Pharmacokinetics, Pharmacodynamics, Physiologically-based Pharmacokinetic Modeling of Monoclonal Antibodies

Development of monoclonal antibodies (mAbs) and their functional derivatives represents a growing segment of the development pipeline in the pharmaceutical industry. More than 25 mAbs and derivatives have been approved for a variety of therapeutic applications. In addition, around 500 mAbs and derivatives are currently in different stages of development. mAbs are considered to be … Continued

Optimal Sampling Times for a Drug and Its Metabolite Using Simcyp Simulations as Prior Information

Since 2007, it is mandatory for the pharmaceutical companies to submit a Pediatric Investigation Plan to the Pediatric Committee at the European Medicines Agency for any drug in development in adults, and it often leads to the need to conduct a pharmacokinetic study in children. Pharmacokinetic studies in children raise ethical and methodological issues. Because … Continued

Impact of Low-dose Ritonavir on Danoprevir Pharmacokinetics: Results of Computer-based Simulations and a Clinical Drug-drug Interaction Study

Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) 3A. Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3A inhibitor, is used as a pharmacokinetic enhancer … Continued

Application of a Systems Approach to the Bottom-up Assessment of Pharmacokinetics in Obese Patients: Expected Variations in Clearance

The maintenance dose of a drug is dependent on drug clearance, and thus any biochemical and physiological changes in obesity that affect parameters such as cardiac output, renal function, expression of drug-metabolizing enzymes and protein binding may result in altered clearance compared with that observed in normal-weight subjects (corrected or uncorrected for body weight). Because … Continued

Towards a Better Prediction of Peak Concentration, Volume of Distribution, and Half-life After Oral Drug Administration in Man, Using Allometry

It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (Cmax), area under the plasma concentration-time curve (AUC) and a suitable half-life t(½). The Cmax and … Continued

A Semi-mechanistic Model to Predict the Effects of Liver Cirrhosis on Drug Clearance

Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp® … Continued

Prediction of Clearance of Eleven Drugs and Associated Variability in Neonates

Prediction of the exposure of neonates, infants and children to xenobiotics is likely to be more successful using physiologically based pharmacokinetic models than simplistic allometric scaling, particularly in younger children. However, such models require comprehensive information on the ontogeny of anatomical, physiological and biochemical variables; data that are not available from single sources. The Simcyp® … Continued

Population Pharmacokinetics of Olmesartan Following Oral Administration of Its Prodrug, Olmesartan Medoxomil: In Healthy Volunteers and Hypertensive Patients

Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. The objective of this study was to develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on … Continued

Pharmacokinetics of Melagatran and the Effect on Ex Vivo Coagulation Time in Orthopedic Surgery Patients Receiving Subcutaneous Melagatran and Oral Ximelagatran: A Population Model Analysis

Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as … Continued

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