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Cannabidiol (CBD) is approved for treatment of seizures associated with two forms of epilepsy that become apparent in infancy or early childhood. To consider an adult physiologically based pharmacokinetic (PBPK) model for pediatric scaling, we assessed in vitro-derived cytochrome P450 (CYP) and uridine 5´-diphospho-glucuronosyltransferase (UGT) enzyme contributions to CBD clearance in human. An IV PBPK model was constructed using CBD physicochemical properties and knowledge of disposition. IV datasets were used for model building and evaluation. Oral PBPK models for CBD administered in fasted and fed states were developed using single dose oral datasets and parameters optimized from the IV model and evaluated with multiple dose datasets. Relative contributions of CBD metabolizing enzymes were partitioned according to in vitro studies. Clinical drug-drug interaction (DDI) studies were simulated using CBD fed state, itraconazole, fluconazole, and rifampicin PBPK models. Linear mixed effect modelling was used to estimate AUC

BACKGROUND AND OBJECTIVE The use of continuous renal replacement therapy (CRRT) for renal support has increased substantially in critically ill children compared with intermittent modalities owing to its preferential effects on hemodynamic stability. With the expanding role of CRRT, the quantification of extracorporeal clearance and the effect on primary pharmacokinetic parameters is of the utmost importance. Within this review, we aimed to summarize the current state of the literature and compare published pharmacokinetic analyses of commonly used medications in children receiving CRRT to those who are not. METHODS A systematic search of the literature within electronic databases PubMed, EMBASE, Cochrane Library, and Web of Science was conducted. Published studies that were included contained relevant information on the use of commonly administered medications to children, from neonates to adolescents, receiving CRRT. Pharmacokinetic parameters that were analyzed included volume of distribution, total clearance, extracorporeal clearance, area under the curve, and elimination half-life. Information regarding CRRT circuit, flow rates, and membrane components was analyzed to investigate differences in pharmacokinetics between each modality. RESULTS Forty-five studies met the final inclusion criteria within this systematic review, totaling 833 pediatric patients, with 586 receiving CRRT. Antimicrobials were the most common pharmacological class represented within the literature, representing 81% (35/43) of studies analyzed. Children receiving CRRT largely had similar volume of distribution and total clearance to critically ill children not receiving CRRT, suggesting reno-protective dose adjustments may lead to subtherapeutic dosing regimens in these patients. Overall, there was a tendency for hydrophilic agents, with a low protein binding to undergo elevated total clearance in these children. However, results should be interpreted with caution because of the large variability amongst patient populations and heterogeneity with CRRT modalities, flow rates, and use of extracorporeal membrane oxygenation within studies. This review was able to identify that variation in solute removal, or CRRT modalities, properties (i.e., flow rates), and membrane composition, may have differing effects on the pharmacokinetics of commonly administered medications. CONCLUSIONS The current state of the literature regarding medications administered to children receiving CRRT largely focuses on antimicrobials. Significant gaps remain with other commonly used medications such as sedatives and analgesics. Overall reporting of patient clinical characteristics, CRRT settings, and circuit composition was poor, with only 10% of articles including all relevant information to assess the impact of CRRT on total clearance. Changes in pharmacokinetics because of CRRT often required higher than labeled doses, suggesting renally adjusted or reno-protective doses may lead to subtherapeutic dosing regimens. A thorough understanding of the interplay between patient, drug, and CRRT-circuit factors are required to ensure adequate delivery of dosing regimens to this vulnerable population.

Current methods to assess risk in infants exposed to maternal medication through breast milk do not specifically account for infants most vulnerable to high drug exposure. A workflow applied to lamotrigine incorporated variability in infant anatomy and physiology, milk intake volume, and milk concentration to predict infant exposure. An adult physiologically based pharmacokinetic model of lamotrigine was developed and evaluated. The model was scaled to account for growth and maturation of a virtual infant population (n=100). Daily infant doses were simulated using milk intake volume and concentration models described by a nonlinear equation of weight-normalized intake across infant age and a linear function on the relationship of observed milk concentrations and maternal doses, respectively. Average infant plasma concentration at steady state was obtained through simulation. Models were evaluated by comparing observed to simulated infant plasma concentrations from breastfeeding infants based on a 90% prediction interval (PI). Upper AUC ratio (UAR) was defined as a novel risk metric. Twenty-five paired (milk concentrations measured) and 18 unpaired (milk concentrations unknown) infant plasma samples were retrieved from the literature. Forty-four percent and 11% of the paired and unpaired infant plasma concentrations were outside of the 90% PI, respectively. Over all ages (0-7 months), unpaired predictions captured more observed infant plasma concentrations within 90% PI than paired. UAR was 0.18-0.44 when mothers received 200 mg lamotrigine, suggesting that infants can receive 18-44% of the exposure per dose as compared to adults. UARs determined for further medications could reveal trends to better classify at-risk mother-infant pairs.

Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay – 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data. Electronic supplementary material The online version of this article (10.1007/s10928-019-09637-4) contains supplementary material, which is available to authorized users.

Background Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A. Patients and Methods Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD). Results Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold. Conclusion Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes.

The conventional approach to approximating the pharmacokinetics of drugs in patients with chronic kidney disease (CKD) only accounts for changes in the estimated glomerular filtration rate. However, CKD is a systemic and multifaceted disease that alters many body systems. Therefore, the objective of this exercise was to develop and evaluate a whole-body mechanistic approach to predicting pharmacokinetics in patients with CKD. Physiologically based pharmacokinetic models were developed in PK-Sim v8.0 (www.open-systems-pharmacology.org) to mechanistically represent the disposition of 7 compounds in healthy human adults. The 7 compounds selected were eliminated by glomerular filtration and active tubular secretion by the organic cation transport system to varying degrees. After a literature search, the healthy adult models were adapted to patients with CKD by numerically accounting for changes in glomerular filtration rate, kidney volume, renal perfusion, hematocrit, plasma protein concentrations, and gastrointestinal transit. Literature-informed interindividual variability was applied to the physiological parameters to facilitate a population approach. Model performance in CKD was evaluated against pharmacokinetic data from 8 clinical trials in the literature. Overall, integration of the CKD parameterization enabled exposure predictions that were within 1.5-fold error across all compounds and patients with varying stages of renal impairment. Notable improvement was observed over the conventional approach to scaling exposure, which failed in all but 1 scenario in patients with advanced CKD. Further research is required to qualify its use for first-in-CKD dose selection and clinical trial planning for a wider selection of renally eliminated compounds, including those subject to anion transport.

Despite the many benefits of breast milk, mothers taking medication are often uncertain about the risks of drug exposure to their infants and decide not to breastfeed. Physiologically based pharmacokinetic models can contribute to drug‐in‐milk safety assessments by predicting the infant exposure and subsequently, risk for toxic effects that would result from continuous breastfeeding. This review aimed to quantify breast milk intake feeding parameters in term and preterm infants using literature data for input into paediatric physiologically based pharmacokinetic models designed for drug‐in‐milk risk assessment. Ovid MEDLINE and Embase were searched up to July 2, 2019. Key study reference lists and grey literature were reviewed. Title, abstract and full text were screened in nonduplicate. Daily weight‐normalized human milk intake (WHMI) and feeding frequency by age were extracted. The review process retrieved 52 studies. A nonlinear regression equation was constructed to describe the WHMI of exclusively breastfed term infants from birth to 1 year of age. In all cases, preterm infants fed with similar feeding parameters to term infants on a weight‐normalized basis. Maximum WHMI was 152.6 ml/kg/day at 19.7 days, and weighted mean feeding frequency was 7.7 feeds/day. Existing methods for approximating breast milk intake were refined by using a comprehensive set of literature data to describe WHMI and feeding frequency. Milk feeding parameters were quantified for preterm infants, a vulnerable population at risk for high drug exposure and toxic effects. A high‐risk period of exposure at 2–4 weeks of age was identified and can inform future drug‐in‐milk risk assessments.

Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design.Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date.The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations.The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Background Use of population pharmacokinetics (PopPK) to facilitate PK-informed prophylaxis in clinical practice has gained momentum among haemophilia providers due to the accessibility of tools such as the Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and availability of extended half-life (EHL) factor concentrates. It is unknown how clinicians implement PopPK. Aim To investigate the evolution of PopPK use in clinical practice by comparing blood sampling strategies, patient features, and factor group between initial and recent periods of WAPPS-Hemo availability. Methods PK data for haemophilia A and haemophilia B patients from two time periods were extracted from the WAPPS-Hemo database: early availability (10/2015-09/2016) and recent use (10/2017-09/2018). We compared patient characteristics (age, body weight, haemophilia type), product type and dose, and blood sampling times between the time frames. Results Over 1900 eligible infusions were submitted to WAPPS-Hemo during the periods studied, with 85% representing FVIII concentrates. In the recent cohort, PK profiles were requested for younger patients (median age 18 vs 26 years), with increased proportional EHL FVIII use (29% vs 14% of infusions). High-use centres generally submitted fewer blood samples per infusion than non-high-use centres, although the number of samples collected by non-high-use centres decreased significantly over time. During both periods, blood sample timing was generally consistent with ISTH recommended windows. Conclusion The use of WAPPS-Hemo by haemophilia providers grew by over threefold between the time periods investigated. While sampling times have included key time points proposed first by Bjorkman since early WAPPS-Hemo usage, a trend towards minimizing sampling was observed.

Background Rare diseases are a global public health priority. Though each disease is rare, when taken together the thousands of known rare diseases cause significant morbidity and mortality, impact quality of life, and confer a social and economic burden on families and communities. These conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment. Clinical practice guidelines are necessary to support clinical and policy decisions. However, creating guidelines for rare diseases presents specific challenges, including a paucity of high certainty evidence to inform panel recommendations. Methods This paper draws from the authors’ experience in the development of clinical practice guidelines for three rare diseases: hemophilia, sickle cell disease, and catastrophic antiphospholipid syndrome. Results We have summarized a number of strategies for eliciting and synthesizing evidence that are compatible with the rigorous, internationally accepted standards for guideline development set out by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. These strategies include: use of pre-existing and ad hoc qualitative research, use of systematic observation forms, use of registry data, and thoughtful use of indirect evidence. Their use in three real guideline development efforts, as well as their theoretical underpinnings, are discussed. Avenues for future research to improve clinical practice guideline creation for rare diseases – and any disease affected by a relative lack of evidence - are also identified. Conclusions Rigorous clinical practice guidelines are needed to improve the care of the millions of people worldwide who suffer from rare diseases. Innovative evidence elicitation and synthesis methods will benefit not only the rare disease community, but also individuals with common diseases who have rare presentations, suffer rare complications, or require nascent therapies. Further refinement and improved uptake of these innovative methods should lead to higher quality clinical practice guidelines in rare diseases.

Background Rigorous and transparent methods are necessary to develop clinically relevant and evidence-based practice guidelines. We describe the development of the National Hemophilia Foundation-McMaster Guideline on Care Models for Haemophilia Management, which addresses best practices in haemophilia care delivery. Methods We assembled a Panel of persons with haemophilia (PWH), parents of PWH, clinical experts and guideline methodologists. Conflicts of interest were disclosed and managed throughout. Panel members and key stakeholders were surveyed to develop the guideline questions and identify patient-important outcomes. Systematic reviews of the literature were conducted for all factors important in decision-making: benefits and harms; patient values and preferences; resource implications; acceptability; equity; and feasibility. We used the GRADE approach to create evidence profiles to evaluate the evidence and present key results. Evidence to Decision frameworks were created to guide the Panel in making evidence-based recommendations. When evidence was very low quality or not available, evidence from other chronic disease populations was presented to the Panel to inform the recommendations. Additionally, we systematically pooled observations from experts, and conducted qualitative interviews exploring key stakeholder experiences and perspectives. The Panel made recommendations for each guideline question and elaborated on research priorities, implementation considerations, and monitoring. Final recommendations were circulated for public and peer review. Conclusions Despite the paucity of high-quality evidence typical of a rare condition such as haemophilia, we successfully applied a rigorous and transparent methodology based on GRADE to develop an evidence-based clinical practice guideline.

Introduction Standard prophylaxis dosing based on bodyweight may result in over- or under-dosing due to interpatient variability. Adopting individual pharmacokinetic (PK) based tailoring may improve adherence to treatment guideline, and consequently clinical outcomes. Here we report clinical observations performed across the adoption of individual PK based tailoring in a single center in Japan. Methods An individual PK study on sparse samples was modeled on myPKFiT or WAPPS-Hemo, depending on concentrate, and used to optimize treatment regimens. Adherence to prophylaxis and bleeding rate were calculated from patient diaries. Radiological joint scores were used to assess arthropathy, and SPSS to perform all the analyses. Results Thirty-nine patients underwent PK profiling, and 20 required and accepted a modification of their treatment (8 increases in dose, 5 reductions in frequency, 5 switches to extended half-life (EHL)). Adherence to prophylaxis remained the same in those increasing the dose, whilst increased in all the other groups. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AjBR) decreased in all the groups but reached statistical significance only in those switched to EHL and showed a larger reduction in those patients without baseline arthropathy. Longer time spent above a 1% or 5% threshold was associated with a decrease in the ABR/AjBR. Conclusions Our study results suggest that PopPK based tailoring supported changing treatment regimen in nearly half of the patients, and may have contributed to an improvement in the adherence and a reduction in the ABR/AjBR.

Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease.

Background Catastrophic antiphospholipid syndrome (CAPS) is characterized by the rapid onset of widespread or multifocal large and/or small vessel thrombosis associated with multi-organ failure in patients meeting the serological criteria for antiphospholipid syndrome [1]. Mortality in CAPS approaches 50% [2]. Objectives The RARE-BestPractices project group identified CAPS as a rare disease condition of interest in which to develop a clinical practice guideline. The project was run in partnership with McMaster University, and used the GIN-McMaster Guideline Development checklist and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to develop guidelines on rare diseases [3]. Methods The CAPS guideline was coordinated by a steering committee including representatives from RARE-BP and methodologists from McMaster University. The CAPS guideline panel consisted of 19 international members, including patient representation. The panel used the GradePro software to brainstorm and prioritize potential questions and outcomes. Systematic reviews were performed for each question. To supplement the published evidence, we compiled raw data for mortality from the CAPS Registry, and systematically elicited expert opinion from the panel members using a systematic observation form. For each question an evidence profile and evidence to decision table was generated and shared. Results The question prioritization step generated 47 questions, which were ranked to identify the top priorities. The top 10 questions were chosen for guideline development, yielding 7 therapy and 3 diagnostic questions. The outcome generation step yielded 7 outcomes. The questions were addressed during an in-person panel meeting, held on April 27, 2016 in Barcelona, Spain, with follow-up via webinar on June 3, 2016, and with web-based voting completed July 31, 2016. Recommendations were developed for all questions and will be discussed in detail. Conclusions Ten recommendations were issued by the CAPS Guideline Panel to assist clinicians in diagnosis and management of suspected CAPS patients. Future research is needed to improve evidence quality in rare diseases such as CAPS. The GIN-McMaster Guideline Development Checklist and the GRADE methodology were effective in producing a rigorous guideline in this rare disease. References Asherson R. The catastrophic antiphospholipid syndrome. J Rheumatol 1992. Cervera R, Bucciarelli S, Plasin M, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009;32:240–5. Guyatt G, Oxman A, Vist G, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924–6. Disclosure of Interest None declared

Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data.

Objective: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform allows hemophilia treaters to estimate individual PK parameters for clotting factor concentrates using only a few blood samples drawn from their patients. Population pharmacokinetic (PopPK) models used with WAPPS-Hemo are usually built using clinical trial data provided by drug manufacturers. These trials can be restrictive with respect to patient covariates such as age and body weight. On the other hand, real-world pharmacokinetic data submitted to WAPPS captures the breadth of hemophilia patients. We tested the use of post-infusion clotting factor concentrate measurements collected through routine use of WAPPS-Hemo to develop a plasma-derived FVIII (Fanhdi/Alphanate)-specific model for which no trial data was available. Methods: Plasma factor activity measurements and information on hemophilia A patients were extracted from the WAPPS database. PopPK modeling was completed in NONMEM (ver 7.3, Icon, PLC). Evaluation of model-based Bayesian forecasting to derive the individual PK parameters included 10-fold internal cross validation, limited sampling analysis, and external validation using WAPPS data collected subsequently. The ability of the model to capture age related changes in PK was assessed through separate examination of predictive accuracy for children ≤ 12 yrs and for children and adults >12 yrs of age. Results: Post-infusion FVIII activity levels from 92 patients were used to derive and internally validate the model. Two-thirds of the patients originated from three centres (Campinas, Brazil; Valencia, Spain; and Santiago, Chile) with the remaining patients from 9 other WAPPS centers. Patients were 1-71 yrs (~33.7% ≤12 yrs) with a body weight range between 9 and 119 kg. Each patient provided between 1-8 activity levels up to 72 hours post infusion (386 data points in total). The final PopPK model followed 2-compartment kinetics with fat-free mass and age as covariates. Clearance was consistent across age until 25 years where clearance declined. The ability of the model to capture the PK in children ≤ 12 yrs was similar in accuracy to patients >12 yrs (Figure 1). Limited sampling analysis demonstrated that sampling strategies using two to three samples with one sample being a 72 hour post-infusion sample produced time-above-2% activity estimates, on average, Conclusions: Use of routine clinical care data for model development was feasible and expanded the covariate space (e.g. age) from what is traditionally included in trials. A promising approach would be to supplement clinical trial data with routine clinical data in order to build future PopPK models. On one hand, dense data from clinical trials brings stability to the model and provides a good description of the PK curve and may reduce random error if measured in a central lab; on the other hand, sparse data from routine practice widens the possible observations, inputs and covariates of the model, and could better perform the scope of individual Bayesian forecasting. Our analysis has demonstrated that collecting a few real world samples per patient not only allows accurately determining individual PK parameters, but was also effective for developing a model for a specific brand. This research was supported by Grifols, a manufacturer of plasma-derived FVIII/VWF concentrates. The WAPPS-Hemo team independently performed the derivation and validation of the model. All authors reviewed and approved the abstract as submitted. Disclosures Ozelo: BioMarin: Honoraria, Speakers Bureau; Grifols: Honoraria; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding. Iorio:Shire: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Shire; Pfizer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Pfizer; NovoNordisk: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Novo Nordisk; Grifols: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Grifols; Octapharma: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Octapharma; CSL: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with CSL; Bayer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Bayer; Roche: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Roche. Spears:Grifols: Employment. Mir:Grifols: Employment. Edginton:Bayer: Honoraria.

This guideline was developed to identify evidence-based best practices in haemophilia care delivery, and discuss the range of care providers and services that are most important to optimize outcomes for persons with haemophilia (PWH) across the United States. The guideline was developed following specific methods described in detail in this supplement and based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation approach). Direct evidence from published literature and the haemophilia community, as well as indirect evidence from other chronic diseases, were reviewed, synthesized and applied to create evidence-based recommendations. The Guideline panel suggests that the integrated care model be used over non-integrated care models for PWH (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence. The panel suggests that a haematologist, a specialized haemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over an integrated care team that does not include all of these components (conditional recommendation, very low certainty in the evidence). Based on available evidence, the integrated model of care in its current structure, is suggested for optimal care of PWH. There is a need for further appropriately designed studies that address unanswered questions about specific outcomes and the optimal structure of the integrated care delivery model in haemophilia.

Background Haemophilia care is commonly provided via multidisciplinary specialized management. To date, there has been no systematic assessment of the impact of haemophilia care delivery models on patient-important outcomes. Objective To conduct a systematic review of published studies assessing the effects of the integrated care model for persons with haemophilia (PWH). Search methods We searched MEDLINE, EMBASE and CINAHL up to April 22, 2015, contacted experts in the field, and reviewed reference lists. Selection criteria Randomized and non-randomized studies of PWH or carriers, focusing mainly on the assessment of care models on delivery. Data collection and analysis Two investigators independently screened title, abstract, and full text of retrieved articles for inclusion. Risk of bias and overall quality of evidence was assessed using Cochrane's ACROBAT-NRSI tool and GRADE respectively. Relative risks, mean differences, proportions, and means and their variability were calculated as appropriate. Results 27 non-randomized studies were included: eight comparative and 19 non-comparative studies. We found low- to very low-quality evidence that in comparison to other models of care, integrated care may reduce mortality, hospitalizations and emergency room visits, may lead to fewer missed days of school and work, and may increase knowledge seeking. Conclusion Our comprehensive review found low- to very low-quality evidence from a limited number of non-randomized studies assessing the impact of haemophilia care models on some patient-important outcomes. While the available evidence suggests that adoption of the integrated care model may provide benefit to PWH, further high-quality research in the field is needed.

Introduction Care for persons with haemophilia (PWH) is most commonly delivered through the integrated care model used by Hemophilia Treatment Centers (HTCs). Although this model is widely accepted as the gold standard for the management of haemophilia; there is little evidence comparing different care models. Aim We performed a qualitative study to gain insight into issues related to outcomes, acceptability, equity and feasibility of different care models operating in the US. Methods We used a qualitative descriptive approach with semi-structured interviews. Purposive sampling was used to recruit individuals with experience providing or receiving care for haemophilia in the US through either an integrated care centre, a specialty pharmacy or homecare company, or by a specialist in a non-specialized centre. Persons with haemophilia, parents of PWH aged ≤18, healthcare providers, insurance company representatives and policy developers were invited to participate. Results and Conclusions Twenty-nine interviews were conducted with participants representing 18 US states. Participants in the study sample had experience receiving or providing care predominantly within an HTC setting. Integrated care at HTCs was highly acceptable to participants, who appreciated the value of specialized, expert care in a multidisciplinary team setting. Equity and feasibility issues were primarily related to health insurance and funding limitations. Additional research is required to document the impact of care on health and psychosocial outcomes and identify effective ways to facilitate equitable access to haemophilia treatment and care.

Background Integrated care models have been adopted for individuals with chronic conditions and for persons with rare diseases, such as haemophilia. Objective To summarize the evidence from reviews for the effects of integrated multidisciplinary care for chronic conditions in adults and to provide an example of using this evidence to make recommendations for haemophilia care. Search methods We searched MEDLINE, EMBASE, CINAHL and Cochrane Database of Systematic Reviews up to January 2016, and reviewed reference lists of retrieved papers. Selection criteria Systematic reviews of at least one randomized study, on adults with non-communicable chronic conditions. Data collection and analysis Two investigators independently assessed eligibility and extracted data. Quality of reviews was assessed using ROBIS, and the evidence assessed using GRADE. Results We included seven reviews reporting on three chronic conditions. We found low to high quality evidence. Integrated care results in a reduction in mortality; likely a reduction in emergency visits and an improvement in function; little to no difference in quality of life, but shorter hospital stays; and may result in little to no difference in missed days of school or work. No studies reported educational attainment, or patient adherence and knowledge. When used for haemophilia, judgment about the indirectness of the evidence was driven by disease, intervention or outcome characteristics. Conclusion This overview provides the most up to date evidence on integrated multidisciplinary care for chronic conditions in adults, and an example of how it can be used for guidelines in rare diseases.

Background In people with haemophilia or other congenital bleeding disorders undergoing surgical interventions, haemostatic treatment is needed in order to correct the underlying coagulation abnormalities and minimise the bleeding risk. This treatment varies according to the specific haemostatic defect, its severity and the type of surgical procedure. The aim of treatment is to ensure adequate haemostatic coverage for as long as the bleeding risk persists and until wound healing is complete. Objectives To assess the effectiveness and safety of different haemostatic regimens (type, dose and duration, modality of administration and target haemostatic levels) administered in people with haemophilia or other congenital bleeding disorders for preventing bleeding complications during and after surgical procedures. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of the last search: 20 November 2014. Selection criteria Randomised and quasi-randomised controlled trials comparing any hemostatic treatment regimen to no treatment or to another active regimen in children and adults with haemophilia or other congenital bleeding disorders undergoing any surgical intervention. Data collection and analysis Two authors independently assessed trials (eligibility and risks of bias) and extracted data. Meta-analyses were performed on available and relevant data. Main results Of the 16 identified trials, four (112 participants) were eligible for inclusion. Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial. Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 μg/kg) was compared with a low-dose regimen (35 μg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. Authors' conclusions There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost-effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies.