Compliance-Guided Therapy

Blesius, Alexia; Chabaud, Sylvie; Cucherat, Michel; Mismetti, Patrick; Boissel, Jean-Pièrre; Nony, Patrice

doi:10.2165/00003088-200645010-00007

Cited by 11 publications

(4 citation statements)

References 37 publications

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“…Notably, mean steady-state trough concentrations with all weekly doses are predicted to be higher than the protective venous trough level of 20 ng/mL reported recently (which is predicted to correspond to a capillary level of approximately 50 ng/mL) [ 17 , 29 ]. Splitting a total dose into two or more fractional doses (and giving more frequently) has the additional benefit that if a dose is missed, it does not have as much impact on the average systemic exposure [ 31 ]. If the same (or even greater) percentage of pills are missed overall relative to monthly dosing, dividing a similar total monthly dose into multiple doses throughout the month is still likely to result in higher PQ trough concentrations.…”

Section: Discussionmentioning

confidence: 99%

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

et al. 2016

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BackgroundThe combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children.MethodsBased on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1–2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose).ResultsOnce daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention.ConclusionsOnce weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.

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Section: Discussionmentioning

confidence: 99%

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

et al. 2016

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“…Steiner’s seminal description of methods of assessing refill compliance introduced the concept of the “compliance-adjusted daily dose” [ 2 ]. More recently, an individualized method of drug selection and dose adjustment based on adherence patterns has been described for the oral anticoagulant agents warfarin and acenocoumarol [ 35 ]. Such individualized prescription patterns have the potential to reduce costs and prevent adverse effects over a long-term course of treatment.…”

Section: Discussionmentioning

confidence: 99%

The Adherence Rate Threshold is Drug Specific

Stauffer¹,

Hutson

Kaufman³

et al. 2017

Drugs R D

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IntroductionPatient adherence to a medication regimen is usually expressed as an adherence rate, defined as the proportion of prescribed doses actually taken. An adherence rate threshold, above which the therapeutic effect is maintained, is typically assigned an arbitrary value, commonly 0.8.ObjectiveHere, we determined the value of the adherence rate threshold objectively in different drugs of the same class, using statins as an example.MethodsWe used pharmacokinetic/pharmacodynamic (PK/PD) modeling to predict serum levels of low-density lipoprotein cholesterol (LDL-C) in patients taking simvastatin 20 mg or atorvastatin 5 mg once daily for 30 days. LDL-C reduction was modeled for adherence rates of 1.0, 0.8, 0.6, 0.4, and 0.2. The results were expressed as the percentage of time spent at the LDL-C goal (< 70 mg/dL). The adherence rate threshold was defined as the minimum adherence rate that resulted in the same amount of time at goal as perfect adherence (i.e., a rate of 1.0).ResultsFor simvastatin, an adherence rate of 0.8 resulted in a significant decrease in time at the LDL-C goal compared to perfect adherence (54.8% versus 85.1%; P < 0.001), and rates < 0.8 resulted in progressively less time at goal. For atorvastatin, the rates of 0.8 and 0.6 resulted in essentially the same amount of time at goal as perfect adherence (87.8% and 87.7%, respectively, versus 88.1%; P > 0.05 for both), with less time at goal only occurring at rates ≤ 0.4 (P < 0.001). Thus, the adherence rate thresholds are > 0.8 for simvastatin and between 0.4 and 0.6 for atorvastatin.ConclusionThese results indicate that a value of 0.8 cannot be applied universally.

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“…Treatment effect modeling is most often based on pharmacokinetic-pharmacodynamics relationships and models on this topic are already available [ 44 ]. These models are especially useful for predicting biomarker changes after changing the dosage of an administered treatment [ 45 , 46 ]. In cystic fibrosis, Smith et al [ 47 ] reviewed existing mathematical models of the fluid mechanics of mucociliary clearance, taking into account the morphology of the bronchial and tracheal airway surface liquid and ciliated epithelium, the cilia beat cycle, beat frequency and metachronal coordination and also the rheology of the mucous layer.…”

Section: Introductionmentioning

confidence: 99%

“…A simulation plan is then set-up with a list of linked models [ 45 , 52 ]. For a given therapeutic strategy, each simulation model is classified by one of these sub-models:…”

Section: Introductionmentioning

confidence: 99%

A methodological framework for drug development in rare diseases

Nony

Kurbatova

Bajard

et al. 2014

Orphanet J Rare Dis

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IntroductionDeveloping orphan drugs is challenging because of their severity and the requisite for effective drugs. The small number of patients does not allow conducting adequately powered randomized controlled trials (RCTs). There is a need to develop high quality, ethically investigated, and appropriately authorized medicines, without subjecting patients to unnecessary trials.Aims and ObjectivesThe main aim is to develop generalizable framework for choosing the best-performing drug/endpoint/design combinations in orphan drug development using an in silico modeling and trial simulation approach. The two main objectives were (i) to provide a global strategy for each disease to identify the most relevant drugs to be evaluated in specific patients during phase III RCTs, (ii) and select the best design for each drug to be used in future RCTs.Methodological approachIn silico phase III RCT simulation will be used to find the optimal trial design and was carried out in two steps: (i) statistical analysis of available clinical databases and (ii) integrative modeling that combines mathematical models for diseases with pharmacokinetic-pharmacodynamics models for the selected drug candidates.ConclusionThere is a need to speed up the process of orphan drug development, develop new methods for translational research and personalized medicine, and contribute to European Medicines Agency guidelines. The approach presented here offers many perspectives in clinical trial conception.

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Compliance-Guided Therapy

Cited by 11 publications

References 37 publications

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

The Adherence Rate Threshold is Drug Specific

A methodological framework for drug development in rare diseases

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