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S D Baker

Publications and source records attributed to S D Baker.

At least 37 records · Page 2Linked to original sources
PubMed1999

Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.

The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.

Absorption↗
PubMed1999

Paclitaxel steady-state plasma concentration as a determinant of disease outcome and toxicity in lung cancer patients treated with paclitaxel and cisplatin.

The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (Css) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m2 cisplatin i.v. on day 1 and 100 mg/m2 etoposide i.v. on days 1-3 (EC arm) or 75 mg/m2 cisplatin i.v. combined with either a low dose of paclitaxel (135 mg/m2, 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m2 i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrated to be nearly equal to CssS on this schedule, were obtained during the first and second courses in patients on the PC and PCG arms. Relationships between the average paclitaxel Css (Css,avg) and the best response to treatment, time to treatment failure (TTF), survival, and worst grade of leukopenia and neurotoxicity were evaluated by univariate analysis. A multivariate model was used to assess the influence of paclitaxel Css in conjunction with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance status, weight loss during the previous 6 months, and disease stage. Paclitaxel Css in both courses 1 and 2 were obtained in 71 patients treated with PC and 75 patients treated with PCG. Although Css,avgS in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 micromol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3719). In addition, there were no differences between the PC and PCG arms in TTF (median, 5.1 versus 5.5 months, P = 0.6201) or survival (median, 11.6 versus 11.3 months, P = 0.7173). Combined analysis of paclitaxel concentrations from both treatment arms revealed no significant difference in paclitaxel Css,avg between responders and nonresponders [median, 0.40 (range, 0.16-1.6) micromol/liter versus 0.55 (range, 0.11-3.6)], and Css,avgS were similar in patients segregated according to whether they had a complete response, partial response, stable disease, or progressive disease as their best response to treatment (P = 0.7612). In addition, the relationship between Css,avg and TTF was weak (r2 = 0.00003, P = 0.94), as was the relationship between Css,avg and survival (P = 0.1267). With regard to the principal toxicities, neither the propensity to develop neuromuscular and neurosensory toxicity nor the worst grade of these adverse effects were related to Css,avg (P = 0.5000 and 0.2033, respectively); however, the relationship between Css,avg and the worst grade of leukopenia experienced was marginally significant (P = 0.0796). In a multivariate model, neither the combined effect of relevant demographic and stratification variables nor paclitaxel Css,avg predicted for either response (P = 0.1544) or TTF (P = 0.2574), whereas the combined effect of all covariates predicted for survival (P = 0.0249). With regard to individual covariates, a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant favorable predictor for TTF (P = 0.0195), and a lower ECOG performance status (= 0) was the only significant positive determinant of survival (P = 0.0121) in the multivariate model. In summary, paclitaxel Css,avg was not a determinant of response, TTF, or survival in patients with advanced NSCLC treated with paclitaxel as a 24-h i.v. infusion combined with cisplatin. On the basis of both the clinical and pharmacodynamic results of E5592, there is no compelling reason to treat patients with advanced NSCLC with paclitaxel on a 24-h i.v. schedule at doses of > 135 mg/m2 in combination with cisplatin, although highe

Adult↗
PubMed1999

A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies.

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.

Adult↗
PubMed1998

Characterization of topotecan-mediated redistribution of DNA topoisomerase I by digital imaging microscopy.

Topographical image measures have been used to characterize the subnuclear distribution of DNA topoisomerase I in human tumor cell lines. This topographical analysis allowed a mathematical description of staining patterns to be produced that did not depend on subjective grading. The redistribution of topoisomerase I in response to increasing concentrations of topotecan was then monitored by this method. The cell lines were stained for topoisomerase I by indirect immunofluorescence methods. Digital imaging microscopy and image analysis were used to extract the nucleus from each cell, and nine parameters describing the topography of the distribution of topoisomerase I within the nucleus were computed for each. Use of multivariate analysis of variance enabled this nine-parameter set to be reduced to a single canonical variable, representing 60-90% of the observed internuclear variance. Plotting the canonical variable vs drug concentration resulted in dose-response curves that could be fitted well by a simple Emax model. From these curve fits, EC50 and Emax values for drug-induced redistribution of topoisomerase I were determined. Our results indicate that neither the maximum extent of topoisomerase I redistribution (Emax) nor the EC50 for drug-induced redistribution correlated well with the growth inhibition produced by continuous exposure to topotecan in these cell lines. However, the EC50 determined for the 1-h high-concentration exposure did reflect the growth inhibition produced in cells exposed to the drug for 1 h. The methodology described may also be generally applied to any antigen of interest.

Biological Transport↗
PubMed1998

A phase I and pharmacologic study of DMP 840 administered by 24-hour infusion.

PURPOSE: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. PATIENTS AND METHODS: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. RESULTS: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25-86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P < 0.01, Wilcoxon Rank Sum test). CONCLUSION: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.

Adult↗
PubMed1998

High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: a phase II and pharmacodynamic study.

PURPOSE: The premise for this study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-SCF in patients with fluoropyrimidine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. PATIENTS AND METHODS: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advance colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimidine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling with performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. RESULTS: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/microliters for longer than 5 days in 17% of courses involving seven of seventeen (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/microliters were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short--2.5 and 4 months respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANC's during course 1, although patients with severe toxic effects (ANC below 500/microliters for more than five days and/or platelets < 25,000/microliters) had higher drug exposure than patients with less severe toxicity (P < 0.018 and P = 0.09, respectively). CONCLUSIONS: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

Adult↗
PubMed1998

Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS: Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS: Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION: The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

Adult↗
PubMed1998

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗
PubMed1997

Pharmacology of cancer chemotherapy in the older person.

With more widespread use of effective chemotherapy, more elderly patients are candidates for treatment with cytotoxic drugs. This article reviews and discusses the relevant age-related factors that may alter drug disposition and its relationship to pharmacokinetics effects and to pharmacodynamic effects in the elderly.

Aged↗
PubMed1996

Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors.

The purpose of this study was to describe the cerebrospinal fluid (CSF) penetration of topotecan in humans, to generate a pharmacokinetic model to simultaneously describe topotecan lactone and total concentrations in the plasma and CSF, and to characterize the CSF and plasma pharmacokinetics of topotecan administered as a continuous infusion (CI). Plasma and CSF samples were collected from 17 patients receiving 5.5 or 7.5 mg/m2 per day as a 24-h CI (5 patients, 7 courses), or 0.5 to 1.25 mg/m2 per day as a 72-h CI (12 patients, 12 courses). CSF samples were obtained from either a ventricular reservoir (VR) or a lumbar puncture (LP). Topotecan lactone and total (lactone plus hydroxy acid) concentrations were determined by HPLC and fluorescence detection. Using MAP-Bayesian modelling, a three-compartment model was fitted simultaneously to topotecan lactone and total concentrations in the plasma and CSF. The penetration of topotecan into the CSF was determined from the ratio of the CSF to the plasma area under the concentration-time curve. The median CSF ventricular lactone concentrations, obtained prior to the end of infusion (EOI), were 0.86, 1.4, 0.73, 5.3, and 4.6 ng/ml for patients receiving 0.5, 1.0, 1.25, 5.5, and 7.5 mg/m2 per day, respectively. EOI CSF lumbar lactone concentrations measured in three patients were 0.44, 1.1, and 1.7 ng/ml for topotecan doses of 1.0, 5.5, and 7.5 mg/m2 per day, respectively. In two patients receiving 1.25 mg/m2 per day, EOI CSF concentrations were obtained simultaneously from a VR and LP; the lumbar lactone concentrations were 30% and 49% lower than the ventricular concentrations. During a 24-h and a 72-h CI, the median CSF penetration of topotecan lactone was 0.29 (range 0.10 to 0.59) and 0.42 (range 0.11 to 0.86), respectively. A three-compartment model adequately described topotecan lactone and total concentrations in the plasma and CSF. Topotecan was therefore found to significantly penetrate into the CSF in humans. The pharmacokinetic model presented may be useful in the design of clinical studies of topotecan to treat CNS tumors.

Adolescent↗
PubMed1996

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

PURPOSE: A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS: TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS: Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION: The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Adenocarcinoma↗
PubMed1996

Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase.

PURPOSE: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule. PATIENTS AND METHODS: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/ m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmaco-kinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3. RESULTS: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122% +/- 40% (mean +/- SD), the terminal half-life (t1/2 beta) was 4.5 +/- 1.6 hours, the apparent volume of distribution (V beta) was 21.4 +/- 5.9 L/ m2, and the systemic clearance (Clsys) was 57.6 +/- 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85. CONCLUSION: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.

Absorption↗
PubMed1996

Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.

PURPOSE: To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. PATIENTS AND METHODS: Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. RESULTS: Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. CONCLUSION: The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.

Acute Disease↗
PubMed1996

A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia.

The principal objectives of this study were to determine the feasibility of escalating doses of the hydrophilic topoisomerase I (topo I) inhibitor topotecan (TPT) as a 30-min infusion daily for 5 days in adults with refractory or relapsed acute leukemia and to study the pharmacokinetic behavior of high doses of TPT and pharmacodynamic determinants of TPT activity. Fourteen patients received 27 courses of TPT at doses ranging from 3.5 to 5.75 mg/m2/day every 3 weeks. A constellation of unusual adverse effects, consisting of high fever, rigors, precipitous anemia, and hyperbilirubinemia, was the principal dose-limiting toxicity of high doses of TPT on this schedule. These toxicities were consistently intolerable at the 5.75 mg/m2/day dose level; however, they were neither severe nor common at lower doses. Although the precise etiology of these effects is not known, high doses of TPT may induce acute hemolytic reactions in this patient population. Severe, albeit transient, mucositis was experienced by two of eight patients in 2 of 17 courses at the next lower dose level, 4.5 mg/m2/day, which was determined to be the maximum tolerated dose and the dose recommended for further trials. The pharmacokinetic behavior of TPT at high doses was not dose dependent and resembled that at lower doses. In view of preclinical data suggesting that TPT sensitivity might correlate with topo I levels, topo I content in leukemia blasts was assessed by Western blotting. Variations in topo I content were observed. Moreover, strong correlations were evident between topo I content and two markers of proliferation, proliferating cell nuclear antigen and nuclear protein B23, raising the possibility that differences in topo I content observed among various leukemia specimens might reflect differences in the proliferating fractions of cells in various leukemia samples. Although complete clearance of circulating leukemia blasts occurred in most courses, neither sustained responses nor hematopoietic recovery were observed in the heavily pretreated, poor-risk patients enrolled in this study, and it was not possible to correlate these differences in topo I content with clinical response. These results indicate that substantial dose escalation of TPT as a 30-minute infusion for a 5-day schedule above myelosuppressive doses is feasible in adults with refractory or relapsed leukemias; however, further development of alternate high-dose schedules in leukemia may be warranted in view of the nature of the dose-limiting toxicity and the lack of sustained clinical responses in this preliminary investigation.

Acute Disease↗
PubMed1995

Cell cycle analysis of amount and distribution of nuclear DNA topoisomerase I as determined by fluorescence digital imaging microscopy.

Fluorescence digital imaging microscopy (FDIM) has been used to perform a cell cycle analysis of both the amount and the distribution of nuclear DNA topoisomerase I in individual CEM human leukemia cells. Cells were stained by indirect immunofluorescence methods using a polyclonal antiserum generated with a 21-amino-acid peptide representing amino acids 219-239 of human topoisomerase I. Immunohistochemical staining was followed by staining with Hoechst dye 33342, allowing DNA content to be determined in each cell. Cell cycle analysis showed that nuclear topoisomerase I content doubled (2.2-fold increase) as the cells progressed from G1 to G2/M phases of the cell cycle. However, when normalized for nuclear size, topoisomerase I content per nuclear area remained almost constant (1.3-fold increase). For comparison, we measured the amount of proliferating cell nuclear antigen (PCNA), a protein whose expression fluctuates during the cell cycle. Nuclear PCNA content increased 2.7-fold from G1 to S phase, then declined in G2/M- phases, whereas PCNA content per nuclear area increased 1.7-fold from G1 to S phase. We also measured topoisomerase I content in leucine-deprived cells to determine if altered growth conditions affect topoisomerase I protein expression. Compared to CEM cells in logarithmic growth, leucine-deprived CEM cells had 1.8-fold less topoisomerase I content per nuclear area. Subnuclear distribution studies of proliferating CEM cells showed topoisomerase I to be localized predominantly in the nucleoli throughout the cell cycle. In contrast, leucine-deprived cells exhibited a perinuclear distribution of topoisomerase I. Our results show that FDIM is a useful technique in determining the cell cycle position and both the content and the distribution of topoisomerase I as well as other nuclear proteins in individual cells.

Antibody Specificity↗
PubMed1994

Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity.

PURPOSE: Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS: Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS: Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION: These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.

Adolescent↗