ABSTRACT
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.
Subject(s)
Hemophilia A , Humans , Hemophilia A/drug therapy , Adult , Adolescent , Young Adult , Middle Aged , Child , Aged , Child, Preschool , Male , Infant , Aged, 80 and over , Age Factors , Female , Factor VIII/therapeutic use , Factor VIII/pharmacokineticsABSTRACT
INTRODUCTION: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring. AIM: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients. METHODS: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim. RESULTS: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment. CONCLUSION: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care.
Subject(s)
Plasminogen , Humans , Plasminogen/deficiency , Plasminogen/therapeutic useABSTRACT
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.
Subject(s)
Hemophilia A , Quality of Life , Humans , Hemophilia A/complications , Retrospective Studies , Adult , Male , Middle Aged , Cross-Sectional Studies , Young Adult , Female , Canada , Adolescent , Aged , Cohort StudiesABSTRACT
BACKGROUND: The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. AIM: To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. METHODS: Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. RESULTS: Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. CONCLUSION: The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.
Subject(s)
Factor IX/pharmacokinetics , Factor IX/therapeutic use , Factor VIII/pharmacokinetics , Factor VIII/therapeutic use , Hemophilia A/genetics , Female , Humans , MaleABSTRACT
BACKGROUND: Recurrence of colorectal cancer (CRC) may arise due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to chemotherapy. Proteins responsible for this recurrence include the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12. METHODS: We evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays. RESULTS: 5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations. CONCLUSION: Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity.
Subject(s)
Chemokine CXCL12/biosynthesis , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Dipeptidyl Peptidase 4/biosynthesis , Receptors, CXCR4/biosynthesis , Animals , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carcinogenesis/drug effects , Cell Lineage , Cell Movement/drug effects , Chemokine CXCL12/genetics , Colonic Neoplasms/pathology , Dipeptidyl Peptidase 4/genetics , Fluorouracil/administration & dosage , Gene Expression Regulation, Neoplastic/drug effects , HT29 Cells , Humans , Hyaluronan Receptors/genetics , Irinotecan , Mice , Neoplasm Metastasis , Receptors, CXCR4/genetics , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Factor VIII , Hemophilia A , von Willebrand Factor , Humans , Factor VIII/pharmacokinetics , Factor VIII/administration & dosage , Hemophilia A/drug therapy , Hemophilia A/blood , von Willebrand Factor/pharmacokinetics , von Willebrand Factor/administration & dosage , Models, Biological , Adult , Male , Young Adult , Kinetics , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/administration & dosage , AdolescentABSTRACT
We consider survival or duration times associated with spells (sojourns in some state) or events experienced by individuals in a population over a specified time period. Duration distributions can be estimated from data recorded during followup of panel members in longitudinal surveys, but adjustments for the sample design, population structure and losses to followup are typically required. We provided weighted Kaplan-Meier estimates that allow for these features and, in particular, adjust for dependent loss to followup through the use of inverse probability of censoring weights.
Subject(s)
Kaplan-Meier Estimate , Cohort Studies , Employment/statistics & numerical data , Follow-Up Studies , Humans , Longitudinal Studies , Time FactorsABSTRACT
BACKGROUND AND OBJECTIVE: Knowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products. METHODS: Cannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups. A developed pediatric physiologically based pharmacokinetic model produced virtual breastfed infants administered the simulated CBD doses. Predicted breastfed infant exposures and upper area under the curve ratios were compared to the lowest therapeutic dose for approved indications in children. RESULTS: The existing human milk research biorepository contained 200 samples from 181 unique breastfeeding mothers for whom self-reported administration data and CBD concentrations had previously been measured. Samples that were above the lower limit of quantification with only one maternal administration type revealed that administration type, i.e., joint/blunt or edible versus oil or pipe, resulted in significantly different subgroups in terms of milk concentrations. Resulting simulated infant doses (ng/kg) were described by lognormal distributions with geometric means and geometric standard deviations: 0.61 ± 2.41 all concentrations, 0.10 ± 0.37 joint/blunt or edible, and 2.23 ± 8.15 oil or pipe. Doses administered to breastfed infants had exposures magnitudes lower than exposures in children aged 4-11 years administered the lowest therapeutic dose for approved indications, and low upper area under the curve ratios. CONCLUSIONS: Based on real-world use, breastfeeding infants are predicted to receive very small exposures of CBD through milk. Studies examining adverse reactions will provide further insight into potential risk.
Subject(s)
Cannabidiol , Marijuana Use , Female , Infant , Humans , Child , Breast Feeding/adverse effects , Milk, HumanABSTRACT
BACKGROUND AND OBJECTIVE: The renal excretion of drugs via organic anion transporters 1 and 3 (OAT1/3) is significantly decreased in patients with renal impairment. This study uses physiologically based pharmacokinetic models to quantify the reduction in OAT1/3-mediated secretion of drugs throughout varying stages of chronic kidney disease. METHODS: Physiologically based pharmacokinetic models were constructed for four OAT1/3 substrates in healthy individuals: acyclovir, meropenem, furosemide, and ciprofloxacin. Observed data from drug-drug interaction studies with probenecid, a potent OAT1/3 inhibitor, were used to parameterize the contribution of OAT1/3 to the renal elimination of each drug. The models were then translated to patients with chronic kidney disease by accounting for changes in glomerular filtration rate, kidney volume, renal blood flow, plasma protein binding, and hematocrit. Additionally, a relationship was derived between the estimated glomerular filtration rate and the reduction in OAT1/3-mediated secretion of drugs based on the renal extraction ratios of Æ¿-aminohippuric acid in patients with varying degrees of renal impairment. The relationship was evaluated in silico by evaluating the predictive performance of each final model in describing the pharmacokinetics (PK) of drugs across stages of chronic kidney disease. RESULTS: OAT1/3-mediated renal excretion of drugs was found to be decreased by 27-49%, 50-68%, and 70-96% in stage 3, stage 4, and stage 5 of chronic kidney disease, respectively. In support of the parameterization, physiologically based pharmacokinetic models of four OAT1/3 substrates were able to adequately characterize the PK in patients with different degrees of renal impairment. Total exposure after intravenous administration was predicted within a 1.5-fold error and 85% of the observed data points fell within a 1.5-fold prediction error. The models modestly under-predicted plasma concentrations in patients with end-stage renal disease undergoing intermittent hemodialysis. However, results should be interpreted with caution because of the limited number of molecules analyzed and the sparse sampling in observed chronic kidney disease pharmacokinetic studies. CONCLUSIONS: A quantitative understanding of the reduction in OAT1/3-mediated excretion of drugs in differing stages of renal impairment will contribute to better predictive accuracy for physiologically based pharmacokinetic models in drug development, assisting with clinical trial planning and potentially sparing this population from unnecessary toxic exposures.
Subject(s)
Organic Anion Transport Protein 1 , Renal Insufficiency, Chronic , Anions/metabolism , Anions/pharmacology , Humans , Kidney/metabolism , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Renal Elimination , Renal Insufficiency, Chronic/metabolismABSTRACT
BACKGROUND: Existing adult patient pharmacokinetic (PK) data from the published Advate vs Kovaltry PK crossover study were used for this validation study. This data set is appropriate for qualification, given that it has not been previously submitted to Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and will not have impacted the WAPPS-Hemo models for Kovaltry. OBJECTIVE: To compare the population PK parameters for Kovaltry (BAY 81-8973) derived from the WAPPS-Hemo models with PK parameters derived from noncompartmental analysis (NCA), using a validation PK dataset. METHODS: The qualification data set included Kovaltry factor activity (10 samples per infusion) and anthropometric data for 18 patients. Two analyses were performed comparison of Bayesian forecasting from the WAPPS-Hemo models versus NCA using the full 10-sample data set; and comparison of Bayesian forecasting using the full versus reduced 4- and 3-sample data sets. Agreement between outcomes was assessed by quantifying the variability and bias of the error. RESULTS: Comparison of WAPPS-Hemo models versus NCA led to well-correlated outcomes despite a systematic overprediction of clearance. Population PK models demonstrated greater consistency with NCA on one-stage data, compared with chromogenic data. WAPPS-Hemo model results were consistent in reduced sampling compared to full sampling. Inclusion of a 48-hour time point in the reduced sampling greatly improved the consistency with full sampling. DISCUSSION: Qualification of population PK models and their use for Bayesian forecasting in full and reduced sampling is an essential step toward their validation. The evaluations performed in this study support the confidence of PK parameter estimates provided by the models.