New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics.

AIMS: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. METHODS: Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. RESULTS: The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. CONCLUSIONS: The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.

Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis.

The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis.