Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS‐Hemo project

Abstract

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. K E Y W O R D Sfactor IX, factor VIII, population pharmacokinetics | 385 HAJDUCEK Et Al.

A comparison of MyPKFiT and WAPPS‐Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa

“…The corresponding WAPPS‐Hemo model is based on 79 patients with fat‐free mass and age as covariates for the one‐stage assay 15 . For the chromogenic assay, WAPPS‐Hemo uses a brand‐specific model derived from 91 patients with fat‐free mass and age as covariates 16 . For the PK assessments, baseline FVIII activity, year and quarter of birth (age), body weight (BW) and height, timing of the last two administered doses of Octocog alfa, as well as the infused dose in IU, were collected.…”

Personalised Prophylaxis in a Child with Haemophilia A and Type 1 Diabetes

“…The personalisation of treatment has the potential to address each individual patient's needs and preferences, which is likely to increase treatment satisfaction. For patients treated with the rFVIII described in the case study, two options exist to personalise treatment, either based on individual pharmacokinetic (PK) parameters [6] or on a population PK model [19]. Together with the low infusion volume, excellent efficacy in the prevention of bleeding [6] and a demonstrated low immunogenicity, [20] this makes this rFVIII an attractive option to satisfy the diverse demands HA patients may have.…”

Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia

“…Only a minority of the established population PK models has been applied successfully to perform individualized dosing of factor concentrates [79]. Although the established population PK models are validated internally using the same data set used to construct the model, only a limited number of external validations have been conducted comprising an independent data set [80]. As the latter is considered to be the most stringent approach for model evaluation, such studies must first be conducted before the population models can be applied standardly into clinical practice.…”