-
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 -
The Journal of Pharmacy Technology :... Apr 2022When medications dispensed from a hospital inpatient pharmacy aren't able to be found at their intended destination (ie, a missing dose), this can result in delayed...
When medications dispensed from a hospital inpatient pharmacy aren't able to be found at their intended destination (ie, a missing dose), this can result in delayed medication administration and rework to redispense the medication. Technology advancements in the medication use process have led to development of dose-tracking software that has the capability to track medication doses throughout the medication use cycle and document a medication's location to its destination. The primary objective of this study was to evaluate the impact of dose-tracking software on the number of inpatient pharmacy redispenses and nursing requests for missing medications. Secondary objectives included pharmacy staff satisfaction with dose-tracking software, its impact on workflow and patient safety, and compliance with dose-track scanning. The study design was a prospective, pre-post implementation to compare the requests for missing doses and associated dispenses of injectable medications during the set evaluation period. Dose-track scanning compliance data was collected and evaluated. A survey was also administered to staff to evaluate employee perception and satisfaction with usability and value of the software. During the preimplementation period, 40 021 injectable doses were dispensed, and 9841 (24.6%) were documented as redispensed doses. After dose-tracking implementation, 42 975 total injectable doses were dispensed with 9839 (22.9%) being redispensed. The count of medication messages was 10 661 in the preperiod and 11 475 in the postperiod. The data were normalized using case mix index (CMI) and patient days to account for variation in severity of illness. Implementation of dose-tracking software showed a decrease in the percentage of redispensed injectable medications.
PubMed: 35571343
DOI: 10.1177/87551225211069001 -
Frontiers in Allergy 2021Allergic rhinitis in childhood has been often missed, mistreated and misunderstood. It has significant comorbidities, adverse effects upon quality of life and... (Review)
Review
Allergic rhinitis in childhood has been often missed, mistreated and misunderstood. It has significant comorbidities, adverse effects upon quality of life and educational performance and can progress to asthma or worsen control of existing asthma. Accurate diagnosis and effective treatment are important. The new EUFOREA algorithm provides a succinct but wide- ranging guide to management at all levels, based on previous guidelines with updated evidence and has been adjusted and approved by experts worldwide.
PubMed: 35387065
DOI: 10.3389/falgy.2021.706589 -
Cureus Apr 2022In order to determine the prevalence of adherence among diabetes patients treated at Queens Hospital Center's Diabetes Clinic and to determine barriers preventing...
In order to determine the prevalence of adherence among diabetes patients treated at Queens Hospital Center's Diabetes Clinic and to determine barriers preventing adherence, 50 patients were asked a series of questions regarding their medication intake. The majority of patients reported that they understood the self-management steps that were necessary in order to control their diabetes. However, 30% of the interviewed patients with type 1 or type 2 diabetes reported that they missed a dose of their diabetes medication on at least one day in the last month. Forgetting and lifestyle inconveniences were the two most frequently reported reasons for non-adherence. Side effects and problems with the pharmacy or insurance were also significant reasons for non-adherence. Adherence can potentially be increased by combining new forms of treatment and increasing educational reinforcement.
PubMed: 35619860
DOI: 10.7759/cureus.24421 -
Journal of Family Medicine and Primary... Oct 2021The aging population is of growing concern all across the globe as well as in India. Polypharmacy has been defined as the simultaneous use of multiple medications by an... (Review)
Review
The aging population is of growing concern all across the globe as well as in India. Polypharmacy has been defined as the simultaneous use of multiple medications by an individual and the clinical suitability of such use. Polypharmacy is found more frequently in the geriatric population. Researches in India have also reiterated the fact. Polypharmacy in the geriatric population leads to many negative consequences such as increased adverse drug reactions, falls, frailty, and even increased mortality. Moreover, it leads to increased out-of-pocket expenditure. Polypharmacy also poses risk of poor treatment adherence and missed dose in the geriatric population. Mitigation measures in this regard may include increased awareness among physicians, improved medication management and adherence, efforts to reduce self-medication, and improper crosspathy.
PubMed: 34934644
DOI: 10.4103/jfmpc.jfmpc_2581_20 -
The World Allergy Organization Journal Feb 2020Adherence to medications is crucial in patients with severe asthma in light of the negative clinical impact and costs of non-adherence. Adherence to omalizumab has not...
BACKGROUND
Adherence to medications is crucial in patients with severe asthma in light of the negative clinical impact and costs of non-adherence. Adherence to omalizumab has not been well studied in real-world settings. The aim of this study was to assess adherence to omalizumab and evaluate treatment effectiveness in relation to adherence.
METHODS
This was a retrospective, observational, and multicenter real-world study. Omalizumab dose, timing of administration, and duration of treatment (<2 years; 2-4 years; > 4 years) were analyzed. Adherence was evaluated by examining rates of expected and missing doses. Good adherence (<10% of doses missed) and poor adherence (>10% doses missed) were determined. For effectiveness in relation to adherence of omalizumab we considered asthma exacerbations, hospitalizations, asthma control test (ACT), and Forced Expiratory Volume in 1 s (FEV).
RESULTS
A total of 196 patients were evaluated, and 161 were suitable for data analyses. Good adherence was shown in 90.7% of patients and poor adherence in 9.3%. Considering adherence in relation to treatment duration: <2 years, 87.8% of patients were adherent (expected doses, 1186; missed doses, 53); 2-4 years, 85.9% were adherent (expected doses, 2985; missed doses, 127); >4 years, 100% were adherent (expected doses, 6120; missed doses, none). Indices of efficacy between pre- and post-treatment showed significant improvement (p < 0.001). The effectiveness indices between pre- and post-treatment, among adherent and non-adherent patients, ACT, and asthma exacerbations both showed significant differences (p = 0.043 and p = 0.049, respectively). Binomial logistic regression analysis showed that increasing age, better ACT score, and 14-day timing were significantly associated with increased adherence to therapy.
CONCLUSIONS
High adherence to omalizumab was demonstrated in a real-world setting, which was associated with better outcomes and control of asthma.
PubMed: 32082464
DOI: 10.1016/j.waojou.2020.100103 -
PLOS Global Public Health 2022Initiating with a birth dose and a full immunization against hepatitis-B is crucial during early childhood in a country like India where maternal screening of...
Initiating with a birth dose and a full immunization against hepatitis-B is crucial during early childhood in a country like India where maternal screening of hepatitis-B surface antigen is almost negligible and there is a considerable risk of vertical transmission among children. It is also evident that coverage of hepatitis-B is lowest among all other vaccine doses included in the universal immunization program. In addition, the major challenge is posed by the missed and drop-out of different doses of hepatitis-B among Indian children. In this context, this study examined the population and sub-national level diversity in missed and dropout of different doses of hepatitis-B vaccine in India. We analysed a large dataset of 196,654 children aged 12-59 months from a nationally representative cross-sectional survey, the National Family Health Survey (NFHS), 2015-16. Bivariate cross tabulation was used to estimate the prevalence and the dropout rates. Multivariable-adjusted logistic regression was applied to assess the likelihood of the study events. Within a Bayesian framework, a district-level spatial analysis was conducted employing the Besag-York-Mollie (BYM) Model and the Leroux Model. During 2016, 38% of the children missed the birth dose nationally and 45% of the children did not complete full immunization of hepatitis-B. Findings suggest, presence of socio-economic and demographic gradients in missed and drop-out of different doses of hepatitis-B at national level. The sub-national level spatial analysis identifies more than 280 (out of 640) districts with substantially higher risk (Posterior Median Risk>1) in terms of missed and drop-out of different doses. Most of these districts are scattered across the North-Eastern and Northern part of India. The findings hint the existence of a population and sub-national level diversity in India's missed out and dropout of hepatitis-B doses. Identifying high risk population sub-groups and the districts with children at higher risk of missing the birth and consecutive doses informs the existing knowledge base and helps in formulating community-oriented policies and programs.
PubMed: 36962208
DOI: 10.1371/journal.pgph.0000243 -
Journal of Medical Systems May 2022Pharmacy robots and automated dispensing cabinets are commonly used to distribute medications to inpatient units efficiently and safely. Decisions regarding the use of...
Pharmacy robots and automated dispensing cabinets are commonly used to distribute medications to inpatient units efficiently and safely. Decisions regarding the use of these technologies are often made without full knowledge regarding system effects. This paper determines a cost effective and safe way to distribute medications to patients across a hospital system by minimizing the distribution cost and missing dose rate. A mathematical model is formulated which captures key aspects of the pharmacy distribution process to determine a primary pathway to distribute each medication and dose type to each unit. The model focuses on three primary distribution pathways: cart fill via pharmacy robot, cart fill via pharmacy technician, and automated dispensing cabinets. The problem is solved using a complete year of data from the Geisinger Medical Center. The model results demonstrate the trade-off between pharmacy technician and nurse workload and missing dose rates that occur as hospitals move from a centralized pharmacy to automated dispensing cabinets. These results demonstrate the importance of evaluating the labor effort and missing dose rates when determining the best method to distribute medication.
Topics: Hospitals; Humans; Inpatients; Medication Systems, Hospital; Pharmacy Service, Hospital; Workload
PubMed: 35501418
DOI: 10.1007/s10916-022-01822-2 -
Allergologie Select 2019Phase II studies on allergen immunotherapy (AIT) should define the dose with the best balance between efficacy and safety ("optimal dose"). Their key role is based on... (Review)
Review
Phase II studies on allergen immunotherapy (AIT) should define the dose with the best balance between efficacy and safety ("optimal dose"). Their key role is based on dose selection for subsequent pivotal studies (phase III, field studies). Since products for AIT differ in composition and unit definitions, phase II trials are mandatory for new products and preparations being developed according to the German Therapy Allergen Ordinance ("Therapie-Allergeneverordnung", TAV) due to current EMA guidelines since 2009. The latter permit various in-vivo models and endpoints for phase II studies, e.g., AIT-induced changes in skin test, nasal, conjunctival or bronchial provocation, or in exposure chamber or field trials. Selection and graduation of the doses, minimization of placebo effects, and sufficient numbers of patients are a challenge. Effort, required time, and costs are important variables for the initiators of phase II trials. Risks are characterized by e.g., a) too small doses without relevant differences compared to placebo, b) missing true dose-response relationships, c) strong placebo effect and consequently small "therapeutic window", d) large heterogeneity and missing distinct differences (compared to placebo), e) too small effects in field studies due to low allergen exposure, f) missing dose-related increase (in case of too high doses). In the view of the Paul-Ehrlich-Institute, the unambiguous phase II trials with TAV products performed until today were not able to confirm the marketed doses for AIT. Regardless of the utilized model, more raw and single data should illustrate the individual outcome of AIT during phase II trials, facilitating an improved and more intuitive interpretation of the data (placebo effects? scattering?). In the medium term, evidence regarding AIT efficacy will considerably increase due to phase II trials as a prerequisite for subsequent phase III field studies. This affects all manufacturers offering AIT products in Germany and Europe.
PubMed: 32176223
DOI: 10.5414/ALX02033E