A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.

Perception of learners on the effectiveness and suitability of MyDispense: a virtual pharmacy simulation and its integration in the clinical pharmacy module in Viet Nam.

BACKGROUND: My Dispense is a virtual pharmacy simulation developed for students to train and practice dispensing skills in a safe environment that causes no harm to patients. This study was aimed to investigate learners' perspectives on the effectiveness of MyDispense and its suitability to integrate into the clinical pharmacy module in Viet Nam. METHODS: A mixed method approach was undertaken. Fourth- and fifth-year pharmacy students at University of Medicine and Pharmacy at Ho Chi Minh city and community pharmacists were invited to complete a survey questionnaire and to participate in semi-structured interviews. RESULTS: A total of 92/99 participants agreed to take part, of which 75% of participants were students and 65.2% were female. About three-quarters of the participants agreed or strongly agreed that MyDispense improved their dispensing skills, such as patient counselling (70.6%) and collecting patient infomation (85.9%). The majority of the participants (84.8%) considered that MyDispense was suitable to integrate into the clinical pharmacy module. Qualitative analysis from the interviews highlighted the advantages of MyDispense, comprising high interactivity with users, safe environment for practicing medication dispensing, and diversity of common marketed medications. In addition, certain barriers of this programme were also reported, including the complicated process, inconsistent quality of product images, and mixed English-Vietnamese languages. CONCLUSIONS: From learner's perspectives, MyDispense was an effective tool to enhance dispensing skills and was suitable to integrated into the clinical pharmacy module in Viet Nam.

Early clinical and economic outcomes of expanded criteria living kidney donors in the United States.

BACKGROUND: The donation of what might be termed expanded criteria kidneys has become an increasingly common practice. This study aimed to assign expanded criteria and non-expanded criteria donation status and examine early clinical and economic outcomes among expanded criteria and non-expanded criteria living kidney donor (LKD) hospitalizations in the US. METHODS: Healthcare cost and Utilization Project-National (Nationwide) Inpatient Sample (HCUP-NIS) data (Jan 2008-Dec 2019, N = 12,020) were used. Expanded criteria LKDs were identified as admitted patients aged ≥ 60 years, or 50-59 years with any comorbidity that historically precluded donation. The Clavien-Dindo system was applied to classify surgical complications as grade I-IV/V. RESULTS: The number of LKD admissions decreased by 31% over the study period, although this trend fluctuated over time. Compared to non-expanded criteria LKD admissions, expanded criteria LKD admissions had comparable surgical complication rates in Grade I (aOR 1.0, 0.8-1.3), but significantly higher surgical complication rates in Grade II (aOR 1.5, 1.1-2.2) and Grade III (aOR 1.4, 1.0-2.0). The two groups had comparable hospital length of stay and cost in the adjusted models. Notably, Grade II complications were significantly higher in private, for-profit hospitals (15%) compared to government hospitals (2.9%). CONCLUSIONS: Expanded criteria LKDs had comparable early outcomes compared to non-expanded criteria LKDs, but the trends evident in LKDs over time and the variation in complication records warrant further research.

Development of a core outcome set for clinical trials aimed at improving antimicrobial stewardship in care homes.

BACKGROUND: Diverse outcomes reported in clinical trials of antimicrobial stewardship (AMS) interventions in care homes have hindered evidence synthesis. Our main objective was to develop a core outcome set (COS) for use in trials aimed at improving AMS in care homes. METHODS: A refined inventory of outcomes for AMS interventions in care homes, compiled from a previous study, was rated in a three-round international Delphi survey with 82 participants, using a nine-point Likert scale (from 1, unimportant, to 9, critical). This was followed by an online consensus exercise with 12 participants from Northern Ireland to finalise the COS content. Subsequently, a suitable outcome measurement instrument (OMI) was selected for each outcome in the COS by: identifying existing OMIs through a literature search and experts' suggestions, assessing the quality of OMIs, and selecting one OMI for each core outcome via a two-round international Delphi survey with 59 participants. RESULTS: Of 14 outcomes initially presented, consensus was reached for inclusion of five outcomes in the COS after the three-round Delphi survey and the online consensus exercise, comprising the total number of antimicrobial courses prescribed, appropriateness of antimicrobial prescribing, days of therapy per 1000 resident-days, rate of antimicrobial resistance, and mortality related to infection. Of 17 potential OMIs identified, three were selected for the two-round Delphi exercise after the quality assessment. Consensus was reached for selection of two OMIs for the COS. CONCLUSION: This COS is recommended to be used in clinical trials aimed at improving AMS in care homes.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.

Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy.

Quantitative understanding about the dynamics of drug-target interactions in biological systems is essential, especially in rare disease programs with small patient populations. Follistatin, by antagonism of myostatin and activin, which are negative regulators of skeletal muscle and inflammatory response, is a promising therapeutic target for Duchenne Muscular Dystrophy. In this study, we constructed a quantitative systems pharmacology model for FS-EEE-Fc, a follistatin recombinant protein to investigate its efficacy from dual target binding, and, subsequently, to project its human efficacious dose. Based on model simulations, with an assumed efficacy threshold of 7-10% muscle volume increase, 3-5 mg/kg weekly dosing of FS-EEE-Fc is predicted to achieve meaningful clinical outcome. In conclusion, the study demonstrated an application of mechanism driven approach at early stage of a rare disease drug development to support lead compound optimization, enable human dose, pharmacokinetics, and efficacy predictions.

Trends and impact of antimicrobial resistance on older inpatients with urinary tract infections (UTIs): A national retrospective observational study.

Urinary tract infections (UTIs) are one of the most common infections in older people and are associated with increased morbidity and mortality. UTIs are also associated with increased risk of antimicrobial resistance (AR). This study examined changes in AR among older inpatients with a primary diagnosis of UTIs in the United States over an 8-year period and the impact of AR on clinical outcomes and hospital costs. Data were obtained from the longitudinal hospital HCUP-NIS database from 2009 to 2016 for inpatient episodes that involved those aged 65+ years. The ICD-9 and ICD-10 codes were used to identify episodes with a primary diagnosis of UTIs, comorbidities, AR status and age-adjusted Deyo-Charlson comorbidity index (ACCI) for the patient concerned. Weighted multivariable regression was used to examine the impact of AR on all-cause inpatient mortality, discharge destination, length of stay and hospital expenditures, adjusted for socio-demographic and clinical covariates. The proportion of admissions with AR increased, from 3.64% in 2009 to 6.88% in 2016 (p<0.001), with distinct patterns for different types of resistance. The likelihood of AR was higher in admissions with high ACCI scores and admissions to hospitals in urban areas. Admissions with AR were more likely to be discharged to healthcare facilities (e.g. care homes) compared to routine discharge (OR 1.81; 95%CI, 1.75-1.86), had increased length of stay (1.12 days; 95%CI, 1.06-1.18) and hospital costs (1259 USD; 95%CI, 1178-1340). Resistance due to MRSA was specifically associated with increased hospital mortality (OR 1.33; 95%CI, 1.15-1.53). Our findings suggest that the prevalence of AR has increased among older inpatients with UTIs in the USA. The study highlights the impact of AR among older inpatients with a primary diagnosis of UTIs on clinical outcomes and hospital costs. These relationships and their implications for the care homes to which patients are frequently discharged warrant further research.

Interventions to Improve Antimicrobial Stewardship for Older People in Care Homes: A Systematic Review.

BACKGROUND: Inappropriate antimicrobial prescribing has been reported in care homes. This may result in serious drug-related adverse events, Clostridium difficile colonization, and the development of antimicrobial resistance among care home residents. Interventions to improve antibiotic prescribing in nursing homes have been reported through clinical trials, but whether antifungal and antiviral prescribing and residential homes have been considered, or how outcomes were measured and reported in such interventions, remains unclear. OBJECTIVES: Our aims were to evaluate the effect of interventions to improve antimicrobial stewardship in care homes and to report the outcomes used in these trials. METHODS: We searched 11 electronic databases and five trial registries for studies published until 30 November 2018. Inclusion criteria for the review were randomized controlled trials, targeting care home residents and healthcare professionals, providing interventions to improve antimicrobial prescribing compared with usual care or other interventions. The Cochrane tools for assessing risk of bias were used for quality assessment. A narrative approach was taken because of heterogeneity across the studies. RESULTS: Five studies met the inclusion criteria. The studies varied in terms of types of infection, key targets, delivery of interventions, and reported outcomes. In total, 27 outcomes were reported across the studies, with seven not prespecified in the methods. The interventions had little impact on adherence to guidelines and prevalence of antimicrobial prescribing; they appeared to decrease total antimicrobial consumption but were unlikely to have affected overall hospital admissions and mortality. The overall quality of evidence was low because the risk of bias was high across the studies. CONCLUSION: The interventions had limited effect on improving antimicrobial prescribing but did not appear to cause harm to care home residents. The low quality of evidence and heterogeneity in outcome measurement suggest the need for future well-designed studies and the development of a core outcome set to best evaluate the effectiveness of antimicrobial stewardship in care homes.

Pharmacist-Led Intervention to Enhance Medication Adherence in Patients With Acute Coronary Syndrome in Vietnam: A Randomized Controlled Trial.

Background: Patient adherence to cardioprotective medications improves outcomes of acute coronary syndrome (ACS), but few adherence-enhancing interventions have been tested in low-income and middle-income countries. Objectives: We aimed to assess whether a pharmacist-led intervention enhances medication adherence in patients with ACS and reduces mortality and hospital readmission. Methods: We conducted a randomized controlled trial in Vietnam. Patients with ACS were recruited, randomized to the intervention or usual care prior to discharge, and followed 3 months after discharge. Intervention patients received educational and behavioral interventions by a pharmacist. Primary outcome was the proportion of adherent patients 1 month after discharge. Adherence was a combined measure of self-reported adherence (the 8-item Morisky Medication Adherence Scale) and obtaining repeat prescriptions on time. Secondary outcomes were (1) the proportion of patients adherent to medication; (2) rates of mortality and hospital readmission; and (3) change in quality of life from baseline assessed with the European Quality of Life Questionnaire - 5 Dimensions - 3 Levels at 3 months after discharge. Logistic regression was used to analyze data. Registration: ClinicalTrials.gov (NCT02787941). Results: Overall, 166 patients (87 control, 79 intervention) were included (mean age 61.2 years, 73% male). In the analysis excluding patients from the intervention group who did not receive the intervention and excluding all patients who withdrew, were lost to follow-up, died or were readmitted to hospital, a greater proportion of patients were adherent in the intervention compared with the control at 1 month (90.0% vs. 76.5%; adjusted OR = 2.77; 95% CI, 1.01-7.62) and at 3 months after discharge (90.2% vs. 77.0%; adjusted OR = 3.68; 95% CI, 1.14-11.88). There was no significant difference in median change of EQ-5D-3L index values between intervention and control [0.000 (0.000; 0.275) vs. 0.234 (0.000; 0.379); p = 0.081]. Rates of mortality, readmission, or both were 0.8, 10.3, or 11.1%, respectively; with no significant differences between the 2 groups. Conclusion: Pharmacist-led interventions increased patient adherence to medication regimens by over 13% in the first 3 months after ACS hospital discharge, but not quality of life, mortality and readmission. These results are promising but should be tested in other settings prior to broader dissemination.

Enhancing prescribing of guideline-recommended medications for ischaemic heart diseases: a systematic review and meta-analysis of interventions targeted at healthcare professionals.

OBJECTIVES: Ischaemic heart diseases (IHDs) are a leading cause of death worldwide. Although prescribing according to guidelines improves health outcomes, it remains suboptimal. We determined whether interventions targeted at healthcare professionals are effective to enhance prescribing and health outcomes in patients with IHDs. METHODS: We systematically searched PubMed and EMBASE for studies published between 1 January 2000 and 31 August 2017. We included original studies of interventions targeted at healthcare professionals to enhance prescribing guideline-recommended medications for IHDs. We only included randomised controlled trials (RCTs). Main outcomes were the proportion of eligible patients receiving guideline-recommended medications, the proportion of patients achieving target blood pressure and target low-density lipoprotein-cholesterol (LDL-C)/cholesterol level and mortality rate. Meta-analyses were performed using the inverse-variance method and the random effects model. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: We included 13 studies, 4 RCTs (1869 patients) and 9 cluster RCTs (15 224 patients). 11 out of 13 studies were performed in North America and Europe. Interventions were of organisational or professional nature. The interventions significantly enhanced prescribing of statins/lipid-lowering agents (OR 1.23; 95% CI 1.07 to 1.42, P=0.004), but not other medications (aspirin/antiplatelet agents, beta-blockers, ACE inhibitors/angiotensin II receptor blockers and the composite of medications). There was no significant association between the interventions and improved health outcomes (target LDL-C and mortality) except for target blood pressure (OR 1.46; 95% CI 1.11 to 1.93; P=0.008). The evidence was of moderate or high quality for all outcomes. CONCLUSIONS: Organisational and professional interventions improved prescribing of statins/lipid-lowering agents and target blood pressure in patients with IHDs but there was little evidence of change in other outcomes. PROSPERO REGISTRATION NUMBER: CRD42016039188.

Urban heat island effect on cicada densities in metropolitan Seoul.

BACKGROUND: Urban heat island (UHI) effect, the ubiquitous consequence of urbanization, is considered to play a major role in population expansion of numerous insects. Cryptotympana atrata and Hyalessa fuscata are the most abundant cicada species in the Korean Peninsula, where their population densities are higher in urban than in rural areas. We predicted a positive relationship between the UHI intensities and population densities of these two cicada species in metropolitan Seoul. METHODS: To test this prediction, enumeration surveys of cicada exuviae densities were conducted in 36 localities located within and in the vicinity of metropolitan Seoul. Samples were collected in two consecutive periods from July to August 2015. The abundance of each species was estimated by two resource-weighted densities, one based on the total geographic area, and the other on the total number of trees. Multiple linear regression analyses were performed to identify factors critical for the prevalence of cicada species in the urban habitat. RESULTS: C. atrata and H. fuscata were major constituents of cicada species composition collected across all localities. Minimum temperature and sampling period were significant factors contributing to the variation in densities of both species, whereas other environmental factors related to urbanization were not significant. More cicada exuviae were collected in the second rather than in the first samplings, which matched the phenological pattern of cicadas in metropolitan Seoul. Cicada population densities increased measurably with the increase in temperature. Age of residential complex also exhibited a significantly positive correlation to H. fuscata densities, but not to C. atrata densities. DISCUSSION: Effects of temperature on cicada densities have been discerned from other environmental factors, as cicada densities increased measurably in tandem with elevated temperature. Several mechanisms may contribute to the abundance of cicadas in urban environments, such as higher fecundity of females, lower mortality rate of instars, decline in host plant quality, and local adaptation of organisms, but none of them were tested in the current study. CONCLUSIONS: In sum, results of the enumeration surveys of cicada exuviae support the hypothesis that the UHI effect underlies the population expansion of cicadas in metropolitan Seoul. Nevertheless, the underlying mechanisms for this remain untested.

Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models.

The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUCm/AUCp) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich-cultured hepatocytes. Human renal clearance of carboxylosartan was estimated from dog renal clearance using allometric scaling approach. All clearance mechanisms were mechanistically incorporated in a static model to predict the relative exposure of carboxylosartan versus losartan (AUCm/AUCp). The predicted AUCm/AUCp were consistent with the observed data following intravenous and oral administration of losartan. Moreover, the in vitro parameters were used as initial parameters in PBPK permeability-limited disposition models to predict the concentration-time profiles for both parent and its active metabolite after oral administration of losartan. The PBPK model was able to recover the plasma profiles of both losartan and carboxylosartan, further substantiating the validity of this approach.

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine.

Major circulating drug metabolites can be as important as the drugs themselves in efficacy and safety, so establishing methods whereby exposure to major metabolites following administration of parent drug can be predicted is important. In this study, imipramine, a tricyclic antidepressant, and its major metabolite desipramine were selected as a model system to develop metabolite prediction methods. Imipramine undergoes N-demethylation to form the active metabolite desipramine, and both imipramine and desipramine are converted to hydroxylated metabolites by the polymorphic enzyme CYP2D6. The objective of the present study is to determine whether the human pharmacokinetics of desipramine following dosing of imipramine can be predicted using static and dynamic physiologically-based pharmacokinetic (PBPK) models from in vitro input data for CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) populations. The intrinsic metabolic clearances of parent drug and metabolite were estimated using human liver microsomes (CYP2D6 PM and EM) and hepatocytes. Passive diffusion clearance of desipramine, used in the estimation of availability of the metabolite, was predicted from passive permeability and hepatocyte surface area. The predicted area under the curve (AUCm/AUCp) of desipramine/imipramine was 12- to 20-fold higher in PM compared with EM subjects following i.v. or oral doses of imipramine using the static model. Moreover, the PBPK model was able to recover simultaneously plasma profiles of imipramine and desipramine in populations with different phenotypes of CYP2D6. This example suggested that mechanistic PBPK modeling combined with information obtained from in vitro studies can provide quantitative solutions to predict in vivo pharmacokinetics of drugs and major metabolites in a target human population.

Mechanistic Modeling to Predict Midazolam Metabolite Exposure from In Vitro Data.

Methods to predict the pharmacokinetics of drugs in humans from in vitro data have been established, but corresponding methods to predict exposure to circulating metabolites are unproven. The objective of this study was to use in vitro methods combined with static and dynamic physiologically based pharmacokinetic (PBPK) models to predict metabolite exposures, using midazolam and its major metabolites as a test system. Intrinsic clearances (CLint) of formation of individual metabolites were determined using human liver microsomes. Metabolic CLintof hydroxymidazolam metabolites via oxidation and glucuronidation were also determined. Passive diffusion intrinsic clearances of hydroxymidazolam metabolites were determined using sandwich cultured human hepatocytes and the combination of this term along with the metabolic CLint, and liver blood flow was used to estimate the fraction of the metabolite that can enter the systemic circulation after formation in the liver. The metabolite/parent drug area under the plasma concentration-time curve ratio (AUCm/AUCp) was predicted using a static model relating the fraction of midazolam clearance to each metabolite, the clearance rates of midazolam and hydroxymidazolam metabolites, and the availability of the metabolites. Additionally, the human disposition of midazolam metabolites was simulated using a SimCYP PBPK model. Both approaches yielded AUCm/AUCpratios that were in agreement with the in vivo ratios. This study shows that in vivo midazolam metabolite exposure can be predicted from in vitro data and PBPK modeling. This study emphasized the importance of metabolite systemic availability from its tissue of formation, which remains a challenge to quantitative prediction.

A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment.

Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.