Why has model-informed precision dosing not yet become common clinical reality?:Lessons from the past and a roadmap for the future

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap

The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy

Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug-drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non-pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUCratioin the range 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir, respectively, over GW 10-40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post-dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co-infection. However, antiretroviral-mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients

Automated Kidney Segmentation in 3D Ultrasound Imagery, and its Application in Computer-Assisted Trauma Diagnosis

Due to the limitations of emergency healthcare/technology, blunt abdominal bleeding causes a large number of preventable deaths each year. To save a trauma patient's life, a rapid diagnosis is required, which is not always available in emergency situations. This is the thesis of this PhD research that a computer-assisted algorithm based on 3D ultrasound imagery, as a portable imaging modality, provides a systematic solution to facilitate rapid diagnosis of trauma patients in emergency situations by first responders (ie. paramedics). 3D ultrasound imagery, which is a portable imaging system, is selected as the preferred imaging modality for trauma diagnosis, because it can be carried to the location of emergency situation. Therefore, by eliminating the need of moving an unstable patient to an imaging room, rapid trauma diagnosis is achievable. Compared to 2D sonography, 3D ultrasound imaging facilitates automated detection and localization of internal organs. This is essential, specifically in the sense that ultrasonographers are not always present at emergency situations. Hence, a computer-assisted solution is essential to guide first responders to perform trauma diagnosis using a 3D ultrasound device. An abdominal bleeding has a high tendency to align around the right kidney. The right-upper-quadrant view of sonography shows the entire kidney shape, and therefore, it is considered as the most relevant internal view to trauma diagnosis. Paramedics usually lack proper knowledge to find the right-upper-quadrant view, to detect the kidney shape, and to detect an internal bleeding using an ultrasound imaging device. Hence, computer-assisted algorithms are required to perform these tasks. The focus of this thesis is to introduce automated methods to detect and segment the kidney shape. The detected kidney shape will be used for two purposes: (a) it is used to calculate the ultrasound probe's misalignment with respect to the right-upper-quadrant view, which is used to guide the operator to move the probe toward the correct alignment on the patient's body; (b) the detected kidney shape is used to initialize the kidney segmentation process, and thereby, an automated kidney segmentation approach is achieved. The kidney segmentation output can be used to automatically detect an internal bleeding.Ph.D

CYP450-mediated drug-drug interactions: towards prediction and informed dose recommendation using physiologically-based pharmacokinetic (PBPK) modeling

Une des principales sources de la variabilité de réponse aux médicaments est la variabilité pharmacocinétique pour laquelle les interactions médicamenteuses constituent une des explications les plus fréquentes. Ce travail de thèse consiste en grand partie en la conception et la réalisation de deux études cliniques dans lesquelles les interactions entre les médicaments antiplaquettaires clopidogrel, prasugrel, ticagrelor et le ritonavir, un médicament couramment prescrit chez des patients infectés par le VIH, ont été évaluées. Pour la première fois, le technique de modélisation pharmacocinétique basée sur la physiologie, appelée PBPK, a été utilisé afin de prédire l'ampleur de ces interactions. Il s'agit d'une méthode innovante et prometteuse de prédiction du devenir du médicament dans le corps humain sur la base des données in vitro et in vivo du médicament ainsi que des caractéristiques physiopathologiques du sujet virtuel. Une adaptation de dose permettra de réduire les conséquences cliniques de ces interactions

ASSESSMENT OF ENDOMETRIAL-SUBENDOMETRIAL BLOOD FLOW DETECTED BY COLOR DOPPLER SONOGRAPHY AND UTERINE RECEPTIVITY IN INFERTILE WOMEN

"nndometrial vasculature has been shown to play an important role in the early endometrial response to the implanting blastocyst, and vascular changes may contribute to uterine receptivity. The aim of this study was to investigate the role of endometrial and subendometrial vascularity and thickness in uterine receptivity in infertile women treated with assisted reproductive technologies (ART). A total of 175 women were recruited from our ART program from June 2005 to May 2006. In the first stage, down regulation was done using GnRH-a and then ovarian hyperstimulation was initiated with human menopausal gonadotrophin and in vitro fertilization (IVF) procedures were performed. Then, the endometrial-subendometrial blood flow distribution pattern was determined by color Doppler ultrasonography and its characteristics were compared between pregnant (n = 56) and non-pregnant (n = 119) women.  Zones 1, 2 and 3 of vascular penetration were found in 15.4%, 22.3%, and 62.3% of patients, respectively. The number of implanted embryos was 62 and implantation rate was 11.61%. There was no significant association between implantation rate and endometrial thickness or zone of vascular penetration. Among all women, fertility occurred in 56 (32.2%) women. Zone 1 of vascular penetration was found in 10.71% and 10.08% (P = 0.898), zone 2 in 16.07% and 13.44% (P = 0.643), and zone 3 in 41.07% and 41.17% (P = 0.989) of pregnant and non-pregnant groups, respectively. Endometrial-subendometrial blood flow (according the findings of Doppler ultrasonography) in women undergoing ART could not predict endometrial receptivity and IVF outcome

Compilation and Priority Assessment of Scenarios Affecting the Future of Sustainable Tourism in Kerman with the Futures studies Approach

The current study is using a future studies approach to develop and identify the most important effective scenarios for the future of sustainable tourism in Kerman up to 2030.The study purpose is practical and the methods are documentary and survey methods and the study nature is future studies, analytical and explorative.According to the study nature, Delphi method, structural analysis and Scenario Wizard were applied.Therefore, the ideas of fifteen tourism experts of Kerman were counseled as the study sample, and based on their ideas,15 possible ways for developing the scenarios were evaluated. The study results indicate that 80% of the states indicate the desirability and 20% of the indicators of stability and crisis of sustainable tourism in Kerman and finally there are three valid scenarios for future developing of tourism.The most optimal group of scenarios belongs to first group which is based on competitiveness, program-oriented and balanced development

Usefulness of PBPK Modeling in Incorporation of Clinical Conditions in Personalized Medicine

Personalized medicine aims to determine the most adequate treatment and dose regimen to obtain the maximum efficacy and minimum side effect by taking into account patients' characteristics. For numerous reasons, one being ethical and methodological hurdles in including specific populations in clinical trials, innovative methods for optimization of drugs safety and efficacy in such patients have received increasing interest recently. Physiological-based pharmacokinetic (PBPK) modeling has emerged as a promising approach in designing adequate clinical trials and quantifying anticipated changes in unknown clinical situations. In this review, current state of knowledge on the usefulness of PBPK modeling in estimation of drug exposure in specific medical conditions including pregnancy, pediatrics, elderly, patients with liver or renal impairment, obesity, and following bariatric surgery were outlined. Modulations of key system parameters occurring in these patient populations were illustrated. Furthermore, the application of PBPK approach in dose recommendations and quantification of drug exposure in carriers of genetic polymorphisms was summarized. Despite the uncertainties and knowledge gaps related to parameters influencing drugs bioavailability in each clinical condition, PBPK models provide a valuable support for prospective dose recommendations and efficacy/safety assessment in special populations when consistent clinical data are lacking

Dictionary Learning for Short-term Prediction of Solar PV Production

Prediction of power generated from renewable energy resources such as solar photo-voltaic (PV) is a crucial task for stabilization of grids with high renewable penetration levels. Short-term prediction of these resources allow for preemptive regulation of injected power fluctuations. In this paper, a new algorithm based on dictionary learning for prediction of solar power fluctuations is introduced. This algorithm is effective on systems with structural regularities. In this method, a dictionary is trained to carry various behaviors of the system. Prediction is performed by reconstructing the tail of the upcoming signal using this dictionary. After introduction of the proposed algorithm, experimental results are provided to evaluate the prediction mechanism