Estimated prophylactic dose required to achieve 3% trough as a function of age and concentrate class in multi-country severe WAPPS-Hemo haemophilia patients.

INTRODUCTION: Web-Accessible Population-Pharmacokinetic Service-Haemophilia (WAPPS-Hemo) data are available to study factor-concentrate usage, defined as the required weekly dose to achieve a 3% trough (WD3T), across standard and extended half-life (SHL/EHL) products. AIM: To provide baseline usage data including (i) differences across plasma-derived (pdSHL) versus recombinant (rSHL) products, (ii) SHL versus EHL, and (iii) effect of age and positive inhibitor history. METHODS: PK profiles (n = 14,416 patients, 0.3-85.2 years) and linear mixed effects models were used to estimate usage versus age, controlling for significant factors, using 95% confidence intervals to perform comparisons across all ages and posthoc tests to assess the differences. RESULTS: Average usage was significantly higher for pdSHL versus rSHL in patients with a positive inhibitor history (PIH; 1.9-2.5 times higher), for SHL versus EHL (4-10 times), and was significantly associated with age. CONCLUSION: Baseline usage patterns from 2017 to early 2023 provide a benchmark for assessing the impact of emerging technologies in haemophilia.

Health utilities in adults with hemophilia A: A retrospective cohort study.

INTRODUCTION: Haemophilia A negatively affects a patient's quality of life. There is a limited amount of health utility data (a measure of health-related quality of life) available for patients with haemophilia A. This information is crucial for cost-effectiveness analysis for haemophilia A treatment. OBJECTIVES: The goal of this project is to elicit the health utilities and factors impacting utility values for haemophilia A patients in Canada. METHODS: This is a population-based, cross-sectional, retrospective study of health utilities in patients with haemophilia A using Patient Report Outcomes Burdens and Experiences (PROBE) components from the Canadian Bleeding Disorders Registry (CBDR). A review of the mean utilities for three severity states, defined by clotting factor VIII level, was completed. A multiple linear regression analysis was completed to examine the determinants of health utilities including age, treatment type, chronic pain status, number of limited joints, and bleed rate. RESULTS: The average utility values (and standard deviations) for patients with haemophilia A in Canada are .79(.17), .76(.20), and .77(.19) for patients with severe, moderate, and mild haemophilia. The regression showed chronic pain status and the number of additional comorbidities as major significant factors (p-value < .001) in haemophilia A utility. Haemophilia severity was shown to be a major factor with smaller p-value (p-value < .05). CONCLUSIONS: Haemophilia A patients have lower utility than the general population. Chronic pain was shown to be a significant, major factor in health-related quality of life. Our study is essential for valuing health outcomes in haemophilia A-related cost-effectiveness analysis.

Canadian clinical experience on switching from standard half-life recombinant factor VIII (rFVIII), octocog alfa, to extended half-life rFVIII, damoctocog alfa pegol, in persons with haemophilia A ≥ 12 years followed in a Comprehensive Hemophilia Care Program in Canada.

INTRODUCTION: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada. AIM: To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment. METHODS: A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization. RESULTS: Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained. CONCLUSION: This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A.

Cost-utility analysis of emicizumab for the treatment of severe hemophilia A patients in Canada.

INTRODUCTION: EHL FVIII products and emicizumab provide clinicians with other prophylactic options for treating hemophilia A, however, it is unclear if emicizumab is a cost-saving option. The objective of this study is to estimate the health and economic effects of using prophylactic EHL FVIII, SHL FVIII, and emicizumab in severe haemophilia A patients. MATERIALS AND METHODS: A state-transition Markov model evaluated the cost-effectiveness of prophylactic SHL FVIII, EHL FVIII, and emicizumab in a cohort of 2-year-old male patients over a lifetime horizon in the form of a cost-utility analysis using a Canadian provincial ministry of health payer perspective. The transition probabilities, costs, and utilities were obtained from literature and the Canadian Bleeding Disorders Registry. Probabilistic sensitivity and scenario analyses were performed to test the robustness of the model. RESULTS: The base-case analysis, over a lifetime horizon, resulted in a total cost and utilities per person for SHL FVIII, EHL FVIII, and emicizumab of $27.2 million (M), $36.7 M, and $26.2 M, respectively, and 31.30, 31.16, and 31.61 quality-adjusted life years, respectively. Emicizumab treatment resulted in 29 and 16 less bleeds in a lifetime compared to SHL FVIII and EHL FVIII, respectively. Probabilistic sensitivity analysis showed that emicizumab was cost-saving 100% of the time compared to SHL FVIII and EHL FVIII. CONCLUSION: The cost-utility analysis showed that emicizumab is more effective and may be less costly than FVIII for Canadian haemophilia A patients, conditional on drug cost assumptions. Our model indicates that emicizumab may be a potentially favourable treatment option for minimising healthcare costs and providing higher effectiveness.

Model-Based Assessment of the Contribution of Monocytes and Macrophages to the Pharmacokinetics of Monoclonal Antibodies.

PURPOSE: We have hypothesized that a high concentration of circulating monocytes and macrophages may contribute to the fast weight-based clearance of monoclonal antibodies (mAbs) in young children. Exploring this hypothesis, this work uses modeling to clarify the role of monocytes and macrophages in the elimination of mAbs. METHODS: Leveraging pre-clinical data from mice, a minimal physiologically-based pharmacokinetic model was developed to characterize mAb uptake and FcRn-mediated recycling in circulating monocytes, macrophages, and endothelial cells. The model characterized IgG disposition in complex scenarios of site-specific FcRn deletion and variable endogenous IgG levels. Evaluation was performed for predicting IgG disposition with co-administration of high dose IVIG. A one-at-a-time sensitivity analysis quantified the role of relevant cellular parameters on IgG elimination in various scenarios. RESULTS: The plasma AUC of mAbs was highly sensitive to endothelial cell parameters, but had near-nil sensitivity to monocyte and macrophage parameters, even in scenarios with 90% loss of FcRn expression/activity. In mice with normal FcRn expression, simulations suggest that less than 2% of an IV dose is eliminated in macrophages, while endothelial cells are predicted to dominate mAb elimination. CONCLUSIONS: The model suggests that the role of monocytes and macrophages in IgG homeostasis includes extensive uptake and highly efficient FcRn-mediated protection, but not appreciable degradation when FcRn is present. Therefore, it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children, even if FcRn expression/activity was 90% lower in children than in adults.

Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population.

Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential. SIGNIFICANCE STATEMENT: Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.

Pharmacokinetic implications of dosing emicizumab based on vial size: A simulation study.

INTRODUCTION: Emicizumab is dosed as mg/kg and, according to the label, any unused drug left in the vial(s) must be discarded, thereby wasting expensive resources. The aim of this study was to use population pharmacokinetics to illustrate the implications of changing the dosing interval to avoid wastage. METHODS: We used a previously published emicizumab PopPK model after extending its validation to children. We simulated PK parameters for labelled dosing regimens and for regimens using full vials with infusion frequency varied to keep the steady-state drug concentration unchanged. Cost and drug savings were calculated. RESULTS: The model evaluation was successful. When rounding up, the average individual below 53, 47 and 39 has a time-to-trough increase of up to 5.7, 7.9 and 5.8 days for the QW, Q2 W and Q4 W regimen, respectively. This resulted in an annual cost reduction of up to $173,136, $75,747 and $61,319 USD per patient. At higher body weights, rounding down the dose to the nearest vial resulted in negligible changes in the steady state concentration and cost savings of up to $93,781, $46,891 and $23,446 USD per patient, respectively. CONCLUSION: Individuals with a lower body weight may benefit from increasing dose intervals and rounding up dose up to the nearest vial, and individuals with a higher body weight from maintaining the injection frequency and rounding dose down to the nearest vial without significant change in emicizumab levels. Administering the entire vial may result in a reduction of vials used annually and potential cost savings.

Evaluation of models for predicting pediatric fraction unbound in plasma for human health risk assessment.

Pediatric physiologically based pharmacokinetic (PBPK) models facilitate the prediction of PK parameters in children under specific exposure conditions. Pharmacokinetic outcomes are highly sensitive to fraction unbound in plasma (fup) as incorporated into PBPK models. Rarely is fup in children (fupchild) experimentally derived and prediction is based upon fup in adults (fupadult) as well as a ratio of plasma protein concentrations between children and adults. The objectives were to (i) evaluate protein concentration vs. age profile derived from ontogeny models, (ii) assess predictive performances of fup ontogeny models, and (iii) determine overall uncertainty in fupchild prediction resulting from a combination of quantitative structure-property relationship (QSPR) model and ontogeny models. The plasma albumin and alpha-acid glycoprotein (AAG) concentration data for pediatrics and fupchild and fupadult data were obtained from literature. The protein concentration vs. age profile derived from ontogeny models were compared to observed levels. Fupchild values were calculated according to ontogeny models using both observed and QSPR-predicted fupadult as inputs and predictive performances of ontogeny models assessed by comparing predicted fupchild to observed values. Protein concentrations vs. age profiles derived from non-linear equations were more congruent with observed albumin levels than linear or step-wise models. When observed fupadult values were used as input, the fupchild data were under-predicted with average fold error (AFE) amounts ranging 0.79-0.81 and 0.77-0.97 for albumin and AAG ontogeny models, respectively. When QSPR-predicted fupadult values were used as input, AFE of fupchild ranged 1.2-1.35 and 0.98-1.2 for albumin and AAG models, respectively. The choice of ontogeny model with respect to prediction accuracy is more important for AAG, highly bound compounds and infants. For these compounds and scenarios, experimental determination of fupchild for inclusion into a pediatric PBPK model is necessary to have confidence in PBPK model outputs.

Clinical application of Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Patterns of blood sampling and patient characteristics among clinician users.

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 Björkman since early WAPPS-Hemo usage, a trend towards minimizing sampling was observed.

Quantifying breast milk intake by term and preterm infants for input into paediatric physiologically based pharmacokinetic models.

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.

Model qualification of the PK-Sim® pediatric module for pediatric exposure assessment of CYP450 metabolized compounds.

Pediatric physiologically based pharmacokinetic (PBPK) models facilitate the estimation of pharmacokinetic (PK) parameters in children under specific exposure conditions. In human health risk assessment, PBPK modeling has been used to determine a chemical-specific human kinetic adjustment factor (HKAF). Due to increased demands in regulatory assessment, model evaluation and qualification have gained growing attention. The aim of this study was to undertake model qualification of pediatric PBPK models for compounds that are primarily metabolized by cytochrome P450 (CYP) enzymes. The objectives were to determine the appropriateness of the virtual individual creating algorithm in PK-Sim® in predicting PK parameters and their variability in children and identify critical system-specific inputs. PBPK models in adults were constructed for several pharmaceuticals (grouped by major clearance process such as CYP3A4). Several age groups of virtual individuals were created to represent children in pediatric clinical studies. The mean and variance of clearance (CL) from virtual populations were compared to observed values. Sensitivity analysis on area under the curve (AUC) was performed. System-specific parameters of virtual children that contribute to inter-individual PK properties were assessed. Eighty-one percent of the comparisons between simulated and observed clearance values were within twofold error. The mean fold errors were 1.1, 1, 0.7 and 1.8 in adolescents, children, infants and neonates, respectively. CL variability was reasonably predicted for 70% of the comparisons with comparable coefficients of variation between observed and predicted. The sensitivity analysis revealed that fraction unbound in plasma, parameters related to CYP enzyme-mediated metabolism and liver volumewere most important in the estimation of pediatric exposure. A comparison of variabilities in weight, height and liver volume in virtual children showed reliable agreement with observed data. The presented results of predictive performance and properties of virtual populations provide confidence in the use of PK-Sim for pediatric PBPK modeling in toxicological applications including PBPK-based-HKAF derivation.

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization.

Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.

Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.

Population PBPK modelling of trastuzumab: a framework for quantifying and predicting inter-individual variability.

In this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses. The five key factors were the concentration of membrane-bound HER2 ([Formula: see text]), the convective flow rate of mAb through vascular pores ([Formula: see text]), the endocytic transport rate of mAb through vascular endothelium ([Formula: see text]), the degradation rate of mAb-HER2 complexes ([Formula: see text]) and the concentration of shed HER2 extracellular domain in circulation ([Formula: see text]). [Formula: see text] was the most important parameter governing trastuzumab distribution into tissues and primarily affected variability in the first 500 h post-administration. [Formula: see text] was the most significant contributor to variability in clearance. These findings were used together with population generation methods to accurately predict the observed variability in four experimental trials with trastuzumab. To explore anthropometric sources of variability, virtual populations were created to represent participants in the four experimental trials. Using populations with only their expected anthropometric diversity resulted in under-prediction of the observed inter-individual variability. Adapting the populations to include literature-based variability around the five key parameters enabled accurate predictions of the variability in the four trials. The successful application of this framework demonstrates the utility of popPBPK methods to understand the mechanistic underpinnings of pharmacokinetic variability.

Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children?

The small intestine represents the region where the majority of drug and nutrient absorption transpires. Among adults, small intestinal transit kinetics is well delineated; however, the applicability of these values toward children remains unclear. This article serves to examine the relationship between age and mean small intestinal transit time (SITT) based on the available literature. In addition, the influence of alterations in intestinal transit time was explored among children using a model-based approach. Primary literature sources depicting SITT from children to adults were ascertained via the PubMed database. Data were limited to subjects without pathologies that could influence intestinal motility. Random-effect meta-regression models with between-study variability were employed to assess the influence of age on SITT. Three separate models with age as a linear or higher-order (i.e., second- and third-order polynomial) regressor were implemented to assess for the potential of both linear and curvilinear relationships. Examination of the influence of altered intestinal transit kinetics on the absorption of a sustained release theophylline preparation was explored among children between 8 and 14 years using physiologically based pharmacokinetic (PBPK) modeling. Age was not found to be a significant modulator of small intestinal transit within either the linear or higher-order polynomial meta-regression models. PBPK simulations indicated a lack of influence of variations in SITT on the absorption of theophylline from the examined sustained release formulation in older children. Based on the current literature, there is no evidence to suggest that mean SITT differs between children and adults.

Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility.

PURPOSE: Compound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility. METHODS: Solubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37 °C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media. RESULTS: For six of the seven compounds investigated, solubility fell outside an 80-125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II). CONCLUSION: Developmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.

Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein.

The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00µM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01µM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63µM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23µM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500µM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).

A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide.

Predicting the pharmacokinetic (PK) time course of a subcutaneously (SC) administered novel therapeutic protein using in silico approaches offers an opportunity to streamline the drug development process by facilitating selection of starting and target doses in initial human trials. Herein, we propose a workflow for predicting the human exposure time course following SC administration. Leveraging knowledge obtained following both intravenous and SC administration in monkeys, this workflow employs the development of a whole body physiologically-based pharmacokinetic (PBPK) model incorporating vascular circulation, lymphatic uptake and both renal and non-specific clearance mechanisms to predict the PK of a novel pegylated peptide. Optimization of the model was initially performed in monkeys, after which the model was scaled up to human proportion. Inclusion of a SC depot compartment allowed for precise simulation of the SC time course in monkeys. Simulated human exposure after SC administration was within approximately 20 % of the observed values and successfully predicted the time course of two subsequent dosing levels. This workflow represents one of the first publications of a PBPK workflow to predict the time course of a SC administered therapeutic protein based off of a single, non-human primate species and shows promise in facilitating the dose selection in first-in-human dose escalation studies for novel protein therapeutics.

Development of a decision tree to classify the most accurate tissue-specific tissue to plasma partition coefficient algorithm for a given compound.

Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism and are used to predict a drug's pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), key PBPK model parameters, define the steady-state concentration differential between tissue and plasma and are used to predict the volume of distribution. The experimental determination of these parameters once limited the development of PBPK models; however, in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy, and none are considered standard, warranting further research. In this study, a novel decision-tree-based Kp prediction method was developed using six previously published algorithms. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physicochemical space. Three versions of tissue-specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy than that of any single Kp prediction algorithm for all tissues, the current mode of use in PBPK model building. Because built-in estimation equations for those input parameters are not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The presented innovative method will improve tissue distribution prediction accuracy, thus enhancing the confidence in PBPK modeling outputs.

Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.