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Modeling Diverse Anti-Diabetic Drug Effects Using Indirect Response Models: Review

Background: Diabetes is a major health risk in many countries and incidence rates are increasing. Diverse anti-diabetic agents act through various mechanisms on different organs. A large array of mathematical models has been proposed to describe anti-diabetic drug effects. Objectives: 1) To systematically compare structural models that were used to model anti-diabetic drug effects. 2) To […]

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Handling data below the limit of quantification in mixed effect models

Background: Common approaches for handling of concentration measurements reported as below the limit of quantification (BLQ), such as discharging the information or substitution with the limit of quantification (LOQ) divided by two, have been shown to introduce bias to parameter estimates [1,2,4-6]. In 2001, Stuart Beal published an overview of ways to fit a PK model […]

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Mechanistic Modeling of Magnetically Marked Extended Release Formulation of Felodipine

Background: Magnetic Marker Monitoring is a novel technique for visualising the transit of a solid oral dosage form through the GI tract. For dosage forms with erosion controlled drug release, the technique can also be used for obtaining an in-vivo drug release profile [3]. Aim: To assess information gained by a mixed effect modeling approach to data […]

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Pharmacokinetics of L-arginine after intravenous infusion in adults with moderately severe malaria

Background: Plasma L-arginine is a naturally occurring amino acid that has been found to be reduced in patients with malaria to concentrations below the equilibrium constant (Km) of the cationic amino acid transporter (CAT) needed for intracellular transport and may limit cellular nitric oxide (NO) production. Aim: To develop a pharmacokinetic model for L-arginine in adults with […]

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Preclinical Population PK/PD of TGF beta RI Kinase inhibitor for Cancer

Objectives: The primary objective of PK/PD modeling in preparation for the First Human Dose study was to estimate a pharmacologically effective dose range in humans based on preclinical data Methods: Data from tumor growth kinetics Xenograft model in mice and from in vivo target inhibition (IVTI) in rats and in mice were incorporated in our PK/PD […]

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Normalized prediction distribution errors for the evaluation of nonlinear mixed-models

Context: Although population pharmacokinetic and/or pharmacodynamic model evaluation is highly recommended by regulatory authorities, there is no consensus today on the appropriate approach to assess a population model. We have also shown in a recent literature survey [1] that model evaluation was not appropriately performed in most published population pharmacokinetic-pharmacodynamic analyses. Among the different approaches proposed […]

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Optimal Designs of Studying Bioimpedance – Design for Nonlinear Mixed Effects Models

Bioelectrical impedance analysis measures the impedance to flow of an alternating electrical current passed through biological tissue. Such impedance measurements allow one to estimate fat-free body mass which is an accepted estimate for lean body weight, considered by some to be a better predictor of drug clearance in the obese than, for example, total body […]

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Nonlinear Mixed Effects Modeling of the Steady-State Pharmacokinetics (PK) of Tipranavir/Ritonavir 500/200 mg bid (TPV/r) for Adult Healthy Volunteers and HIV+ Patients

Background: TPV is the first of a new class of non-peptidic PIs, and has potent activity against multiple PI-resistant HIV. To enhance TPV PK, it is combined with low-dose ritonavir. This abstract reports the results of nonlinear mixed effects modeling to characterize the PK of TPV and to elucidate the effects of demographic parameters on the population […]

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Maximum likelihood estimation in nonlinear mixed effects models with the SAEM algorithm

The statistical model for most population PK/PD analyses is the nonlinear-mixed effects model (NLMEM). As opposed to linear models, there are statistical issues to express the optimisation criteria for these nonlinear models so that first approximation methods (FO and FOCE) based on linearization of the model were proposed. It is well known that these methods […]

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