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Drug Design, Development and Therapy 2021Schizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population...
BACKGROUND
Schizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population pharmacokinetics of olanzapine in elderly patients. Missed doses are a common and unavoidable issue during the treatment of psychiatric diseases, especially in elderly patients. This study aimed to identify what an elderly person should do if doses are inadvertently missed.
METHODS
Data were collected from 140 elderly psychiatric patients (aged ≥65 years) who received olanzapine therapy. Olanzapine concentrations were determined by high pressure liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) and a population-based approach was used to quantify the characteristics of elderly patients. A non-linear mixed-effects model was used for data analysis. Simulations based on the final model were applied to predict situations involving a single missed dose or three consecutive missed doses under several remedial regimens.
RESULTS
A total of 474 samples from 140 elderly patients were included in the therapeutic drug monitoring (TDM) data analysis. A one-compartment model, with no significant covariates, was developed to describe the population pharmacokinetics of olanzapine in elderly patients. The population predicted systematic clearance (CL/F) and volumes of distribution (V/F) were 18 L/h and 785 L, respectively. The simulation demonstrated that in a missed dose situation, elderly patients should take the regular dose immediately; the refill dose used at the second remedial time point depends on the length of the time delay.
CONCLUSION
Here, we used a simulation to provide a remedial regimen for missed doses of olanzapine in the elderly population. Our simulation can provide valuable suggestions for individualized therapy in elderly patients.
Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Chromatography, High Pressure Liquid; Computer Simulation; Drug Administration Schedule; Drug Monitoring; Female; Humans; Male; Medication Adherence; Models, Biological; Nonlinear Dynamics; Olanzapine; Retrospective Studies; Schizophrenia; Tandem Mass Spectrometry; Time Factors; Tissue Distribution
PubMed: 34376974
DOI: 10.2147/DDDT.S316110 -
European Journal of Drug Metabolism and... Sep 2022Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses...
BACKGROUND AND OBJECTIVE
Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens.
METHODS
Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate.
RESULTS
The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h.
CONCLUSIONS
The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.
Topics: Anticonvulsants; Computer Simulation; Humans; Levetiracetam; Monte Carlo Method; Piracetam; Seizures
PubMed: 35761145
DOI: 10.1007/s13318-022-00774-9 -
BMJ Quality Improvement Reports 2015The unintentional omission of medication is one of the most commonly-reported administration errors on hospital wards throughout the world. The omission of a dose of...
The unintentional omission of medication is one of the most commonly-reported administration errors on hospital wards throughout the world. The omission of a dose of medication can severely harm the patient affected, but to date there is limited evidence about cost-effective means for reducing the incidence of such errors. The current report describes a quality improvement project, conducted on the mental healthcare of older people (MHCOP) wards in East London NHS Foundation Trust, which led to a greater than 90% reduction in the rate of unintentionally omitted doses of medication. The project involved the publication of a fortnightly league table which ranked each of the wards by how many doses they had missed, with the ward missing the fewest doses receiving a prize. PDSA cycles were used to refine the concept, with the final incarnation of the fortnightly league table also incorporating the publication of a poster for each ward which showed how many weeks it had been since the ward missed a dose, and the ward's overall trend in missed doses. The project has resulted in the average missed dose rate on the MCHOP wards decreasing from 1.07% to 0.07%. In real terms, this represents a reduction from an estimated 2878 to 188 missed doses per year on the six MHCOP wards. By greatly reducing the risk of patients experiencing adverse drug events as a result of missed doses, this project has given rise to a potential cost-saving of around £34,000 per year across the wards studied. The use of league tables represents a simple, cost-effective means of tackling the problem of doses of medication being unintentionally omitted on hospital wards.
PubMed: 26734424
DOI: 10.1136/bmjquality.u204237.w3567 -
Radiology Dec 2002To compare clinical, histopathologic, and imaging features of lung cancers missed at low-radiation-dose helical computed tomography (CT). (Comparative Study)
Comparative Study
PURPOSE
To compare clinical, histopathologic, and imaging features of lung cancers missed at low-radiation-dose helical computed tomography (CT).
MATERIALS AND METHODS
Eighty-three primary lung cancers were found during an annual low-dose CT screening program and confirmed histopathologically at either surgery or biopsy. Thirty-two of these lung cancers were missed on 39 CT scans: on 23 scans owing to detection errors and on 16 owing to interpretation errors. The clinical characteristics, CT features, and histopathologic findings of these missed lung cancers were correlated.
RESULTS
All missed cancers were intrapulmonary, and 28 (88%) were stage IA. All 20 detection errors occurred in cases of adenocarcinoma, 17 (85%) of which were well-differentiated tumors and 11 (55%) of which were in nonsmoking women. The mean size of cancers missed owing to detection error, 9.8 mm, was smaller than that of cancers missed owing to interpretation error, 15.9 mm (P <.001). In the detection error group, the percentages of nodules with ground-glass opacity (91%) or judged to be subtle (91%) were greater than those of nodules in the interpretation error group (38% and 25%, respectively) (P <.001). In the detection error group, 83% (19/23) of cancers were overlapped with, obscured by, or similar in appearance to normal structures such as pulmonary vessels. On 14 of the 16 CT scans with which there were interpretation errors, the CT findings mimicked benign disease, and the patients also had underlying lung disease, such as tuberculosis, emphysema, or lung fibrosis.
CONCLUSION
The lung cancers missed at low-dose CT screening in this series generally were very subtle and appeared as small faint nodules, overlapping normal structures, or opacities in a complex background of other disease.
Topics: Adenocarcinoma; Aged; Diagnostic Errors; Female; Humans; Lung; Lung Neoplasms; Male; Mass Screening; Middle Aged; Radiation Dosage; Risk Factors; Tomography, Spiral Computed
PubMed: 12461245
DOI: 10.1148/radiol.2253011375 -
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 -
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 -
Vnitrni Lekarstvi Nov 2014Irregular insulin dose is one of the main problems associated with insulin therapy in patients with type 2 diabetes; its extent is not known precisely. The aim of survey...
[Adherence of type 2 diabetes patients on insulin analogues application: missed dose, time imprecision and dose reduction. The results of GAPP2TM(Global Attitudes of Physicians and Patient) survey in the Czech Republic].
OBJECTIVE
Irregular insulin dose is one of the main problems associated with insulin therapy in patients with type 2 diabetes; its extent is not known precisely. The aim of survey conducted in the Czech Republic in the international project GAPP2 - Global Attitudes of Patients and Physicians was to determine the incidence and the impact of irregular use of basal insulin analogues in patients with type 2 diabetes, to point out the reasons for these irregularities and to focus on how physicians discuss irregular application of insulin with patients.
METHODS
The project GAPP2 is an international cross-sectional study performed on-line via the Internet using a questionnaire filled by diabetic patients treated with insulin analogues and physicians who treat these patients. The survey was conducted in two steps in 17 countries; the first step included 6 countries and was completed in the beginning of 2012, the second step involved 11 other countries including the Czech Republic with termination in 2014. The survey was designed to obtain the views of patients and physicians on certain aspects of insulin treatment and persistent issues in this field in the real daily practice. Special focus was on the incidence and management of hypoglycaemia as well as on irregularities of insulin application. In the part dedicated to adherence to basal insulin application were observed three types of irregular insulin therapy: missed dose, time imprecision of dose (± 2 hours vs. the prescribed time) and dose reduction in all cases in the past 30 days before completing the questionnaire. In addition, it was investigated the attitude and relation of patients to these issues.
RESULTS
The results have shown that irregular insulin dose in the Czech Republic is less frequent than in other countries involved in the GAPP2 research. Nevertheless, approximately one fifth of diabetic patients using insulin analogues in basal-bolus or only basal therapy regimen is related to this problem. The last irregular insulin application was due to missed dose in 13% of cases, time imprecision in 23% and reduction of dose in 61% of cases. The most commonly reported reason was risk reduction of hypoglycaemia and the recommendations of health professionals. Fear of missed dose is present in 40% Czech patients and 35% would feel guilty if their insulin dose is missed (up to 47% in patients with intensified insulin regimen). Only 60% patients are aware of negative impact on their long-term health after missed dose of basal insulin. Questioned doctors have suspected that the patients report lower number of missed doses during regular medical check because one third of patients doesn´t admit missed dose. However, this fact conceded only 11% of patients on basal insulin and 15% of patients on intensified insulin therapy. Quarter of prescribing doctors admit that they usually don´t discuss with patients irregularities in basal insulin treatment.
CONCLUSION
Although, type 2 diabetes patients in the Czech Republic follow prescribed basal insulin therapy scheme more often than patients in other countries participating in the survey GAPP2 , missed dose, time imprecision and reduction of dose is quite common and it deserves more attention from medical side during regular medical check together with appropriate education of patients.
Topics: Adult; Aged; Attitude to Health; Cross-Sectional Studies; Czech Republic; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Internet; Male; Medication Adherence; Middle Aged; Patient Education as Topic; Reminder Systems; Self Administration; Surveys and Questionnaires
PubMed: 25600048
DOI: No ID Found -
Journal of Pharmacokinetics and... Dec 2021Medication adherence is a major problem for patients with chronic diseases that require long term pharmacotherapy. Many unanswered questions surround adherence,...
Medication adherence is a major problem for patients with chronic diseases that require long term pharmacotherapy. Many unanswered questions surround adherence, including how adherence rates translate into treatment efficacy and how missed doses of medication should be handled. To address these questions, we formulate and analyze a mathematical model of the drug concentration in a patient with imperfect adherence. We find exact formulas for drug concentration statistics, including the mean, the coefficient of variation, and the deviation from perfect adherence. We determine how adherence rates translate into drug concentrations, and how this depends on the drug half-life, the dosing interval, and how missed doses are handled. While clinical recommendations require extensive validation and should depend on drug and patient specifics, as a general principle our theory suggests that nonadherence is best mitigated by taking double doses following missed doses if the drug has a long half-life. This conclusion contradicts some existing recommendations that cite long drug half-lives as the reason to avoid a double dose after a missed dose. Furthermore, we show that a patient who takes double doses after missed doses can have at most only slightly more drug in their body than a perfectly adherent patient if the drug half-life is long. We also investigate other ways of handling missed doses, including taking an extra fractional dose following a missed dose. We discuss our results in the context of hypothyroid patients taking levothyroxine.
Topics: Humans; Medication Adherence; Treatment Outcome
PubMed: 34506001
DOI: 10.1007/s10928-021-09777-6 -
AIDS Care Jul 2007The construct 'missed dose' is central to many assessments of medication adherence. However, few studies have investigated how patients or clinicians conceptualize...
The construct 'missed dose' is central to many assessments of medication adherence. However, few studies have investigated how patients or clinicians conceptualize missed doses or the extent of the concordance or discordance between clinicians and patients. To address this gap we conducted semi-structured interviews with 45 sero-positive African American adults taking HAART and 17 of their clinicians. Results reveal large variability in missed dose conceptions among both patients and physicians and significant differences between the two groups. Overall, patients reported a stricter definition of missed dose than did clinicians. Fifty-five percent of patients thought that a pill-taking delay of six hours beyond the prescribed dosing time constituted a missed dose, by comparison, only one physician agreed with this assessment. More than one-third of patients thought that the proper response to a missed dose would be to skip it altogether, but only about 12% of clinicians agreed. These findings have implications for the construct validity of self-report measures of adherence, for patient adherence behaviours based on missed dose conceptions and for patient-physician relationships and communication within the clinical environment.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Interviews as Topic; Male; Patient Compliance; Self Disclosure; Treatment Refusal
PubMed: 17573598
DOI: 10.1080/09540120600708501 -
The Journal of Surgical Research Jan 2019Missing doses of antibiotics in hospitalized patients is a well-described but inadequately recognized issue. We hypothesized that missing doses of antibiotics decreases...
BACKGROUND
Missing doses of antibiotics in hospitalized patients is a well-described but inadequately recognized issue. We hypothesized that missing doses of antibiotics decreases quality of care.
METHODS
Retrospective study on patients admitted to the Shock Trauma ICU from February to June 2015. Patients prescribed a multidose course of antibiotics were evaluated. A missed antibiotic dose was one ordered but never given (a completely missed dose) or a dose that was not given within an hour before or after the planned time (an off-schedule missed dose). Patient outcomes included a positive culture, ventilator, ICU and hospital length of stay (LOS), and mortality. Multiple statistical methods were used as appropriate; significance was set as P < 0.05.
RESULTS
For the 5-mo study period, 280 patients were admitted and 200 met inclusion criteria. Eight percent of patients (16/200) did not miss any antibiotic doses, 39% (77/200) had only off-schedule doses, 2% (4/200) had only completely missed doses, and 51% (103/200) had both off-schedule and completely missed doses. For the 200 patients, 8167 doses were ordered and 2096 (26%) were missed. Adjusting for age, gender, BMI, injury severity score, and doses of antibiotics showed that those who miss doses off-schedule had longer LOS than those who do not miss doses of antibiotics. There was a significant nonlinear relationship between LOS and frequency of early (P-value = 0.02) and late (P-value = 0.01) doses.
CONCLUSIONS
To reduce length of hospital stay and optimize quality, methods to improve compliance with antibiotic dosing schedules should be investigated.
Topics: Adult; Aged; Anti-Bacterial Agents; Drug Prescriptions; Female; Hospital Mortality; Humans; Injury Severity Score; Intensive Care Units; Length of Stay; Male; Medication Errors; Middle Aged; Outcome and Process Assessment, Health Care; Quality of Health Care; Retrospective Studies; Trauma Centers; Wounds and Injuries
PubMed: 30502260
DOI: 10.1016/j.jss.2018.08.015