Tag Archives | 2008

What to do about missing dosage history?

Background: An inaccurate or missing dose history (MDH) is one of the major obstacles in determining unbiased estimates of the pharmacokinetic (PK) parameters of a drug in clinical practice.  This is particularly the case with drug overdose when the patient may either not recall the events or choose not to provide an accurate history. Methods have […]

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Population pharmacokinetics of acyclovir in children with malignancy

Background: Acyclovir exhibits a selective inhibition of herpes virus replication with potent clinical antiviral activity against the herpes simplex and varicella-zoster virus (King & Madera, 1988).Valacyclovir, a pro-drug of acyclovir, increases the oral bioavailability of acyclovir (Soul-Lawton et al. 1995). Acyclovir is primarily renally eliminated. Acyclovir displays variability in treatment response which supports the need for individualised dose […]

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Handling Correlated Variables

Many situations exist where multiple responses are measured during an experiment, e.g. parent and drug metabolite concentration and drug toxicity and efficacy. Typically the responses will be mixed (continuous and discrete) and display varying dependence structures. When standard multivariate distributions do not exist or are not applicable, a more flexible approach to the construction of […]

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Lean Body Weight as a Robust Size Descriptor for Quantifying the Impact of Body Composition on Drug Clearance

Background: Determination of optimal doses for obese patients is challenging due to the paucity of clear dosing guidelines for this population. Empirical dosing strategies based on total body weight (WT) may result in overdoses in the obese, whereas arbitrary dose capping by physicians may produce sub-therapeutic concentrations. Quantifying the impact of obesity on drug clearance using […]

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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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Population pharmacokinetics of melphalan in myeloma patients undergoing an autograft

Background: High dose melphalan is standard conditioning for autologous stem cell transplantation in the treatment of multiple myeloma. Appropriate dosing is critical as melphalan may be associated with profound toxicity, including cytopenia and gastrointestinal toxicity, which can lead to significant treatment-related mortality, while insufficient dose intensity can lead to disease relapse. The aim of this study was […]

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When Missing Does Not Mean Lost [OED]

Background: Missing data due to subject dropout from study is common in late phase clinical trials. It is possible for missing to be equivalent to lost and has no relevance to time course of the data. On the other hand, circumstances exist where compelling reasons could be formed to argue that dropout is related to underlying […]

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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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