Timothy Carrothers

Exposure-response Analysis of Pertuzumab in HER2-positive Metastatic Breast Cancer: Absence of Effect on QTc Prolongation and Other ECG Parameters

The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) […]

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Model-supported Development of CS-8635: A Fixed-dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide

CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. […]

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Modeling and Simulation of Edoxaban Exposure and Response Relationships in Patients with Atrial Fibrillation

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify […]

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Population Pharmacokinetic Model for a Novel Oral Hypoglycemic Formed In Vivo: Comparing the Use of Active Metabolite Data Alone Versus Using Data of Upstream and Downstream Metabolites

The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria.

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Is a Thorough QTc Study Necessary? The Role of Modeling and Simulation in Evaluating the QTc Prolongation Potential of Drugs

Concentration-QT (C-QT) modeling has been conducted for multiple compounds at various stages of development in different therapeutic areas. Data from available single and multiple ascending-dose (SAD/MAD) studies were pooled to construct population C-QT models, with post hoc predictions of concentration from a pharmacokinetic model.

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