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Bulletin of Mathematical Biology Dec 2021Medication adherence is a well-known problem for pharmaceutical treatment of chronic diseases. Understanding how nonadherence affects treatment efficacy is made...
Medication adherence is a well-known problem for pharmaceutical treatment of chronic diseases. Understanding how nonadherence affects treatment efficacy is made difficult by the ethics of clinical trials that force patients to skip doses of the medication being tested, the unpredictable timing of missed doses by actual patients, and the many competing variables that can either mitigate or magnify the deleterious effects of nonadherence, such as pharmacokinetic absorption and elimination rates, dosing intervals, dose sizes, and adherence rates. In this paper, we formulate and analyze a mathematical model of the drug concentration in an imperfectly adherent patient. Our model takes the form of the standard single compartment pharmacokinetic model with first-order absorption and elimination, except that the patient takes medication only at a given proportion of the prescribed dosing times. Doses are missed randomly, and we use stochastic analysis to study the resulting random drug level in the body. We then use our mathematical results to propose principles for designing drug regimens that are robust to nonadherence. In particular, we quantify the resilience of extended release drugs to nonadherence, which is quite significant in some circumstances, and we show the benefit of taking a double dose following a missed dose if the drug absorption or elimination rate is slow compared to the dosing interval. We further use our results to compare some antiepileptic and antipsychotic drug regimens.
Topics: Anticonvulsants; Humans; Mathematical Concepts; Medication Adherence; Models, Biological; Treatment Outcome
PubMed: 34928435
DOI: 10.1007/s11538-021-00976-3 -
British Journal of Nursing (Mark Allen... Aug 2023Elective surgical patients need accurate drug charts to reduce missed medication doses, decreasing the chance of peri-operative complications. The quality improvement...
Elective surgical patients need accurate drug charts to reduce missed medication doses, decreasing the chance of peri-operative complications. The quality improvement project described in this article used four interventions to improve the percentage of missed medication doses. A driver diagram was produced to interrogate the current pathway which highlighted multiple interventions, including changes to elective pro formas, the initial clerking process and nurse-based prescribing. Once implemented, a plan-do-study-act (PDSA) cycle was completed as per NHS Improvement guidelines. Overall, missed medication dose percentage decreased from 9.8% to 0% after the interventions. Two of these changes have been deemed sustainable and have been integrated into elective patient pathways, improving both patient safety and streamlining surgical elective patient services. This project highlights the importance of prescribing practice in a multidisciplinary team. Simple changes to established systems allow for better patient care, and the authors' project provides evidence that empowering nursing staff to take the lead in the medication management of patients can reduce the likelihood of negative outcomes in a patient's admission.
Topics: Humans; Elective Surgical Procedures; Hospitalization; Patient Safety; Patients; Quality Improvement
PubMed: 37596075
DOI: 10.12968/bjon.2023.32.15.730 -
ERJ Open Research Oct 2020Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation... (Review)
Review
Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy - as adopted by the international adherence community - to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the "forgiveness" of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress.
PubMed: 33263043
DOI: 10.1183/23120541.00315-2020 -
Bipolar Disorders Nov 2022Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow...
OBJECTIVES
Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations.
METHODS
Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L.
RESULTS
The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable.
CONCLUSIONS
This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.
Topics: Humans; Monte Carlo Method; Lithium; Bipolar Disorder
PubMed: 35766143
DOI: 10.1111/bdi.13241 -
Journal of Pharmacokinetics and... Aug 2022Missed doses, late doses, and other dosing irregularities are major barriers to effective pharmacotherapy, especially for the treatment of chronic conditions. What...
Missed doses, late doses, and other dosing irregularities are major barriers to effective pharmacotherapy, especially for the treatment of chronic conditions. What should a patient do if they did not take their last dose at the prescribed time? Should they take it late or skip it? In this paper, we investigate the pharmacokinetic effects of taking a late dose. We consider a single compartment model with linear absorption and elimination for a patient instructed to take doses at regular time intervals. We suppose that the patient forgets to take a dose and then realizes some time later and must decide what remedial steps to take. Using mathematical analysis, we derive several metrics which quantify the effects of taking the dose late. The metrics involve the difference between the drug concentration time courses for the case that the dose is taken late and the case that the dose is taken on time. In particular, the metrics are the integral of the absolute difference over all time, the maximum of the difference, and the maximum of the integral of the difference over any single dosing interval. We apply these general mathematical formulas to levothyroxine, atorvastatin, and immediate release and extended release formulations of lamotrigine. We further show how population variability can be immediately incorporated into these results. Finally, we use this analysis to propose general principles and strategies for dealing with dosing irregularities.
Topics: Anticonvulsants; Delayed-Action Preparations; Humans
PubMed: 35726046
DOI: 10.1007/s10928-022-09812-0 -
Australian Prescriber Apr 2015Long-term treatment with warfarin is recommended for patients with atrial fibrillation at risk of stroke and those with recurrent venous thrombosis or prosthetic heart... (Review)
Review
Long-term treatment with warfarin is recommended for patients with atrial fibrillation at risk of stroke and those with recurrent venous thrombosis or prosthetic heart valves. Patient education before commencing warfarin - regarding signs and symptoms of bleeding, the impact of diet, potential drug interactions and the actions to take if a dose is missed - is pivotal to successful use. Scoring systems such as the CHADS2 score are used to determine if patients with atrial fibrillation are suitable for warfarin treatment. To rapidly achieve stable anticoagulation, use an age-adjusted protocol for starting warfarin. Regular monitoring of the anticoagulant effect is required. Evidence suggests that patients who self-monitor using point-of-care testing have better outcomes than other patients.
PubMed: 26648615
DOI: 10.18773/austprescr.2015.016 -
European Journal of Clinical... Nov 2022To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes...
PURPOSE
To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes using Monte Carlo simulations.
METHODS
Monte Carlo simulations were performed for various replacement dosing schemes using the parameters from the published population pharmacokinetic models. The lowest percentage of deviation of simulated concentrations outside the reference range of 5-20 mg/L from the compliance scenario for each replacement dosing scheme was used as a criterion for choosing the proper replacement dosing scheme.
RESULTS
For the one missed dose, the replacement with an immediate regular dose and a partial dose resulted in the lowest and highest percentages of concentration below 5 mg/L, respectively. While the opposite results were observed for the upper bound of the reference range (20 mg/L). For the two consecutive missed doses, the replacement with one and a half-missed doses resulted in a lower percentage of deviation of concentrations below 5 mg/L from the compliance scenario than the replacement with one regular dose.
CONCLUSIONS
For the one missed dose, taking an immediate regular dose might be suitable for patients who require higher TPM levels, while for patients who require lower TPM levels, an immediate partial dose could be used. For the two consecutive missed doses, an immediate one and a half regular dose might be suitable. However, these results were merely based on simulations; thus, they should be used alongside the clinician's justification based on seizure control.
Topics: Anticonvulsants; Drug Administration Schedule; Fructose; Humans; Monte Carlo Method; Topiramate
PubMed: 36121498
DOI: 10.1007/s00228-022-03390-3 -
Respiratory Medicine 2019Smart inhalers, connected to smartphones, can provide real-life objective information about the patterns of a patient's adherence and their inhaler technique during... (Review)
Review
Smart inhalers, connected to smartphones, can provide real-life objective information about the patterns of a patient's adherence and their inhaler technique during routine use. The e-modules contain the battery and measuring sensors. Many of these are add-on modules attached externally whilst others are integrated inside the inhaler. Smart inhalers that identify a dose has either been actuated or prepared do not confirm the dose was inhaled but they can send missed dose reminders and clinical studies have highlighted their potential to improve adherence and outcomes. The e-modules that measure an inhalation profile confirm a dose has been inhaled together with providing useful information about the inhaler technique. Studies confirm that the sensors are accurate and confirm their usefulness to provide information about real-life inhaler use. Add-on e-modules are generic whereas integrated smart inhalers can be approved containing active agents and, therefore, prescribed and instructed under healthcare guidance. Real-life studies need to be carried out to demonstrate their potential to improve disease control and prevent exacerbations to justifying their increased cost.
Topics: Female; Humans; Male; Nebulizers and Vaporizers; Patient Compliance
PubMed: 31563027
DOI: 10.1016/j.rmed.2019.09.008 -
CPT: Pharmacometrics & Systems... Dec 2022Response-based dose individualization or dose titration is a powerful approach to achieve precision dosing. Yet, titration as an individualization strategy is underused...
Response-based dose individualization or dose titration is a powerful approach to achieve precision dosing. Yet, titration as an individualization strategy is underused in drug development and therefore not reflected in labeling, possibly partly because of the data analysis challenges associated with assessing dose/exposure-response under dose titration, where there is an inherent risk of selection bias because poor responders would get high doses, whereas good responders would get low doses. In a recent article, this issue of selection bias was termed the "titration paradox." In this study, we demonstrate by means of simulation that the titration paradox may be overcome if longitudinal data from dose titration trials is analyzed using a population approach that accounts for the fact that dose/exposure-response relationships differ between individuals. We show that with an appropriate sample size and missing data missing at random, stepwise dose/exposure-response modeling based on data obtained under dose titration is not by definition subject to model selection bias or bias in parameter estimates. We also illustrate the challenges of graphical exploration of data obtained under dose titration and discuss the use of model diagnostic tools with such data. Our study shows that if, at every timepoint in the course of a trial, there is a clear causal relationship between the response and the dose/exposure level, and a population approach is used, it will in many cases be possible to develop, estimate, and appropriately qualify a dose/exposure-response model also for data obtained under dose titration, thus overcoming the titration paradox.
Topics: Humans; Computer Simulation; Dose-Response Relationship, Drug
PubMed: 36125910
DOI: 10.1002/psp4.12863 -
European Journal of Endocrinology May 2022Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients.... (Clinical Trial)
Clinical Trial
OBJECTIVE
Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose-insulin-like growth factor I (IGF-I) responses in AGHD patients.
DESIGN
Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.
METHODS
Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose-IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.
RESULTS
The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.
CONCLUSIONS
This study extends the knowledge of the somapacitan dose-IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.
Topics: Adult; Dwarfism, Pituitary; Estrogens; Female; Histidine; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Mannitol; Phenol; Pituitary Hormones, Anterior
PubMed: 35521713
DOI: 10.1530/EJE-21-1167