ABSTRACT
AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically-based pharmacokinetic (PBPK) model for BMS-823778 and use the model to predict PK and drug-drug interaction (DDI) in virtual populations with multiple polymorphic genes. METHODS: The PBPK model was built and verified using existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes. RESULTS: The verified PBPK model of BMS-823778 accurately recovered observed PK in different populations. In addition, the model was able to capture the exposure differences between subjects with different CYP2C19 genotypes. PK simulation indicated higher exposures of BMS-823778 in CYP2C19 poor metabolizers who were also devoid of UGT1A4 activity, compared to those with normal UGT1A4 functionality. Moderate DDI with itraconazole was predicted in subjects with wild-type CYP2C19 or UGT1A4. However, in subjects without CYP2C19 or UGT1A4 functionality, significant DDI was predicted when BMS-823778 was coadministered with itraconazole. CONCLUSIONS: A PBPK model was developed using clinical data that accurately predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was probably an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely to be dependent on the genotypes of CYP2C19 and UGT1A4.
Subject(s)
Cytochrome P-450 CYP2C19/genetics , Models, Biological , Pharmacogenomic Variants , Pyridines/pharmacokinetics , Triazoles/pharmacokinetics , Adult , Asian People/genetics , Computer Simulation , Cytochrome P-450 CYP2C19/metabolism , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Drug Interactions , Genotype , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Humans , Itraconazole/adverse effects , Male , Middle Aged , Pharmacogenetics , Phenotype , Pyridines/adverse effects , Risk Factors , Substrate Specificity , Triazoles/adverse effects , White People/genetics , Young AdultABSTRACT
BMS-823778 is a potent and selective inhibitor of 11ß-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 and UGT1A4. The clinical pharmacokinetics (PK) of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after the oral dose, and systemic exposure at steady state increased proportionally to the dose. Large intersubject variability in BMS-823778 exposure was likely because of the polymorphism of metabolic enzymes. The impact of genetic polymorphism of CYP2C19, UGT1A4, and CYP3A5 on BMS-823778 PK was assessed in healthy Chinese and Japanese subjects, as well as in a human absorption, distribution, metabolism, and excretion study in which all subjects were genotyped either before or after treatment. A clear trend of high exposure and low clearance was seen in poor metabolizers (PMs) of CYP2C19 compared with extensive (EM) and intermediate metabolizer (IM) subjects. The impact of UGT1A4 or CYP3A5 polymorphism on BMS-823778 PK was statistically not significant in CYP2C19 EM and IM subjects; however, in a subject with predicted CYP2C19 PM phenotype, the PK of BMS-823778 was affected significantly by UGT1A4 polymorphism. Overall, BMS-823778 was safe and well tolerated in healthy subjects after single or multiple oral doses. The PK of BMS-823778 was characterized by rapid absorption, and the systemic clearance directly correlated with the genetic polymorphism of CYP2C19.
Subject(s)
Cytochrome P-450 CYP2C19/genetics , Polymorphism, Genetic/genetics , Pyridines/pharmacokinetics , Triazoles/pharmacokinetics , Adolescent , Adult , Cytochrome P-450 CYP3A/genetics , Double-Blind Method , Genotype , Healthy Volunteers , Humans , Male , Middle Aged , Phenotype , Young AdultABSTRACT
AIMS: BMS-823778 is an inhibitor of 11ß-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials. METHODS: The metabolism of BMS-823778 was characterized in multiple in vitro assays. Pharmacokinetics were evaluated in healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor metabolizers (PM), with a single oral dose of [14 C]BMS-823778 (10 mg, 80 µCi). RESULTS: Three metabolites (<5%) were identified in human hepatocytes and liver microsomes (HLM) incubations, including two hydroxylated metabolites (M1 and M2) and one glucuronide conjugate (M3). As the most abundant metabolite, M1 was formed mainly through CYP2C19. M1 formation was also correlated with CYP2C19 activities in genotyped HLM. In humans, urinary excretion of dosed radioactivity was significantly higher in EM (68.8%; 95% confidence interval 61.3%, 76.3%) than in PM (47.0%; 43.5%, 50.6%); only small portions (<2%) were present in faeces or bile from both genotypes. In plasma, BMS-823778 exposure in PM was significantly (5.3-fold, P = 0.0097) higher than in EM. Furthermore, total radioactivity exposure was significantly higher (P < 0.01) than BMS-823778 exposure in all groups, indicating the presence of metabolites. M1 was the only metabolite observed in plasma, and much lower in PM. In urine, the amount of M1 and its oxidative metabolite in EM was 7-fold of that in PM, while more glucuronide conjugates of BMS-823778 and M1 were excreted in PM. CONCLUSIONS: CYP2C19 polymorphisms significantly impacted systemic exposure and metabolism pathways of BMS-823778 in humans.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Cytochrome P-450 CYP2C19/genetics , Polymorphism, Genetic , Pyridines/pharmacokinetics , Renal Elimination/genetics , Triazoles/pharmacokinetics , Adult , Drug Administration Schedule , Genotype , Glucuronides/metabolism , Healthy Volunteers , Hepatocytes/metabolism , Humans , Hydroxylation , Male , Microsomes, Liver/metabolism , Oxidation-Reduction , Pyridines/administration & dosage , Pyridines/blood , Pyridines/metabolism , Triazoles/administration & dosage , Triazoles/blood , Triazoles/metabolism , Young AdultABSTRACT
BMS-823778 is a potent 11-ß-hydroxysteroid-dehydrogenase 1 (11ßHSD-1) inhibitor and a potential therapeutic agent for type 2 diabetes mellitus (T2DM). A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated to enable reliable separation and quantification of both enantiomers of a chiral hydroxy metabolite (BMT-094817) in human plasma. Following liquid-liquid extraction in a 96-well plate format, chromatographic separation of the metabolite enantiomers was achieved by isocratic elution on a Chiralpak IA-3 column. Chromatographic conditions were optimized to ensure separation of both metabolite enantiomers. Metabolite enantiomers and stable isotope-labeled (SIL) internal standards were detected by positive ion electrospray tandem mass spectrometry. The LC-MS/MS assay was validated over a concentration range of 0.200-200ng/mL. Intra- and inter-assay precision values for replicate quality control samples were less than 9.9% for both enantiomers during the assay validation. Mean quality control accuracy values were within ±7.3%. Assay recoveries were high (>75%) and consistent across the assay range. The metabolite enantiomers were stable in human blood for 2h on ice. The analytes were also stable in human plasma for 25h at room temperature, 34days at -20°C and -70°C, and following five freeze-thaw cycles. No interconversion of the metabolite enantiomers was detected under any bioanalytical stress conditions, from blood collection/processing through extracted sample storage. The validated assay was successfully applied to the quantification of both metabolite enantiomers in human plasma in support of a human pharmacokinetic study.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Chromatography, Liquid/methods , Enzyme Inhibitors/blood , Tandem Mass Spectrometry/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Reproducibility of Results , StereoisomerismABSTRACT
BACKGROUND: Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. RESULTS: The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. CONCLUSIONS: The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.
Subject(s)
Epothilones/therapeutic use , Neoplasms/drug therapy , Tubulin Modulators/therapeutic use , Adult , Aged , Aged, 80 and over , Epothilones/pharmacokinetics , Epothilones/pharmacology , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Treatment Outcome , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacologyABSTRACT
PURPOSE: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies. RESULTS: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease. CONCLUSIONS: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.
Subject(s)
Antineoplastic Agents/therapeutic use , Fibronectins/therapeutic use , Neoplasms/drug therapy , Peptide Fragments/therapeutic use , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adult , Aged , Antibody Formation , Antineoplastic Agents/adverse effects , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Female , Fibronectins/adverse effects , Fibronectins/immunology , Fibronectins/pharmacokinetics , Humans , Male , Maximum Tolerated Dose , Middle Aged , Molecular Targeted Therapy , Peptide Fragments/adverse effects , Peptide Fragments/immunology , Peptide Fragments/pharmacokineticsABSTRACT
A sensitive method was developed and validated for the measurement of ixabepilone (BMS-247550, Ixempra) using a demethylated analogue of ixabepilone (BMS-212188) as an internal standard. A 0.050 mL portion of each plasma sample was extracted with 0.450 mL of acetonitrile containing the internal standard via protein precipitation. The supernatant was analyzed on a LC-MS/MS system. Chromatography was carried out on a 2.0 mm x 100 mm YMC ODS-AQ 3 microm column using an isocractic mobile phase consisting of acetonitrile:10 mM ammonium acetate, pH 5.0 (70:30, v/v) at a flow rate of 0.30 mL/min. The mass spectrometer was fitted with a TurboIonSpray source and operated in negative ionization mode. Detection of ixabepilone and BMS-212188 were accomplished using multiple reaction monitoring (MRM) of precursor>product ion pairs of m/z 505.2>405.2, and 492.1>392.1, respectively. The assay range was 2.00-500 ng/mL and was fitted to a 1/x(2) weighted quadratic regression model. Replicate sample analysis indicated that intra- and inter-day accuracy and precision are within +/-15.0%. The recovery of ixabepilone from 0.050 mL of plasma containing 5.00 and 400 ng/mL was greater than 94%. The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies. This paper also discussed approaches used for resolving a curve splitting issue observed during quantitative analysis of ixabepilone in biological matrices. Finally, to adapt the methodology to pharmacokinetics of ixabepilone after oral administration, the potential interference of chemical degradants on the determination of ixabepilone was evaluated.
Subject(s)
Chromatography, Liquid/methods , Epothilones/blood , Tandem Mass Spectrometry/methods , Tubulin Modulators/blood , Epothilones/administration & dosage , Humans , Sensitivity and Specificity , Tubulin Modulators/administration & dosageABSTRACT
PURPOSE: To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4. EXPERIMENTAL DESIGN: Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone. RESULTS: Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m(2) when compared with single-agent therapy of 40 mg/m(2). Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC(0-infinity). The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia. CONCLUSIONS: Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Epothilones/administration & dosage , Epothilones/pharmacokinetics , Ketoconazole/administration & dosage , Ketoconazole/pharmacology , Microsomes, Liver/metabolism , Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Computational Biology , Cytochrome P-450 CYP3A Inhibitors , Epothilones/adverse effects , Epothilones/pharmacology , Female , Genital Neoplasms, Female/drug therapy , Genital Neoplasms, Female/metabolism , Humans , Ketoconazole/adverse effects , Leukocytes, Mononuclear/metabolism , Liver/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Male , Middle Aged , Neoplasms/drug therapy , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Tubulin Modulators/administration & dosage , Tubulin Modulators/adverse effects , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacologyABSTRACT
PURPOSE: To characterize the population pharmacokinetics of topotecan lactone in children with cancer and identify covariates related to topotecan disposition. PATIENTS AND METHODS: The study population consisted of 162 children in seven clinical trials receiving single agent topotecan as a 30-min infusion. A population approach via nonlinear mixed effects modeling was used to conduct the analysis. RESULTS: A two-compartment model was fit to topotecan lactone plasma concentrations (n = 1874), and large pharmacokinetic variability was observed among studies, among individuals, and within individuals. We conducted a covariate analysis using demographics, biochemical data, trial effects, and concomitant drugs. The most significant covariate was body surface area, which explained 54% of the interindividual variability for topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interindividual variability in both variables. Other covariates related to clearance were concomitant phenytoin, calculated glomerular filtration rate, and age (<0.5 years). Including them in the model reduced the interindividual variability for topotecan clearance by an additional 48% relative to the body surface area-normalized model. The full covariate model explained 76% and 50% of interindividual variability in topotecan clearance and volume, respectively. CONCLUSIONS: We developed a descriptive and robust population pharmacokinetic model which identified patient covariates that account for topotecan disposition in pediatric patients. Additionally, dosing topotecan based on the covariate model led to a more accurate and precise estimation topotecan systemic exposure compared with a fixed dosing approach, and could be a tool to assist clinicians to individualize topotecan dosing.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Topoisomerase I Inhibitors , Topotecan/pharmacokinetics , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Enzyme Inhibitors/therapeutic use , Female , Humans , Infant , Male , Models, Biological , Topotecan/therapeutic useABSTRACT
The purpose of this study was to estimate ventricular cerebrospinal fluid (vCSF) topotecan lactone (TPT) exposures in pediatric medulloblastoma patients from plasma concentration-time data by using a pharmacokinetic (PK) model. We studied children with high-risk medulloblastoma who received pharmacokinetically guided TPT (target plasma area under the concentration-time curve [AUC], 120-160 ng/ml-h) and obtained serial vCSF samples to assess TPT exposure. Population pharmacokinetic parameters were determined by using linear mixed-effects modeling via the two-stage approach. We simulated TPT vCSF exposure duration at plasma TPT AUC values of 120 to 200 ng/ml-h and determined percentages of studies meeting or exceeding the vCSF exposure duration threshold (EDT) of 1 ng/ml for 8 h. We then used bootstrap methods to estimate variability in vCSF EDT. Eighteen PK studies were conducted in six patients (median age, 4.8 years). In these patients, seven of nine studies attaining target plasma TPT AUC achieved the vCSF EDT. Given a plasma TPT AUC of 120 ng/ml-h, the median percentage of results meeting or exceeding EDT was 78% (95% CI, 61%-100%). One patient (four studies) with tumor blockage of CSF flow, which can alter CSF pharmacokinetics, was removed, and the bootstrap analysis was repeated. In this subset, a median 93% (95% CI, 79%-100%) of studies achieved vCSF EDT. Increasing plasma TPT AUC values resulted in increased ability to achieve vCSF EDT. We demonstrated that a plasma PK model could estimate vCSF TPT concentrations. Further, our results indicate that the TPT vCSF EDT can be achieved in more than 80% of studies targeted to a plasma TPT AUC of 120 ng/ml-h.
Subject(s)
Antineoplastic Agents/cerebrospinal fluid , Antineoplastic Agents/pharmacokinetics , Cerebellar Neoplasms/drug therapy , Medulloblastoma/drug therapy , Topotecan/cerebrospinal fluid , Topotecan/pharmacokinetics , Adolescent , Adult , Antineoplastic Agents/blood , Area Under Curve , Child , Child, Preschool , Female , Humans , Male , Models, Biological , Topotecan/bloodABSTRACT
Although limited data are available about cyclophosphamide disposition in patients with renal insufficiency, nothing has been reported in anephric patients. We characterized cyclophosphamide pharmacokinetics in an anephric child with bilateral Wilms tumor, both on (day 1) and off (day 2) hemodialysis. The median cyclophosphamide clearance on and off hemodialysis was 5.34 and 3.82 L/hr*m(2), respectively, demonstrating elimination of cyclophosphamide in this anephric child. The off hemodialysis clearance was similar to that in children with normal renal function. Hydroxycyclophosphamide (HCY) AUC was 20.6 and 8.77 microM*hr on and off hemodialysis. Carboxyethylphosphoramide mustard (CEPM) AUC obtained on hemodialysis (i.e., 194 microM*hr) was similar to that in children with normal renal function, although an elevated CEPM AUC was observed when hemodialysis was not received (i.e., 383 microM*hr). With the recent findings that clinical outcomes are related to CEPM AUC, further data are needed regarding the pharmacokinetics of cyclophosphamide and relevant metabolites in anephric children.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Cyclophosphamide/pharmacokinetics , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Child , Humans , Kidney Neoplasms/surgery , Male , Nephrectomy , Renal Dialysis , Wilms Tumor/surgeryABSTRACT
PURPOSE: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic studies in children. METHODS: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the full sampling method. Predictive performance of the LSM was validated using additional data and Monte-Carlo simulations based on these data. RESULTS: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy (absolute predicted error) and bias (predicted error) are < or =8% and < or =6.1%, respectively. For oral topotecan, the optimal LSM includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. CONCLUSIONS: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose, and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and blood collection.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Topotecan/pharmacokinetics , Administration, Oral , Antineoplastic Agents/administration & dosage , Child , Humans , Injections, Intravenous , Models, Statistical , Monte Carlo Method , Reproducibility of Results , Specimen Handling , Topotecan/administration & dosageABSTRACT
Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Glioma/drug therapy , Adolescent , Adult , Antineoplastic Agents, Alkylating/pharmacokinetics , Antineoplastic Agents, Phytogenic/therapeutic use , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Chemotherapy, Adjuvant , Child , Child, Preschool , Combined Modality Therapy , Dacarbazine/pharmacokinetics , Dacarbazine/therapeutic use , Female , Glioma/mortality , Glioma/radiotherapy , Humans , Irinotecan , Male , Survival Analysis , Temozolomide , Treatment OutcomeABSTRACT
BACKGROUND: Epoetin alfa (EPO, PROCRIT) pharmacokinetics and pharmacodynamics were evaluated in children with malignant solid tumors receiving chemotherapy. PROCEDURE: Children initially received IV EPO 600 IU/kg (max dose 40,000 IU) or placebo once weekly for 16 weeks. Dose was increased to 900 IU/kg (max dose 60,000 IU) for patients not achieving a 1 g/dl increase in hemoglobin by study week 3 or 4. Serial PK samples were collected for 24 hr after the first study dose, and after the 10th or 11th dose. Serum EPO concentrations were analyzed using an ELISA assay, and pharmacokinetics were evaluated using compartmental methods. RESULTS: Twelve children participated; six (median age 15.2 years; range 9.3-18.6 years) were randomized to receive EPO. All children required dosage increases to 900 IU/kg due to no response. The median (range) apparent EPO AUC0-24 and clearance (CL) were 67.1 IU/ml.hr (13.8-102.6) and 0.26 L/hr/m2 (0.19-1.08), respectively. After the 10th or 11th EPO dose in four of these six EPO patients, the median (range) apparent AUC0-24 and CL of EPO was 126.5 IU/ml.hr (107.3-161.1) and 0.21 L/hr/m2 (0.15-0.25), respectively. No significant correlations were observed between pharmacokinetic parameters and pharmacodynamic effects. CONCLUSIONS: EPO disposition in our patients was similar to other pediatric patient populations or adults receiving IV EPO. Interesting but insignificant trends were noted in pharmacodynamic effects.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Chondrosarcoma/drug therapy , Erythropoietin/pharmacokinetics , Melanoma/drug therapy , Osteosarcoma/drug therapy , Skin Neoplasms/drug therapy , Adolescent , Child , Dose-Response Relationship, Drug , Double-Blind Method , Epoetin Alfa , Erythropoietin/therapeutic use , Female , Hematinics/pharmacokinetics , Hematinics/therapeutic use , Humans , Injections, Intravenous , Male , Placebos , Recombinant Proteins , Time Factors , Treatment OutcomeABSTRACT
PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
Subject(s)
Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Neoplasms/drug therapy , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Age Factors , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , ErbB Receptors/antagonists & inhibitors , Female , Gefitinib , Humans , Infant , Male , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. EXPERIMENTAL DESIGN: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. RESULTS: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. CONCLUSIONS: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/analogs & derivatives , Esterases/deficiency , Sarcoma, Experimental/drug therapy , Animals , Body Weight/drug effects , Camptothecin/blood , Camptothecin/pharmacokinetics , Camptothecin/pharmacology , Dose-Response Relationship, Drug , Esterases/genetics , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/enzymology , Humans , Irinotecan , Mice , Mice, SCID , Neoplasm Transplantation , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/pathology , Sarcoma, Experimental/metabolism , Sarcoma, Experimental/pathologyABSTRACT
PURPOSE: To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children. METHODS: LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145-200 mg/m(2) per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations. RESULTS: The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively. CONCLUSIONS: Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Central Nervous System Neoplasms/metabolism , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacokinetics , Monte Carlo Method , Antineoplastic Agents, Alkylating/metabolism , Area Under Curve , Child , Dacarbazine/blood , Dacarbazine/metabolism , Humans , Infant , Metabolic Clearance Rate , TemozolomideABSTRACT
BACKGROUND: The role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting. METHODS: Patients ages 3-21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5-day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), were analyzed during Cycles 1 and 3. RESULTS: Thirty-three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n=5) or toxicity (n=1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty-nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one-third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1-year survival rate was 48% (standard error, 8%). CONCLUSIONS: The administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Stem Neoplasms/drug therapy , Camptothecin/analogs & derivatives , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Glioma/drug therapy , Administration, Oral , Adolescent , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/pharmacokinetics , Brain Stem Neoplasms/pathology , Brain Stem Neoplasms/radiotherapy , Camptothecin/administration & dosage , Child , Child, Preschool , Dacarbazine/adverse effects , Dacarbazine/pharmacokinetics , Female , Glioma/pathology , Glioma/radiotherapy , Humans , Infusions, Intravenous , Irinotecan , Male , Temozolomide , Treatment OutcomeABSTRACT
Although limited data are available about topotecan disposition in patients with renal insufficiency, nothing has been reported in anephric patients. The objective of this report is to characterize topotecan disposition in an anephric child with Wilms tumor, both on and off hemodialysis. The patient received topotecan and cyclophosphamide for four cycles; topotecan was administered daily for 5 days, with hemodialysis on the second and fourth day. Therapy was well tolerated, with grade 3 thrombocytopenia and grade 2 neutropenia noted after cycle four. The median topotecan lactone clearance was 15.5 L/h/m off hemodialysis and 18.7 L/h/m on hemodialysis. Topotecan clearance was minimally affected by hemodialysis and was similar to that observed in children without renal failure.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Kidney Neoplasms/metabolism , Renal Insufficiency/metabolism , Topotecan/pharmacokinetics , Wilms Tumor/metabolism , Child , Cyclophosphamide/administration & dosage , Humans , Kidney Neoplasms/drug therapy , Male , Renal Dialysis , Topoisomerase I Inhibitors , Wilms Tumor/drug therapyABSTRACT
PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.