The influence of genotype on warfarin maintenance dose predictions produced using a Bayesian dose individualization tool

Background A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In the following study, we aimed to (1) determine if the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from two different clinical settings, (2) explore the influence of CYP2C9 and VKORC1 genotype on the predictive performance of the Bayesian dosing tool, and (3) determine if the prior population used to develop the kinetic-pharmacodynamic (KPD) model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. Methods The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared to the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (e.g., EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates to published values. Results The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% CI]; 0.32 mg/day [0.14, 0.5]). The bias was only observed in patients requiring ≥7 mg/day. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, suggesting that the bias was not caused by different prior and posterior populations. Conclusions Maintenance doses for patients requiring ≥7 mg/day were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose–response relationship at higher warfarin dose

最大后验贝叶斯估算法制定华法林个体化给药案例探讨

目的:探讨临床药师在华法林个体化给药方案制定及实施监护过程中发挥的作用。方法:临床药师采用最大后验贝叶斯估算法制定华法林患者的给药方案,并对方案实施过程进行了监护,及时识别了药物相互作用导致的INR升高,避免了出血不良反应的发生,同时也及时发现了患者漏服药物导致的国际标准化比值(INR)降低,避免了患者再次发生血栓。结果:最大后验贝叶斯估算法可以较好地估算和指导临床用药,对于个体化给药方案具有极大的参考价值。结论:根据基因检测结果选择合适的算法为华法林患者制定了个体化给药方案后,临床药师还需要对整个给药方案实施过程提供全程化的监护,以便及时发现疾病、药物相互作用、依从性不佳等导致的INR异常波动,从而提供抗凝效果,减少出血和栓塞等不良反应。福建省科技计划引导性项目(编号:2015Y0020

Application of a warfarin dosing calculator to guide individualized dosing versus empirical adjustment after fixed dosing: a pilot study

Background: Warfarin has a narrow therapeutic window and individual variation, and patients require regular follow-up and monitoring of the International Normalized Ratio (INR) for dose adjustment. The calculation method of Warfarin Dosing Calculator (WDC) software is based on the European and American populations, and its accuracy in the Chinese population is yet to be verified.Objective: This study was to evaluate the feasibility of applying Warfarin Dosing Calculator software intervention in a real-world clinical research setting in China.Methods: The pilot study divided the included patients after valve replacement into an experimental group and a control group, with 38 cases in each group. In the control group, the initial dose was fixed at 2.5 mg/d and the dose was adjusted empirically during the study period; in the experimental group, the Warfarin Dosing Calculator software was applied to guide the dosing, and patients in both groups were followed up for 3 months. Analysis of the incidence anticoagulation outcomes and excessive anticoagulation events in both groups. Kaplan-Meier survival curves were used to analyze the correlation between different dosing regimens and first International Normalized Ratio attainment, and Logrank tests were performed.Results: The mean time required for first International Normalized Ratio compliance in the experimental group was 4.38 days less than in the control group, and the mean number of tests was 1.43 less (p < 05). Time in therapeutic range (TTR) was significantly higher in the experimental group than in the control group (p < 05). Kaplan-Meier survival curve analysis showed that the first International Normalized Ratio attainment rate was significantly higher in the experimental group than in the control group (p = 01). No major bleeding events occurred in either group, but other excessive anticoagulation events (INR>3.5 and minor bleeding) were significantly reduced in the experimental group compared with the control group (p < 05).Conclusion: Application of Warfarin Dosing Calculator software to guide individualized warfarin dosing may be better than a fixed dose of 2.5 mg/d. It may be shorten the time to first International Normalized Ratio attainment, and the attainment rate in the same time, and can better improve the mean Time in therapeutic range level value and reduce excessive anticoagulation events, which improves the safety of warfarin anticoagulation therapy in clinical practice.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=52793, ChiCTR2000032393

Bioinformaatika meetodid personaalses farmakoteraapias

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKogutavate terviseandmete hulk kasvab kiiresti. Tänu neile andmetele on meditsiinilise ravi pakkumisel võimalik senisest enam arvesse võtta individuaalseid bioloogilisi andmeid. See doktoritöö käsitleb mitmeid personaalses meditsiinis esinevaid probleeme ja näitab, et ravi individualiseerimiseks kasutatavad andmed tulevad väga erinevatest allikatest. Inimestevahelised erinevused teevad ravimite metabolismi ennustamise keerukaks, siiski on ravi käigus kogutavad kontsentratsioonimõõtmised ravimiefekti hindamisel heaks allikaks. Me arendasime välja täppisdoseerimise tööriista, mis võimaldab vankomütsiini ravil vastsündinutele määrata ravi tõhustavat personaalseid doose kasutades selleks nende endi ravi käigus kogutud kontsentratsioone. Suurema osa ravimiteraapiate puhul ei ole võimalik pidevalt ravimi kontsentratsioone koguda. Nende ülejäänud ravimite puhul on heaks informatsiooniallikaks geneetika. Paljude ravimimetabolismiga seotud geneetiliste variantide mõju on piisav, et tingida muutuseid ravi läbiviimisel. Me uurisime geneetika ja ravimite kõrvalmõjude omavahelisi seoseid kasutades rahvastikupõhist lähenemist. See toetus Eesti Geenivaramu geeniandmetele ja teistele laiapõhjalistele terviseandmete registritele. Me leidsime ja valideerisime seose, et CTNNA3 geenis olev geenivariant tõstab oksikaamide ravil olevate inimeste jaoks kõrvalmõjude sagedust. Arvutuslik geneetika toetub kvantitatiivsetele meetoditele, millest kõige levinum on ülegenoomne assotsiatsiooni analüüs (GWAS). Sagedasti kasutatav GWASi järelsamm on aega nõudev GWASist ilmnenud p-väärtuste visuaalne hindamine teiste samas genoomi piirkonnas olevate geneetiliste variantide kontekstis. Selle sammu automatiseerimiseks arendasime me kaks tööriista, Manhattan Harvester ja Cropper, mis võimaldavad automaatselt huvipakkuvaid piirkondi tuvastada ja nende headust hinnata.The amount of collected health data is growing fast. Insights from these data allow using biological patient specifics to improve therapy management with further individualization. This thesis addresses problems in multiple sub-fields of personalised medicine and aims to illustrate that data for precision medicine emerges from different sources. Drug metabolism is difficult to predict because individual biological differences. Fortunately, drug concentrations are a good proxy for drug effect. To address the growing need for tools that allow on-line therapy adjustment based on individual concentrations we have developed and externally evaluated a precision dosing tool that allows individualised dosing of vancomycin in neonates. Other than drugs used in therapeutic drug monitoring, most pharmacotherapies can not rely on continuous concentration measurements but for such drugs genetics provides a valuable source of information for individualization. Effects of many genetic variants in drug metabolism pathways are often large enough to require changes in drug prescriptions or schedules. We have applied a population-based approach in testing relations between drug related adverse effects and genomic loci, and found and validated a novel variant in CTNNA3 gene that increases adverse drug effects in patients with oxicam prescriptions. This was done by leveraging the data in Estonian Genome Center and linking these to nation-wide electronic health data registries. Computational genetics relies on quantitative methods for which the most common is the genome-wide association analysis (GWAS). A common GWAS downstream step involves time-consuming visual assessment of the association study p-values in context with other variants in genomic vicinity. In order to streamline this step, we developed, Manhattan Harvester and Cropper, that allow for automated detection of peak areas and assign scores by emulating human evaluators.https://www.ester.ee/record=b524282

Development and Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Population Model for Elderly Individuals

Clinical drug development is traditionally focused on young and middle-aged adults. The elderly are often underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, there is a knowledge gap on dose-exposure relationships in elderly subjects. This thesis aimed at contributing to a better understanding of the age-related mechanisms governing the pharmacokinetics (PK) in this clinically understudied population. First, a physiologically based pharmacokinetic (PBPK) database for the course of healthy ageing was successfully established. For parameterization of the PBPK model for healthy ageing individuals, anthropometric and physiological data were identified in the literature, which were incorporated into the PBPK software PK-Sim®. Although age-related changes occurring from 65 to 100 years of age were the main focus of this work, data on anatomical and physiological changes beginning from early adulthood to the elderly age range were also included for a sound and continuous description of ageing humans. In total, 118 studies comprising 47029 male and 67419 female subjects were included to build the elderly PBPK database. As next step, the capability of the elderly PBPK approach to predict the distribution and elimination of drugs was verified using the test compounds morphine and furosemide administered intravenously. Both drugs are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations – with regard to age, gender, anthropometric measures and dosage – were generated. Profiles of plasma drug concentration over time, volume of distribution at steady-state (Vss) and elimination half-lives (t1/2) from the literature were compared to those predicted by PBPK simulations, for both younger adults and the elderly. Based on age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error (RMSE) for the prediction of plasma concentrations for furosemide and morphine in the elderly was improved by 32% and 49%, respectively, compared to predictions without age-informed physiology. The majority of the individual Vss and t1/2 values of the two model compounds furosemide and morphine were well predicted in the elderly population, except for long furosemide half-lives. Finally, the reliability of predictions outside the tested adult age range towards the extremes of ages was assessed using the multi-elimination pathway compound ciprofloxacin as probe drug. Mean data of 69 published clinical trials were identified and used for model building, simulation as well as the verification process. The predictive performance on both ends of the age scale was assessed using individual data of 236 pediatric and 22 geriatric patients observed in clinical trials. Ciprofloxacin model verification demonstrated no concentration-related bias and accurate predictions for the adult age range with only 4.8 % of the mean observed concentrations following intravenous and 12.1 % following oral administration outside the simulated 2-fold range. Predictions towards both extremes of ages for the area under the plasma concentration–time curve (AUC) and the maximum plasma concentration (Cmax) were reliable. The results of this thesis support the feasibility of using a knowledge-driven PBPK ageing model to predict PK alterations throughout the entire course of ageing, and thus to optimize drug therapy also in older adult individuals. Overall, the predictive power of a thoroughly informed middle-out approach towards older adults to potentially support the decision making process for pharmacotherapy in the elderly was demonstrated. These results indicate that medication safety in geriatric patients may be greatly facilitated by the information gained from PBPK predictions

Application of Pharmacometric Methods to Improve Pediatric Drug Development

Pharmacometrics is a quantitative science that is rapidly changing the landscape of drug development, and particularly so for the pediatric population. The motivation behind the research underlying this dissertation is to contribute towards the improvement of pediatric drug development by the astute application of pharmacometric methods. Two distinct research areas have been focused upon: 1- improving pediatric pharmacokinetic (PK) trial design and 2- improving pediatric dosing of warfarin by using a genetics-based dosing regimen. The first project examined in detail the feasibility of and simulation-based methodology for implementing a recent regulatory PK quality standard. The focus was on designing pediatric PK trials that employ sparse sampling and population analysis methods, using a simulation-estimation platform. The research provided clarity on the impact of various trial design elements, such as PK sampling, adult data inclusion, PK variability and analysis method on sample size adequacy to honor the standard. The PK quality standard was found to be practically feasible in terms of sample size adequacy. Informative sampling schedule for a given number of PK samples per subject is assumed during trial design. Recommendations are made to: 1- use prior adult or pediatric data for trial design and analysis, wherever possible and 2 - use one-stage population analysis methods and biologically feasible covariate models for designing pediatric PK studies. The second project involved derivation of the first ever pediatric warfarin dosing regimen, including starting dose and titration scheme, based on pharmacogenetics (Cyp2c9 *1/*2/*3 and VKORc1 -1629 G\u3eA polymorphisms). While extensive research and several dosing models for warfarin use in adults exist, there is paucity of data in pediatrics. A validated adult warfarin population PKPD model was bridged using physiological principles and limited pediatric data to arrive at a pediatric PKPD model and dosing regimen. Pediatric data (n=26) from an observational study conducted at the Children’s Hospital Los Angeles (CHLA) was used to qualify the pediatric model. A 2-step pediatric starting dose based on body weight (\u3c20 kg and ≥20 kg) for each of 18 (6 Cyp2c9 x 3 VKORC1) genotype categories is proposed. The titration scheme involves percentage changes relative to previous dose, based on latest patient INR. The dosing regimen targets a major (≥ 60%) proportion of INRs within therapeutic range of 2.0-3.0, by the second week into warfarin therapy. Simulataneously, bleeding and thromboembolic risks are minimized via minimal proportions (≤ 10% and ≤ 20%) of INRs \u3e 3.5 and INRs \u3c 2.0, respectively. In simulations, the proposed dosing regimen performed better on target INR outcomes than the standard-of-care dosing used in the CHLA patients. Given the challeneges in and low likelihood of conducting pediatric warfarin clinical studies, the proposed dosing regimen is believed to be an important advance in pediatric warfarin therapy. Prospective warfarin studies in pediatrics using the proposed dosing regimen are recommended to refine and validate the suggested dosing strategy

The dose individualisation of oral anticoagulants

Oral anticoagulants are used to treat and prevent blood clots. All anticoagulants carry the risk of bleeding if the systemic exposure is too high, while inadequate exposure will increase the risk of thrombosis. Therefore, the safe and effective use of all oral anticoagulants will require dose individualisation and monitoring. The overarching goal of this thesis is to critically evaluate and explore dose individualisation methods for warfarin and dabigatran therapy to improve patient outcomes. For warfarin, methods for predicting the maintenance dose were investigated. Specifically, Chapter 2 investigates the predictive performance of a Bayesian dose individualisation tool for warfarin. It was found that the maintenance dose was over-predicted especially in patients requiring higher daily doses and further studies into the source of bias were conducted. Chapter 3 further evaluates whether published warfarin maintenance dose prediction algorithms can accurately predict the observed maintenance dose in patients who require ≥7 mg daily (the upper quartile of dose requirements). A systematic review and meta-analysis was conducted to answer this question. It was found that all warfarin dosing algorithms included in the study under-predicted the maintenance dose in this group of patients. One common metric to measure predictive performance of a model is the mean prediction error, which is a measure of bias. The work conducted in Chapter 2 and 3 suggests that the mean prediction error may not capture non-constant bias. This is when the predictions systematically deviate away from the line of identity in one direction in relation to the observed data. Chapter 4 proposes new method to assess predictive performance to analyse non-constant systematic deviation from the line of identity. The proposed method is not specific to warfarin, but can be applied to the analysis of predictive performance in general. For dabigatran dosing, aspects of concentration monitoring as a means of determining a suitable dosing rate were explored. In Chapter 5, an assay using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed to measure all active entities of dabigatran concentrations in human plasma. The assay was used to measure dabigatran concentrations collected from a previous study. A de novo population pharmacokinetic model was not pursued in the first instance as the data were fairly sparse. Instead, the measured concentrations were used in Chapter 6 in a simulation based study to select an appropriate prior population pharmacokinetic model that might be used in a future Bayesian dose individualisation method for dabigatran. The overall intention of Chapter 6 was to develop a Bayesian dose individualisation method for dabigatran. In conclusion, this thesis has identified the limitations of current methods for predicting warfarin maintenance dose and has explored dabigatran concentration monitoring as a means of improving dabigatran dosing. Models for predicting warfarin maintenance dose were critically evaluated and it was found that all existing models can not accurately predict the maintenance dose in patients requiring higher daily doses. An improvement in the method to assess predictive performance was proposed. The work conducted in this thesis on dabigatran dosing provides the basis for future research to individualise dosing and monitoring using population pharmacokinetic models

Personalised warfarin dosing in children after congenital heart surgery using the model-based approach

Oral anticoagulation with warfarin represents a major challenge to successful drug therapy in children. The aims of this study was to investigate the implementation in routine clinical practice, personalised warfarin dosing using a PK/PD model, in children after congenital heart surgery and to explore the experience of patients/parents and health care professionals with managing long-term warfarin treatment as well as their experience with the model-based dosing approach. The predictive performance of the PK/PD model was first validated using retrospectively collected data from a cohort of 60 children on long-term warfarin treatment. Seventy percent of the predicted doses were ideal with bias of -0.10 and precision of 0.19. A prospective interventional quantitative study was then conducted in two groups of children. Group 1 included 5 patients who started warfarin treatment for the first time after cardiac surgery. For the case subjects compared to the controls, the median time to achieve the first therapeutic INR values was longer (5 vs 2 days), the median time to stable anticoagulation was shorter (29.0 vs 96.5 days), the median time to over-anticoagulation was longer (15.0 vs 4.0 days), the median percentage of the INR observations within the target range (%ITR) was higher (70% vs 47.4%), the median percentage of time in therapeutic range (%TTR) was higher (83.4% vs 62.3%), the median frequency of INR measurements per month was comparable (5.0 vs 6.3) and the median frequency of dose alterations was also comparable (20.0 vs 21.0). Group 2 included 26 patients who were established on maintenance warfarin therapy. For the model-based dosing phase compared to the traditional dosing phase, the mean %ITR was 68.82% compared to 67.9% (p=0.84) and the mean %TTR was 85.47% compared to 80.2% (p=0.09). After excluding 5 patients who experienced medical issues during either phases of treatment, the mean %ITR was 71.28% compared to 65.51% (p=0.22) and the median %TTR was 91.8% compared to phase 77.3 % (p=0.03). The median frequency of INR measurements per month was 2.3 compared to 1.9 (p=0.08) and the median frequency of dose alteration was 6.5 compared to 2.5 (p=0.02). Patients with Fontan circulation had significantly higher %TTR during the model-based dosing phase than during the traditional dosing phase after excluding the 5 patients with medical issues (p=0.02). Semi-structured interviews were conducted with 3 doctors, 2 cardiac liaison nurses and four family representatives. Three thematic areas emerged from the doctors’ interviews; ‘medical and clinical knowledge’, ‘INR monitoring’ and ‘dose decision’. Four thematic areas emerged from the nurses’ interviews; ‘role of the cardiac liaison nurses in managing warfarin treatment’, ‘INR monitoring’, ‘dose decision’ and ‘adherence to the prescribed regimen’. Three thematic areas emerged from the families’ interviews; ‘managing warfarin treatment and the coping mechanism’, ‘warfarin dose decision’ and ‘adherence to warfarin treatment’. Both doctors and nurses found the new dosing approach useful and acceptable in patients with stable medical condition. Additionally, three of the families favoured that dosing be performed by a professional experienced with warfarin treatment regardless of the method used. This study has shown that model-based dosing can improve the anticoagulation control of warfarin and hence reduce its adverse events in children after congenital heart surgery. Further work is required to establish the clinical effectiveness and cost-effectiveness of the new dosing approach in this group of children.University of Baghdad/Ira