Impact of timing and combination of different BNT162b2 and ChAdOx1-S COVID-19 basic and booster vaccinations on humoral immunogenicity and reactogenicity in adults.

In this single-center observational study with 1,206 participants, we prospectively evaluated SARS-CoV-2-antibodies (anti-S RBD) and vaccine-related adverse drug reactions (ADR) after basic and booster immunization with BNT162b2- and ChAdOx1-S-vaccines in four vaccination protocols: Homologous BNT162b2-schedule with second vaccination at either three or six weeks, homologous ChAdOx1-S-vaccination or heterologous ChAdOx1-S/BNT162b2-schedule, each at 12 weeks. All participants received a BNT162b2 booster. Blood samples for anti-S RBD analysis were obtained multiple times over a period of four weeks to six months after basic vaccination, immediately before, and up to three months after booster vaccination. After basic vaccination, the homologous ChAdOx1-S-group showed the lowest anti-S RBD levels over six months, while the heterologous BNT162b2-ChAdOx1-S-group demonstrated the highest anti-S levels, but failed to reach level of significance compared with the homologous BNT162b2-groups. Antibody levels were higher after an extended vaccination interval with BNT162b2. A BNT162b2 booster increased anti-S-levels 11- to 91-fold in all groups, with the homologous ChAdOx1-S-cohort demonstrated the highest increase in antibody levels. No severe or serious ADR were observed. The findings suggest that a heterologous vaccination schedule or prolonged vaccination interval induces robust humoral immunogenicity with good tolerability. Extending the time to boost-immunization is key to both improving antibody induction and reducing ADR rate.

[Polypharmacy in nursing homes: options to improve drug therapy safety]. / Multimedikation in Einrichtungen der stationären Langzeitpflege: Möglichkeiten einer Verbesserung der Arzneimitteltherapiesicherheit (AMTS).

Patients in need of care usually suffer from multiple chronic conditions and therefore receive a high number of drugs. Polypharmacy involves multiple risks, for example, drug-drug and drug-disease interactions, adverse effects and potentially inappropriate medication (PIM), more hospital admissions, and increased mortality.Residents in long-term care facilities are particularly sensitive to adverse drug reactions because of age-related changes, frailty, and the high prevalence of dementia. Numerous drugs have side effects that lead to sedation, particularly in old age, and increase the risk of falls. In addition, anticholinergic effects negatively modify cognition. These PIMs are frequently prescribed to nursing home residents.The medication process in long-term care facilities is complex and requires numerous coordinated processes. In addition to the correct administration, the nursing staff have other important tasks such as monitoring the effects and potential adverse drug reactions and communicating their observations to the prescribing physicians and home-supplying pharmacists. The nursing staff therefore play a crucial role in the prescription of psychotropic drugs and contribute to the medication quality for nursing home residents. National and international studies indicate that improvements of polypharmacy and drug therapy safety in nursing homes can only be achieved by interprofessional collaboration.

Potentially Inadequate Medications in the Elderly: PRISCUS 2.0.

BACKGROUND: The term potentially inadequate medication (PIM) is used to describe substances that may be unsuitable for use inthe elderly and should be avoided. The PRISCUS list, published in 2010, was the first catalog of PIM designed for the Germandrug market to become adopted in practice. While 24% of German patients aged ≥ 65 years were prescribed at least one PIMper year in 2009, the proportion in 2019 was only 14.5%. METHODS: In a three-round Delphi process, experts from clinical practice and research evaluated whether selected substancesare PIM for the elderly. The participants were provided with dedicated literature including systematic reviews carried out for theparticular purposes of this project. RESULTS: Fifty-nine persons took part in the Delphi process and, in addition, contributed comments and therapeutic alternatives.Altogether, 187 substances were classed as PIM. One hundred thirty-three of the substances now listed were not in the originalPRISCUS list: these include some oral antidiabetics, all of the selective COX-2 inhibitors, and moderately long acting benzodiazepinessuch as oxazepam. For some other substances, e.g., proton pump inhibitors (PPI), the advisability of treatment formore than 8 weeks was considered as potentially inappropriate, as was the use of ibuprofen in doses >1200 mg/day and formore than 1 week without PPI. Risperidone for more than 6 weeks is also PIM. CONCLUSION: The new, greatly extended PRISCUS list must now be validated in epidemiological and prospective studies and itspracticability in routine daily use must be verified.

Development of a deprescribing manual for frail older people for use in the COFRAIL study and in primary care.

Introduction: Many older adults are affected by multimorbidity and subsequent polypharmacy which is associated with adverse outcomes. This is especially relevant for frail older patients. Polypharmacy may be reduced via deprescribing. As part of the complex intervention in the COFRAIL study, we developed a deprescribing manual to be used by general practitioners (GPs) in family conferences, in which GPs, patients and caregivers jointly discuss treatments. Methods: We selected indications with a high prevalence in older adults in primary care (e.g. diabetes mellitus, hypertension) and conducted a literature search to identify deprescribing criteria for these indications. We additionally reviewed clinical practice guidelines. Based on the extracted information, we created a deprescribing manual which was then piloted in an expert workshop and in family conferences with volunteer patients according to the inclusion and exclusion criteria of the study protocol. Results: Initially, 13 indications/topics were selected. The literature search identified deprescribing guides, reviews and clinical trials as well as lists of potentially inappropriate medication and systematic reviews on the risk and benefits of specific drugs and drug classes in older patients. After piloting and revisions, the deprescribing manual now covers 11 indications/topics. In each chapter, patient- and medication-related deprescribing criteria, monitoring and communication strategies, and information about concerns related to the use of specific drugs in older patients are provided. Discussion: We found varying deprescribing strategies in the literature, which we consolidated in our deprescribing manual. Whether this approach leads to successful deprescribing in family conferences is being investigated in the cluster-randomised controlled COFRAIL study. Plain Language Summary: Development of a manual to help doctors to identify which medications can be withdrawn Many older adults suffer from chronic diseases and take multiple medications concurrently. This can lead to side effects and other undesired events. We developed a manual to help doctors identify which medications can be withdrawn, so that they can discuss this with their patients. This manual was used in the COFRAIL study where doctors, patients and caregivers met in family conferences to discuss their preferences and decide together how future treatments should be handled. The manual contains information on common medications, symptoms and diseases in older patients such as diabetes and high blood pressure. Before the manual was used in the study, it was tested by volunteer patients and their doctors and caregivers to make sure that it is user-friendly.

HIOPP-6 - a pilot study on the evaluation of an electronic tool to assess and reduce the complexity of drug treatment considering patients' views.

BACKGROUND: A complex drug treatment might pose a barrier to safe and reliable drug administration for patients. Therefore, a novel tool automatically analyzes structured medication data for factors possibly contributing to complexity and subsequently personalizes the results by evaluating the relevance of each identified factor for the patient by means of key questions. Hence, tailor-made optimization measures can be proposed. METHODS: In this controlled, prospective, exploratory trial the tool was evaluated with nine general practitioners (GP) in three study groups: In the two intervention groups the tool was applied in a version with (GI_with) and a version without (GI_without) integrated key questions for the personalization of the analysis, while the control group (GC) did not use any tools (routine care). Four to eight weeks after application of the tool, the benefits of the optimization measures to reduce or mitigate complexity of drug treatment were evaluated from the patient perspective. RESULTS: A total of 126 patients regularly using more than five drugs could be included for analysis. GP suggested 117 optimization measures in GI_with, 83 in GI_without, and 2 in GC. Patients in GI_with were more likely to rate an optimization measure as helpful than patients in GI_without (IRR: 3.5; 95% CI: 1.2-10.3). Thereby, the number of optimization measures recommended by the GP had no significant influence (P = 0.167). CONCLUSIONS: The study suggests that an automated analysis considering patient perspectives results in more helpful optimization measures than an automated analysis alone - a result which should be further assessed in confirmatory studies. TRIAL REGISTRATION: The trial was registered retrospectively at the German Clinical Trials register under DRKS-ID DRKS00025257 (17/05/2021).

Prevalence and patient-rated relevance of complexity factors in medication regimens of community-dwelling patients with polypharmacy.

PURPOSE: To describe the prevalence of complexity factors in the medication regimens of community-dwelling patients with more than five drugs and to evaluate the relevance of these factors for individual patients. METHODS: Data were derived from the HIOPP-6 trial, a controlled study conducted in 9 general practices which evaluated an electronic tool to detect and reduce complexity of drug treatment. The prevalence of complexity factors was based on the results of the automated analysis of 139 patients' medication data. The relevance assessment was based on the patients' rating of each factor in an interview (48 patients included for analysis). RESULTS: A median of 5 (range 0-21) complexity factors per medication regimen were detected and at least one factor was observed in 131 of 139 patients. Almost half of these patients found no complexity factor in their medication regimen relevant. CONCLUSION: In most medication regimens, complexity factors could be identified automatically, yet less than 15% of factors were indeed relevant for patients as judged by themselves. When assessing complexity of medication regimens, one should especially consider factors that are both particularly frequent and often challenging for patients, such as use of inhalers or tablet splitting. TRIAL REGISTRATION: The HIOPP-6 trial was registered retrospectively on May 17, 2021, in the German Clinical Trials register under DRKS-ID DRKS00025257.

[Potentially Inappropriate Medication of Nursing Home Residents: An Analysis of Risk Factors Based on National Claims Data (AOK) for 2017]. / Potentiell inadäquate Medikation bei Heimbewohnern: Eine Analyse von Risikofaktoren anhand bundesweiter GKV-Routinedaten der AOK für das Jahr 2017.

AIM OF THE STUDY: The aim of this study was to assess risk factors for prescription of potentially inappropriate medication (PIM) to nursing home residents using the PRISCUS list in 2017. METHODS: Using claims data (AOK) we analysed insured nursing home residents aged 65 or older in 2017. The PRISCUS list was used to identify PIMs. A multivariate logistic regression analysis was performed to analyse risk factors. RESULTS: The study population in 2017 included 259 328 nursing home residents, out of them 25.5% received at least one potentially inappropriate medication (women: 25.6%/men: 24.9%). Female and younger aged nursing home residents had a higher risk for at least one PRISCUS prescription. Polypharmacy, an increasing number of attending physicians, and hospital stays were additional risk factors for a PRISCUS prescription. Furthermore, regional (Bundesland) variations contributed to differences in PRISCUS prescriptions. CONCLUSION: The frequent PIM prescriptions in nursing home residents are a relevant topic regarding drug therapy safety. Regional differences, which cannot be explained by nursing home resident characteristics, show options for modifications and the need for further research.

Development and Pilot-Testing of Key Questions to Identify Patients' Difficulties in Medication Administration.

PURPOSE: The development and testing of key questions suitable to identify patients' difficulties with medication administration. MATERIALS AND METHODS: We used a consecutive five-step process to draft key questions regarding 43 aspects of medication administration that can be difficult for patients who manage a complex drug treatment: Step 1) Identification of potentially error-prone characteristics of drug treatment (such as certain dosage forms) and initial draft of key questions. Step 2) Assessment of how comprehensible the questions are for patients. Step 3) Pre-testing of exemplary key questions with patients and monitoring of patient's actual medication administration behavior. Step 4) Evaluation by general practitioners of how well the questions may be integrated into actual patient visits. Step 5) Final approval of the questions in an expert panel. Thereafter, we pilot-tested exemplary questions with 36 patients (43 tests). In the course of this pilot-testing, the patients' answers to the key questions were tested against both their actual behavior during medication administration and against their answers to more general questions regarding potential difficulties with medication administration. RESULTS: More than half of the key questions (N = 24/43) were revised at least once during the development process. During the pilot-testing, 55.8% of the pilot-tests (N = 24/43) revealed medication administration difficulties. It was observed that the key questions identified significantly more difficulties (N = 17) than the general questions (N = 8; P = 0.021, positive predictive value = 94.4% vs 88.9%). In one case, both a key question and a general question identified difficulties, which, however, was not confirmed during the drug administration demonstration, indicating a false positive rate of 5.3% in both cases. CONCLUSION: We developed key questions aimed at detecting administration errors with a high specificity and a significantly higher sensitivity than general questions, suggesting that the resource-intensive demonstration of medication administration can be reserved for the detection of rarer and uncommon administration errors.

Comparing Predictions of a PBPK Model for Cyclosporine With Drug Levels From Therapeutic Drug Monitoring.

This study compared simulations of a physiologically based pharmacokinetic (PBPK) model implemented for cyclosporine with drug levels from therapeutic drug monitoring to evaluate the predictive performance of a PBPK model in a clinical population. Based on a literature search model parameters were determined. After calibrating the model using the pharmacokinetic profiles of healthy volunteers, 356 cyclosporine trough levels of 32 renal transplant outpatients were predicted based on their biometric parameters. Model performance was assessed by calculating absolute and relative deviations of predicted and observed trough levels. The median absolute deviation was 6 ng/ml (interquartile range: 30 to 31 ng/ml, minimum = -379 ng/ml, maximum = 139 ng/ml). 86% of predicted cyclosporine trough levels deviated less than twofold from observed values. The high intra-individual variability of observed cyclosporine levels was not fully covered by the PBPK model. Perspectively, consideration of clinical and additional patient-related factors may improve the model's performance. In summary, the current study has shown that PBPK modeling may offer valuable contributions for pharmacokinetic research in clinical drug therapy.

Trends and patterns in EU(7)-PIM prescribing to elderly patients in Germany.

PURPOSE: The aim of this study was to explore patterns and long-term development in prescribing potentially inappropriate medication (PIM) according to the EU(7)-PIM list to elderly patients in Germany. METHODS: We analysed anonymized German claims data. The study population comprised 6.0 million insured individuals at least 65 years old, including all their prescriptions reimbursed in 2019. For the analysis of long-term development, we used data for the years 2009-2019. Factors associated with PIM prescribing were considered from two perspectives: patient-oriented analysis was performed with logistic regression and prescriber-oriented analysis was performed with multiple linear regression. RESULTS: EU(7)-PIM prevalence was reduced from 56.9% in 2009 to 45.1% in 2019. Average annual volume (DDDs/insured) decreased from 145 in 2009 to 121 in 2019. These figures are substantially greater than those for the older PRISCUS list. The majority of investigated ATC level 2 groups with the highest EU(7)-PIM DDD volume exhibited substantial decreases; moderate increases were found for antihypertensive and urological drugs. Antithrombotics increased strongly with the introduction of direct oral anticoagulants. The most prevalent EU(7)-PIM medication was diclofenac; however, in the age group 85+ years, apixaban was twice as prevalent as diclofenac. Polypharmacy, female sex, age < 90 years, need for nursing care and living in Eastern regions were identified as risk factors. Prescriber specialty was the most marked factor in the prescriber-oriented analysis. CONCLUSION: Although the use of EU(7)-PIMs has been declining, regional differences indicate considerable room for improvement. The comparison with PRISCUS highlights the necessity of regular updates of PIM lists.

[Operationalisation for Portugal of the EU(7)-PIM List for Identification of Potentially Inappropriate Medicines in Older Adults]. / Operacionalização para Portugal da Lista EU(7)-PIM para Identificação de Medicamentos Potencialmente Inapropriados nos Idosos.

INTRODUCTION: In 2015, the EU(7)-PIM List was published, which identifies potentially inappropriate medicines in older patients and resulted from a consensus of experts from seven European countries. Portugal was not part of this group, so it was not originally adapted to the Portuguese reality. With this work, we intend to elaborate a list of potentially inappropriate medicines adapted to the reality of medicines marketed in Portugal, through the operationalization of the EU(7)-PIM List for the national reality and to evaluate the adequacy of its use for clinical practice. MATERIAL AND METHODS: Search, in INFARMED's Infomed database, of drugs that are included in the EU(7)-PIM List that have marketing authorization, and analysis of possible new drugs for inclusion in the list. The tool adapted to the Portuguese reality was applied to a sample of 1089 outpatient, polymedicated older patients from 38 primary care units in Central Portugal. RESULTS: The final PIM list adapted to the Portuguese reality includes 184 potentially inappropriate medicines (from these, 178 are active substances, five are classes of drugs, and one corresponds to the sliding scale therapeutic scheme used in insulin therapy). Of 1089 polymedicated older patients, 83.7% took at least one drug included in the final potentially inappropriate medicines list or belonging to one of the groups included in the list, and, on average, each patient took 1.74 (IQR 1 - 2). DISCUSSION: Even though the availability of drugs on the market is quite diverse, the EU(7)-PIM List has been used in several European countries. With this study, we operationalized the European list for the Portuguese reality, which will enable its application in clinical practice. CONCLUSION: The list drawn up is a useful tool for the identification of potentially inappropriate medicines, easy to use in clinical practice and research.

Introdução: Em 2015 foi publicada a lista EU(7)-PIM, que identifica medicamentos potencialmente inapropriados na população idosa e resultou de um consenso de peritos de sete países europeus. Portugal não fez parte deste grupo, pelo que na sua origem não foi adaptada para a realidade portuguesa. Com este trabalho pretendemos elaborar uma lista de medicamentos potencialmente inapropriados adaptada à realidade dos medicamentos comercializados em Portugal, através da operacionalização da lista EU(7)-PIM para a realidade nacional, avaliar a adequabilidade do seu uso na prática clínica.Material e Métodos: Pesquisa, na base de dados Infomed do INFARMED, dos medicamentos incluídos na lista EU(7)-PIM que apresentam autorização de introdução no mercado, e análise de possíveis novos medicamentos para inclusão na lista. A ferramenta adaptada para a realidade Portuguesa foi aplicada a uma amostra de 1089 idosos polimedicados não institucionalizados, utentes de 38 unidades de cuidados de saúde primários da região centro.Resultados: A lista final adaptada para a realidade portuguesa inclui 184 medicamentos potencialmente inapropriados (dos quais 178 são substâncias ativas, cinco são classes de medicamentos e um corresponde ao esquema terapêutico sliding scale usado nas insulinas). Dos 1089 idosos polimedicados, 83,7% tomavam pelo menos um fármaco incluído na lista final de medicamentos potencialmente inapropriados ou pertencente a um dos grupos incluídos na lista e, em média, cada doente tomava 1,74 (IQR 1 ­ 2).Discussão: Apesar da disponibilidade de fármacos no mercado ser bastante diversa, a lista EU(7)-PIM tem sido utilizada em vários países europeus. Com este estudo operacionalizamos a lista europeia para a realidade portuguesa, facilitando assim a sua aplicação na prática clínica.Conclusão: A lista elaborada apresenta-se como uma ferramenta útil para a identificação de medicamentos potencialmente inapropriados, de fácil utilização na prática clínica e em investigação.

Development of an algorithm to detect and reduce complexity of drug treatment and its technical realisation.

BACKGROUND: The increasing complexity of current drug therapies jeopardizes patient adherence. While individual needs to simplify a medication regimen vary from patient to patient, a straightforward approach to integrate the patients' perspective into decision making for complexity reduction is still lacking. We therefore aimed to develop an electronic, algorithm-based tool that analyses complexity of drug treatment and supports the assessment and consideration of patient preferences and needs regarding the reduction of complexity of drug treatment. METHODS: Complexity factors were selected based on literature and expert rating and specified for integration in the automated assessment. Subsequently, distinct key questions were phrased and allocated to each complexity factor to guide conversation with the patient and personalize the results of the automated assessment. Furthermore, each complexity factor was complemented with a potential optimisation measure to facilitate drug treatment (e.g. a patient leaflet). Complexity factors, key questions, and optimisation strategies were technically realized as tablet computer-based application, tested, and adapted iteratively until no further technical or content-related errors occurred. RESULTS: In total, 61 complexity factors referring to the dosage form, the dosage scheme, additional instructions, the patient, the product, and the process were considered relevant for inclusion in the tool; 38 of them allowed for automated detection. In total, 52 complexity factors were complemented with at least one key question for preference assessment and at least one optimisation measure. These measures included 29 recommendations for action for the health care provider (e.g. to suggest a dosage aid), 27 training videos, 44 patient leaflets, and 5 algorithms to select and suggest alternative drugs. CONCLUSIONS: Both the set-up of an algorithm and its technical realisation as computer-based app was successful. The electronic tool covers a wide range of different factors that potentially increase the complexity of drug treatment. For the majority of factors, simple key questions could be phrased to include the patients' perspective, and, even more important, for each complexity factor, specific measures to mitigate or reduce complexity could be defined.

Reduction of potentially inappropriate medication in the elderly: design of a cluster-randomised controlled trial in German primary care practices (RIME).

BACKGROUND: Potentially inappropriate medication (PIM) is considered to have potentially more harmful than beneficial health effects in elderly patients. A German example for a PIM list is the PRISCUS list that has been available since 2010. PIMs are associated with an increased risk of hospitalisation and adverse health outcomes. Furthermore, drug-drug interactions (DDI) may pose additional risks to patients. It is not yet clear how numbers of PIM and DDI can be reduced in community-dwelling seniors in primary care; nor is it clear whether patients would benefit from such deprescribing. METHODS: The cluster-randomised controlled study on the "Reduction of potentially Inappropriate Medication in the Elderly" (RIME study) is designed to examine whether an intervention based on the PRISCUS list can lower the proportion of community-dwelling people of ⩾70 years taking at least one PIM and/or medication inducing at least one dangerous DDI. The intervention consists of professional education and training on the reduction of PIM and DDI, and will be offered to either general practitioners (GPs) alone or GPs and their office staff in the experimental study arm. The control group will be offered professional education and training on more general issues of prescribing in the elderly, not specifically addressing PIM or DDI. The primary endpoint is the difference in the proportion of patients with at least one PIM or DDI between the start of the study and study closure after 12 months as compared between intervention and control group. Secondary endpoints include overall mortality, number of hospitalisations during the course of the study, quality of life and costs. Secondary analyses will be explorative, with the cluster randomisation being factored in. DISCUSSION: The RIME study will contribute to answering the question of whether an intervention based on the PRISCUS list can reduce the proportion of community-dwelling seniors aged ⩾70 years with at least one PIM and/or DDI, and whether this will result in positive health effects, for example, as regards hospitalisations. TRIAL REGISTRATION: The Study has been registered in the German Clinical Trials Register (DRKS) under the number DRKS00003610.

Individual factors increasing complexity of drug treatment-a narrative review.

PURPOSE: Complexity of drug treatment is known to be a risk factor for administration errors and nonadherence promoting higher healthcare costs, hospital admissions and increased mortality. Number of drugs and dose frequency are parameters often used to assess complexity related to the medication regimen. However, factors resulting from complex processes of care or arising from patient characteristics are only sporadically analyzed. Hence, the objective of this review is to give a comprehensive overview of relevant, patient-centered factors influencing complexity of drug treatment. METHODS: A purposeful literature search was performed in MEDLINE to identify potential complexity factors relating to the prescribed drug (i.e. dosage forms or other product characteristics), the specific medication regimen (i.e. dosage schemes or additional instructions), specific patient characteristics and process characteristics. Factors were included if they were associated to administration errors, nonadherence and related adverse drug events detected in community dwelling adult patients. RESULTS: Ninety-one influencing factors were identified: fourteen in "dosage forms", five in "product characteristics", twelve in "dosage schemes", nine in "additional instructions", thirty-one in "patient characteristics" and twenty in "process characteristics". CONCLUSIONS: Although the findings are limited by the non-systematic search process and the heterogeneous results, the search shows the influence of many factors on the complexity of drug treatment. However, to evaluate their relevance for individual patients, prospective studies are necessary.

[Geriatric intensive care : Consensus paper of DGIIN, DIVI, DGAI, DGGG, ÖGGG, ÖGIAIN, DGP, DGEM, DGD, DGNI, DGIM, DGKliPha and DGG]. / Geriatrische Intensivmedizin : Konsensuspapier der DGIIN, DIVI, DGAI, DGGG, ÖGGG, ÖGIAIN, DGP, DGEM, DGD, DGNI, DGIM, DGKliPha und DGG.

The proportion of elderly, frail, and multimorbid people has increased dramatically in recent decades resulting from demographic changes and will further increase, which will impact acute medical care. Prospective, randomized studies on geriatric intensive care are still lacking. There are also no international or national recommendations regarding the management of critically ill elderly patients. Based on an expert opinion, this consensus paper provides 16 statements that should be considered when dealing with geriatric critical care patients.

Pharmacodynamics and pharmacokinetics in older adults.

PURPOSE OF REVIEW: With the growing of the aging population, increased and new methods of anesthesia and surgery allow for surgery and other interventions in older adults.Pharmacokinetics and pharmacodynamics of drugs in older adults differ from those in younger and middle-aged adults. However, the geriatric population is frequently neglected in the context of clinical trials. The present review focuses on the consequences of multimorbidity and pharmacokinetic and pharmacodynamic alterations and their implications on anesthesia. RECENT FINDINGS: Physiologically based pharmacokinetic and pharmacodynamic modeling may serve as an option to better understand the influence of age on drugs used for anesthesia. However, difficulties to adequately characterize geriatric patients are described. SUMMARY: Further research of drug effects in the aging population may include physiologically based pharmacokinetic and pharmacodynamic complex models and randomized controlled trials with thoroughly conducted geriatric assessments.