京都大学 / 新制・課程博士 / 博士(医学) / 甲第24084号 / 医博第4860号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 柳田 素子, 教授 長船 健二, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Class of 2014 Abstract / Specific Aims: To assess appropriate use or cessation of metformin therapy in the presence of renal impairment. Methods: A retrospective chart review was conducted on 785 charts of patients at El Rio Community Health Center between June 2011 and December 2012. Eligibility criteria were adults aged 18 years or older with a diagnosis of Type 2 Diabetes Mellitus (DM), a history of metformin therapy, and renal function data. Data was accessed through the electronic medical record (EMR) at El Rio and metformin history, presence of contraindications, renal function, weight, age, gender, and race/ethnicity were collected. Group 1 were patients who were currently taking metformin and Group 2 were patients with a history of taking metformin. Main Results: A larger proportion of patients had renal impairment (eGFR 30-60 ml/min/1.73 m2) in Group 1 than Group 2 (Yates’ p = 0.002). Only one patient in the entire study had severe renal impairment (eGFR < 30 ml/min/1.73 m2). There was a greater proportion of inappropriate cessation in Group 2 than inappropriate use or cessation in Group 1 (Yates’ p < 0.001). Conclusion: Most patients were found to have normal renal function. Group 2 had a greater proportion of inappropriate metformin cessation than inappropriate use or cessation in Group 1.

Class of 2015 Abstract / Objectives: To characterize the types of renal dosing recommendations provided in the prescribing information (aka package insert) before and after the FDA guidance for industry document regarding renal dosing, released in 1998. Methods: The prescribing information (PI) for all new molecular entities (NMEs) for three time periods was collected from the FDA website. Time period 1 was January 1995 to December 1997 and represents dosing recommendations prior to the FDA guidance statement. Time period 2 was January 2000 to December 2002 and time period 3 was January 2011 to December 2013. These represent recommendations after the FDA guidance statement. The renal dosing recommendations for each NME were reviewed and classified as either specific (includes CrCl, serum creatinine), nonspecific (mild, moderate, or severe impairment), caution, unnecessary, no information or other by two investigators independently. A further analysis was conducted for NMEs in time periods 1 and 2 with LexiComp and the most recent PIs located on FDA or company website. Presence of dialysis (hemodialysis or peritoneal) dosing recommendations was also recorded. Results: Time period 1 had significantly less NMEs characterized as No information in Lexicomp in comparison to original PIs (p= 0.02). A statistically significant decrease in original PIs characterized as Caution was observed between time periods 2 and 3 (p= .0004) and time periods 1 and 3 (p= 0.001). Conclusions: Terminology used in renal dosing recommendations in PIs does not seem to be clearer over the past years. There remains a need for improved quality of dosing information within PIs.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.