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Gerald Hajian

Publications and source records attributed to Gerald Hajian.

2 recordsLinked to original sources
PubMed2003

A maximum likelihood approach for estimating the QT correction factor using mixed effects model.

Assessment of QT interval prolongation is often used for assessing the cardiac safety of a new drug. However, the correction of the QT interval for varying heart rates has potential bias due to various different correction factors. This article proposes a maximum likelihood (ML) approach for calculating the appropriate individual correction factor using the data. The data come from a study with 24 subjects participating in a 10 day multiple dose (NEW RX) placebo-controlled cross-over trial with repeat ECGs obtained at baseline and at day 10. ML techniques were used to fit a random-effects model to observed QT and HR values for estimating the pooled and individual correction factors. QT(c) values using four correction factors (Bazett, Friderecia, pooled and individual) were investigated. The relative performance of the various correction factors are given in terms of variability and graphical techniques. The pooled correction factor was estimated to be 0.292 and the individual correction factors ranged from 0.19 to 0.41. The assessment of the treatment effect on QT(c) yielded inconsistent results. Bazett's factor indicated prolongation (6.55+/-1.20), Friderecia's factor indicated no change, while the pooled (-2.92+/-0.94) and individual (-2.82+/-1.00) factors showed a significant decrease. Graphical examination of individual QT(c) data showed a significant advantage in the use of individual correction factors versus Bazett's factor both in terms of sensitivity as well as reduction in bias. Use of individual correction factors is advocated for the assessment of possible drug-induced QT(c) prolongation.

Arrhythmias, Cardiac↗
PubMed2002

Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models.

BACKGROUND: Combination therapy of ribavirin with interferon alfa-2b and pegylated interferon alfa-2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight. OBJECTIVE: Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles. METHODS: Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose-concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800-mg/d dose, empiric weight-adjusted doses (ie, 1000 mg/d for patients who weighed < or =75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights < or =75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65-85/>85 kg]), a dose of 13 mg/kg per day, and other per-body weight doses between 9 and 16 mg/kg per day. RESULTS: Simulation results showed that both efficacy and toxicity increased as the milligrams-per-kilogram dose of ribavirin increased. The body weight-based 800/1000/1200-mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800-mg/d dose. In particular, patients with genotype-1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200-mg/d and 13-mg/kg per day dose groups. CONCLUSIONS: This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa-2b) for patients with chronic hepatitis C should be based on body weight.

Adult↗