Construction of an optimal destructive sampling design for noncompartmental AUC estimation

Based on toxicokinetic studies of a destructive sampling design, this work was aimed at selecting the number of time points, their locations, and the number of replicates per time point in order to obtain the most accurate and precise noncompartmental estimate of the area under the concentration-time curve (AUC). From a prior population pharmacokinetic model, the design is selected to minimize the scaled mean squared error of AUC. Designs are found for various sample sizes, number of time paints, and a distribution of animals across time points from being very unbalanced to balanced. Their efficiencies are compared both theoretically and based on simulations. An algorithm has been implemented for this purpose using the symbolic resolution and numerical minimization capabilities of Mathematica(TM) and an example of its use is provided. This method provides efficient tools for constructing, validating and comparing optimal sampling designs for destructive sampled toxicokinetic studies

Adherence to treatment regimen in depressed patients treated with amitriptyline or fluoxetine

Objective: Non-compliance presents a constant challenge to effective therapy, Many studies only investigate early treatment discontinuation and not other measures like adherence to treatment regimen. We compared adherence in depressed patients using either a selective serotonin reuptake inhibitor (fluoxetine) or a tricyclic antidepressant (amitriptyline), and examined its clinical relevance through adverse events, drop-out rates, and outcome. Adherence was measured electronically with the MEMS (Medication Event Monitoring System). Design: Nine-week double blind, randomized controlled trial. Setting: Ambulatory psychiatric care. Patients: Random sample of 66 depressed (DSM-RI-R criteria) patients. Intervention: Fluoxetine 20 mg or amitriptyline 150 mg. Main outcome measures: Time course of adherence and its relation to severe adverse events, drop-outs and outcome. Results: Non-adherence to the treatment regimen occurred frequently in both treatment groups: 31% of patients had at least one 3-day drug holiday, and 34% of patients had at least one episode of three pills in a 24-h period. Over-consumption occurred more frequently during the -early phases of treatment while underconsumption occurred more frequently during the later phases. Patients on amitriptyline (P = 0.03) and patients with a higher pill intake (P = 0.01) experienced more severe adverse events. Patients on amitriptyline (P = 0.009) and patients with a lower adherence to the treatment regimen (P = 0.004) discontinued from treatment more frequently. The final Hamilton score was significantly predicted by a longer duration of treatment and by a better adherence, but only in amitriptyline. users. Conclusions: Non-adherence to the treatment regimen has important clinical consequences. Pharmacodynamics. and human behavior predict risk for severe adverse events and drop-outs. Moreover, in amitriptyline users but not in fluoxetine users, better adherence predicts a better outcome. (C) 2001 Elsevier Science BY All rights reserved