies in each patient had demonstrated high teniposide clearances, and thus the increased dosage requirements were necessary to attain plasma concentrations similar to those expected for patients with average drug clearance. At 3-4 h after the beginning of the 4-h simultaneous infusions of teniposide and cytarabine, these patients experienced somnolence, hypotension, and metabolic acidosis. The adverse events were associated with elevated teniposide plasma concentrations during the infusions compared with those in patients receiving similar doses without toxicity, and clinically significant ethanol concentrations, presumably from the teniposide formulation. Blood concentrations of cremophor and histamine, which are also constituents of the teniposide formulation, were not measured. In addition, concomitant therapy with antiemetic agents in patients who may have been mildly volume-depleted due to emesis may also play a contributory role. Prolonging the infusion time for patients receiving teniposide doses above 500 mg/m2 will avoid excessive teniposide and ethanol plasma concentrations and minimize the risk of this potentially serious side effect.

Acidosis↗
PubMed1991

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Adolescent↗