Biomedical subjects

Peter L Bonate

Publications and source records attributed to Peter L Bonate.

12 recordsLinked to original sources

PubMed2006

Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors.

PURPOSE: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. EXPERIMENTAL DESIGN: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. RESULTS: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. CONCLUSIONS: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

Adult↗

PubMed2006

Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment.

PURPOSE: Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocytic leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias. The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-agent clofarabine in CLL. EXPERIMENTAL DESIGN: Previously treated patients with relapsed/refractory CLL were eligible for this study. Clofarabine was infused over 1 hour daily for 5 days. Most patients received 3 or 4 mg/m2/d x 5 days, whereas the other two were treated with 15 mg/m2/d x 5 days. Clinical outcome and associated pharmacologic end points were assessed. RESULTS: Myelosuppression limited the maximum tolerated dose of clofarabine to 3 mg/m2/d on this schedule. Cellular pharmacokinetic studies showed a median clofarabine triphosphate concentration in CLL lymphocytes of 1.5 micromol/L (range, 0.2-2.3 micromol/L; n = 9). In the majority of cases, >50% of the analogue triphosphate was present 24 hours after infusion, indicating prolonged retention of the triphosphate in CLL cells. Although cytoreduction was observed, no patients achieved a response. In vitro clofarabine incubation of leukemic lymphocytes from 29 CLL patients showed that clofarabine monophosphate accumulated to a higher concentration compared with the triphosphate. Nonetheless, the triphosphate increased in a dose-dependent fashion and upon successive clofarabine infusions, suggesting benefit from greater doses given at less frequent intervals. CONCLUSION: Levels of clofarabine triphosphate at higher doses and prolonged maintenance of clofarabine triphosphate in leukemic lymphocytes provide a rationale to treat CLL in a weekly clofarabine schedule.

Adenine Nucleotides↗

PubMed2006

Discovery and development of clofarabine: a nucleoside analogue for treating cancer.

The treatment of acute leukaemias, which are the most common paediatric cancers, has improved considerably in recent decades, with complete response rates approaching approximately 90% in some cases. However, there remains a major need for treatments for patients who do not achieve or maintain complete remission, for whom the prognosis is very poor. In this article, we describe the challenges involved in the discovery and development of clofarabine, a second-generation nucleoside analogue that received accelerated approval from the US FDA at the end of 2004 for the treatment of paediatric patients 1-21 years old with relapsed or refractory acute lymphoblastic leukaemia after at least two prior regimens. It is the first such drug to be approved for paediatric leukaemia in more than a decade, and the first to receive approval for paediatric use before adult use.

Adenine Nucleotides↗

PubMed2005

Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m(2). Pharmacokinetic samples were collected during the first course. RESULTS: Neutropenia was the principal DLT at the 45.7 mg/m(2)/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m(2), experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of < or =55 minutes, and approximately 11% was excreted unchanged in the urine. CONCLUSION: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m(2). The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.

Adult↗

PubMed2005

A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. EXPERIMENTAL DESIGN: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m(2). Pharmacokinetic samples were collected in cycle 1. RESULTS: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m(2)/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m(2), 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m(2)/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m(2)/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. CONCLUSION: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m(2)/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.

Adult↗

PubMed2005

Plasma and cerebrospinal fluid pharmacokinetics of clofarabine in nonhuman primates.

INTRODUCTION: Clofarabine (2-chloro-2'fluoro-2'-deoxy-9-beta-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model. METHODS: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy. RESULTS: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 mumol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%). CONCLUSION: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.

Adenine Nucleotides↗

PubMed2005

Covariate detection in population pharmacokinetics using partially linear mixed effects models.

PURPOSE: To introduce partially linear mixed effects models (PLMEMs), to illustrate their use, and to compare the power and Type I error rate in detecting a covariate effect with nonlinear mixed effects modeling using NONMEM. METHODS: Sparse concentration-time data from males and females (1:1) were simulated under a 1-compartment oral model where clearance was sex-dependent. All possible combinations of number of subjects (50, 75, 100, 150, 250), samples per subject (2, 4, 6), and clearance multipliers (1 to 1.25) were generated. Data were analyzed with and without sex as a covariate using PLMEM (maximum likelihood estimation) and NONMEM (first-order conditional estimation). Four covariate screening methods were examined: NONMEM using the likelihood ratio test (LRT), PLMEM using the LRT, PLMEM using Wald's test, and analysis of variance (ANOVA) of the empirical Bayes estimates (EBEs) for CL treating sex as a categorical variable. The percent of simulations rejecting the null hypothesis of no covariate effect at the 0.05 level was determined. 300 simulations were done to calculate power curves and 1000 simulations were done (with no covariate effect) to calculate Type I error rate. Actual implementation of PLMEMs is illustrated using previously published teicoplanin data. RESULTS: Type I error rates were similar between PLMEM and NONMEM using the LRT, but were inflated (as high as 36%) based on PLMEM using Wald's test. Type I error rate tended to increase as the number of observations per subject increased for the LRT methods. Power curves were similar between the PLMEM and NONMEM LRT methods and were slightly more than the power curve using ANOVA on the EBEs of CL. 80% power was achieved with 4 samples per subject and 50 subjects total when the effect size was approximately 1.07, 1.07, 1.08, and 1.05 for LRT using PLMEMs, LRT using NONMEM, ANOVA on the EBEs, and Wald's test using PLMEMs, respectively. CONCLUSIONS: PLMEM and NONMEM covariate screening using the LRT had similar Type I error rates and power under the data generating model. PLMEMs offers a viable alternative to NONMEM-based covariate screening.

Computer Simulation↗

PubMed2005

The distribution, metabolism, and elimination of clofarabine in rats.

The distribution, metabolism, and elimination of intravenous [14C]clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three phases of exponential elimination, with half-lives of 0.3, 1.3, and 12.8 h after administration of the 25 mg/kg/day regimen. Unscheduled deaths occurred after one to three doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics; therefore, mass balance and radiokinetic profiles could not be obtained. A total of 77.1% (of which 87.2% was clofarabine) and 10.8% (of which 6.9% was clofarabine) of the dose was recovered in urine and feces, respectively. 6-ketoclofarabine, believed to be formed via adenosine deaminase, was the metabolite of greatest concentration found in urine and feces, but in each matrix, it accounted for only 7% of the daily recovery of radioactivity. 6-ketoclofarabine was also found in myocardium and liver but accounted for less than 2% of the total radioactivity in those tissues. Clofarabine was the major analyte found in myocardium (>97% region of integration) and liver (>94% region of integration). Whole body autoradiography demonstrated that the highest postdistributive concentrations of radioactivity were in the excretory organs, kidney, bladder, and gastrointestinal tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8% [14C]clofarabine remained, respectively, after 6 h of incubation. Eleven metabolites were observed, with the largest constituting 2.5% of the radioactivity.

Adenine Nucleotides↗

PubMed2004

Population pharmacokinetics of APOMINE: a meta-analysis in cancer patients and healthy males.

AIMS: 1) To characterize the population pharmacokinetics of apomine in healthy males and in male and female patients with solid tumours and 2) to understand more fully the influence of induction and between- and within-subject variability on exposure to drug using Monte Carlo simulation. METHODS: Apomine was administered once- or twice-daily with or without food in single and multiple oral doses of 30-2100 mg to healthy males (n = 19) and patients with solid tumours (n = 19). The data were divided into model development and validation sets. Models were developed using standard population methods. These were the identification of an appropriate base model, calculation of the empirical Bayes estimates of the primary pharmacokinetic parameters, covariate screening, forward stepwise addition of covariates using the likelihood ratio test as a model selection criteria, and backwards elimination to obtain the final model. To study the influence of data from individual subjects, the model development dataset was subjected to the delete-1 jack-knife and the final model was fitted to each jack-knifed dataset. Principal components analysis of the jack-knifed matrix of model parameters identified two influential subjects who were removed from the dataset, and the final model contained data from the remaining subjects. Model validation was examined using goodness of fit statistics and relative error measures using independent datasets from cancer patients. The model provided a reasonable approximation to the pharmacokinetic measurements in the validation datasets. Computer simulations were undertaken to understand further the pharmacokinetics of apomine in otherwise healthy females, a population not yet studied. RESULTS: Apomine pharmacokinetics were complex and consistent with a two-compartment model with a lag-time. Apparent oral clearance at baseline and apparent volume of distribution at steady-state were larger in healthy males than in cancer patients (41 ml h(-1) and 14.1 l vs 10 ml h(-1) and 8.9 l, respectively, for a 75 kg person). Clearance was time-variant showing a maximal increase with full induction of 320 ml h(-1), independent of patient type. The time to reach 50% maximal induction was about 2 days. The fraction of drug absorbed was relatively constant at doses less than 100-200 mg once daily but decreased at higher doses. Food also decreased relative bioavailability by 36%. Patient characteristics had no effect on apomine pharmacokinetics except for weight, which was proportional to the volume of the central compartment. Between-subject variability (68% for clearance, 30% for central volume, and 141% for peripheral volume) was moderate to large and independent of patient type. Inter-occasion variability was small (18% for both clearance and central volume). Residual variability was modelled with an additive and proportional error model. Cancer patients had slightly higher plasma concentrations than healthy males but this difference was probably not clinically significant. Steady-state was reached in about 3-4 days after once-daily drug administration. The half-life of apomine after three weeks of once-daily dosing was 41 h in cancer patients and 32 h in healthy males. CONCLUSIONS: A population model for apomine has been developed has been developed that characterizes its pharmacokinetics in cancer patients and healthy subjects under a variety of conditions.

Adolescent↗

PubMed2004

Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia.

The population pharmacokinetics of plasma clofarabine and intracellular clofarabine triphosphate were characterized in pediatric patients with acute leukemias. Traditional model-building techniques with NONMEM were used. Covariates were entered into the base model using a forward selection significance level of .05 and a backwards deletion criterion of .005. Model performance, stability, and influence analysis were assessed using the nonparametric bootstrap and n-1 jackknife. Simulations were used to understand the relationship between important covariates and exposure. A 2-compartment model with weight (scaled to a 40-kg reference patient) modeled as a power function on all pharmacokinetic parameters (0.75 on clearance-related terms and 1.0 on volume-related terms) was fit to plasma clofarabine concentrations (n = 32). White blood cell (WBC) count, modeled as a power function (scaled to a WBC count of 10 x 10(3)/microL), was a significant predictor of central volume with power term 0.128 +/- 0.0314. A reference patient had a systemic clearance of 32.8 L/h (27% between-subject variability [BSV]), a central volume of 115 L (56% BSV), an intercompartmental clearance of 20.5 L/h (27% BSV), and a peripheral volume of 94.5 L (39% BSV). Intracellular clofarabine triphosphate concentrations were modeled using a random intercept model without any covariates. The average predicted concentration was 11.6 +/- 2.62 microM (80% BSV), and although clofarabine triphosphate half-life could not be definitively estimated, its value was taken to be longer than 24 hours. The results confirm that clofarabine should continue being dosed on a per-squaremeter or per-body-weight basis.

Adenine Nucleotides↗

PubMed2003

Wet granulation fine particle ethylcellulose tablets: effect of production variables and mathematical modeling of drug release.

In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of various formulation and process variables, such as FPEC content, hardness of the tablet, and solubility of the drug, on the release of drug from these tablets was examined. Tablets were prepared by wet granulation of drug and FPEC in an appropriate mass ratio. Theophylline, caffeine, and dyphylline were selected as nonionizable model drugs with solubilities from 8.3 to 330 mg/mL at 25 degrees C. Ibuprofen, phenylpropanolamine hydrochloride, and pseudoephedrine hydrochloride were selected as ionizable drugs with solubilities from 0.1 to 2000 mg/mL at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection. As the FPEC content and the hardness of the tablets increased, the release rate of the drug decreased. The drug release rate increased with an increase in the solubility of the drug. Model equations, intended to elucidate the drug release mechanism, were fitted to the release data. Parameters were generated and data presented by SAS software. The Akaike Information Criterion was also considered to ascertain the best-fit equation. Fickian diffusion and polymer relaxation were the release mechanisms for nonionizable and ionizable drugs.

Cellulose↗