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Biomedical subjects

E Gibiansky

Publications and source records attributed to E Gibiansky.

10 recordsLinked to original sources
PubMed2002

Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease.

BACKGROUND AND AIMS: To evaluate the safety and efficacy of the intercellular adhesion molecule 1 (ICAM-1) antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) in Crohn's disease. METHODS: Active (Crohn's disease activity index (CDAI) 200-350), steroid dependent (prednisone 10-40 mg) Crohn's patients were randomised into three treatment groups: placebo versus ISIS 2302 (2 mg/kg intravenously three times a week) for two or four weeks. Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14. RESULTS: A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027). CONCLUSIONS: Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy for steroid dependent Crohn's disease.

Adolescent↗
PubMed2001

Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis.

OBJECTIVES: We conducted population anticoagulant pharmacodynamic analysis for patients administered the low-molecular weight heparin tinzaparin. METHODS: Data from 425 patients (2,631 observations) who participated in 2 Phase III clinical studies were utilized in an analysis based on a pharmacodynamic structural model of anti-Xa activity using non-linear mixed effects modeling techniques. Anti-Xa activity from patients participating in a multicenter, randomized, double-blind clinical trial comparing intravenous once daily subcutaneous tinzaparin (175 IU/kg) with heparin for the treatment of deep vein thrombosis (DVT) was first examined using a 2-compartment model with first-order absorption and endogenous anti-Xa activity. Covariates included renal function, body weight, age, gender, race, obesity, concomitant administration of warfarin, and diabetes. RESULTS: The population estimates and 90% confidence intervals (CI) for oral clearance (CL) and apparent volume of distribution of the plasma compartment (Vc) were 0.0176 l/h/kg (CI = 0.012-0.023) and 0.098 l/kg (CI = 0.088 - 0.109), respectively. The elimination half-life was 3.9 h (CI = 2.5-5.2). These estimates are similar to findings in healthy volunteers. The inter-patient variability in clearance was related to plasma creatinine and percent above ideal body weight. Clearance decreased by 22% for patients with severe renal function impairment (creatinine clearance < 30 ml/min), and by about 25% in obese patients (BMI > 30 kg/m2). CONCLUSIONS: Changes of these magnitudes were not clinically important in pooled clinical trial safety and efficacy analyses. Body weight was not a significant covariate in the model supporting the observations in earlier well-defined trials, where tinzaparin was dosed on a weight basis (lU/kg). Clearance was not influenced by age, race or gender. The same model was applied to data obtained from a prospective, randomized, double-blind clinical trial comparing tinzaparin (4,500 IU) to enoxaparin (40 mg) once daily in patients undergoing total hip replacement. Model parameters were similar to those previously obtained supporting the extension of these results across dose and indication. Population analysis in patients with disease and heterogeneity indicated similar pharmacodynamics as in volunteers, supporting weight-based dosing and identified the dependence of clearance on obesity and severe renal function, although the magnitude of these effects are probably not clinically significant.

Adult↗
PubMed1997

The effect of food on the pharmacokinetics of multiple-dose terbinafine in young and elderly healthy subjects.

Pharmacokinetic (PK) parameters for terbinafine were assessed in 15 elderly and 15 young healthy subjects randomized to receive 250 mg Lamisil once daily for 15 d in a two-period, two-treatment, two-sequence, crossover (fed versus fasted) design within age groups. On each treatment day except days 8 and 15, subjects took Lamisil with food at 8:00 a.m. On days 8 and 15, subjects took the drug under either fed or fasting conditions according to treatment sequence, and 24 h PK profiles were obtained. Two analyses of the pharmacokinetic data were undertaken. In a noncompartmental analysis, AUC0-24h, Cmax, C0h, and tmax were computed for each subject on each of days 8 and 15, and the influences of food condition and age on these variables were assessed by analysis of variance. AUC0-24h and C0h were found to be larger (p < 0.5) among elderly subjects than young subjects on day 15, and tmax was prolonged (p < 0.05) under the fed condition on day 15. Similar trends on day 8, as well as generally higher exposures under the fed condition on both days, were not statistically significant. A three-compartment model fitted to the complete sequence of 33 terbinafine concentrations measured over 29 d for each subject separately permitted a within-subject assessment of the food effect that confirmed prolonged absorption and increased bioavailability (p < 0.05) under the fed condition. Across-subject comparisons of oral clearances estimated with the model also confirmed the increased exposures (lower clearances) among the elderly (p < 0.05). The drug was well tolerated in both age groups. In particular, greater drug exposure in the elderly did not result in greater toxicity, as indicated by the safety evaluations in the study.

Adolescent↗
PubMed1996

Pharmacokinetics and pharmacodynamics of multiple-dose terbinafine.

Data from clinical trials of terbinafine for the treatment of onychomycosis were analyzed with the following two objectives: 1) to identify demographic predictors of the duration and extent of systemic drug exposure; and 2) to explore whether increased systemic exposure or demographic predictors of increased exposure were associated with altered safety or efficacy. Demographic predictors of exposure were identified by a model-free, nonparametric approach applied to the sparse pharmacokinetic data from the onychomycosis studies. Those covariates were then incorporated into a multicompartmental nonlinear mixed effects model. Post hoc parameter estimates from the nonlinear mixed effects model provided individual measures of exposure. Safety scores were derived for adverse events that were frequently attributed to drug exposure and for liver function tests. Terbinafine was found to have an average terminal half-life (t1/2) of approximately 3 weeks. That terminal elimination phase contributed so little to the total exposure, however, that average concentrations accumulated only approximately two-fold at steady state with once daily dosing. Age and concomitant hypertension were predictors of higher plasma concentrations of terbinafine; smokers had lower levels than nonsmokers. Although some statistically significant associations between adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events was low, and there were no trends in severity with respect to exposure. Above-normal levels of gamma-glutamyl transferase were associated with exposure, but there was no trend in severity with respect to exposure. No other liver function test abnormalities were associated with exposure, nor were there any significant associations between adverse events or liver function abnormalities and demographic subgroups that differed with respect to exposure. Among patients taking the active drug there were no significant associations between exposure levels and efficacy, nor were there differences in efficacy between demographic subgroups that differed with respect to exposure.

Adult↗
PubMed1995

Applying Bailer's method for AUC confidence intervals to sparse sampling.

Bailer developed a method for constructing confidence intervals for areas under the concentration-vs-time curve (AUC's) with only one sample per subject but with multiple subjects sampled at each of several time points post dose. We have modified this method to account for estimation of the variances. How the need to estimate variances affects study design is discussed. An extension of Bailer's method is proposed where variances are modeled as a function of the means, in order to get more precise estimates of variances. The modified and extended methods are applied to a rat toxicokinetic study with only two rats per time point per treatment group.

Animals↗
PubMed1993

Assessing drug exposure in rodent toxicity studies without satellite animals.

Five major objectives for pharmacokinetic investigations in support of toxicity studies are identified as follows: Assess whether animals exhibited measurable blood concentrations in a dose-dependent manner; estimate average area under the concentration-time curve (AUC) and maximal concentration (Cmax) for each treatment group; elucidate general patterns in the concentration-time (CxT) profile, and summarize relationships between CxT and treatment group; determine CxT dependence on day into study; and judge interanimal variability and identify any animals with unusual concentration response. Such objectives are generally addressed in rodent toxicity studies by including "satellite" animals in the study. Satellite animals are extra animals dosed as per protocol but not subjected to toxicological and pathological observations and tests. Instead, they are used exclusively for the evaluation of pharmacokinetic characteristics of the test compound. In this paper, methods are described for achieving the five listed pharmacokinetic objectives in rodent toxicity studies without the use of satellite animals. A rat toxicity study is presented as an example.

Animals↗
PubMedDate not supplied

Inferring systemic exposure from a pharmacokinetic screen: model-free and model-based approaches.

To infer patterns of average systemic exposure and to estimate individual exposures in phase III clinical trials of a new anxiolytic, two statistical methodologies were applied and compared: non-linear mixed-effect modelling, and a model-free approach based on quartiles of dose-normalized plasma concentrations of the drug. Although the model-based approach provides more quantitative insight about relationships between average exposure and demographic covariates, the model-free approach provides qualitatively similar results about average clearance and quantitatively similar results about individual exposures, and the model-free approach is easy and inexpensive to implement.

Adult↗
PubMedDate not supplied

Multiple-dose pharmacokinetics of a long half-life drug: contributions of mathematical modeling.

A mathematical model was found that consistently described diverse pharmacokinetic data for a development compound from three pharmacokinetic studies in healthy volunteers and two efficacy and safety studies in patients. The model provided: quantification of demographic and random sources of pharmacokinetic variability; estimation of important pharmacokinetic parameters from sparse data; and explanation of observed patterns of pharmacokinetic response.

Adult↗