2021

Laplace approximation and its various approximations are some of the most commonly used techniques in pharmaceutical nonlinear mixed effects modelling to marginalise the the random effects. Classically, only Gaussian random effects have been used with transformations applied after the fact. In this work, the Laplace approximation framework is mathematically analysed showing the theoretical soundness of […]

Introduction Bosentan is an endothelin receptor antagonist used to treat patients with pulmonary arterial hypertension and is known to cause cholestatic liver toxicity. Bosentan is an inhibitor of the bile salt export pump (BSEP), the major efflux transporter for bile salts, but other mechanisms may also be involved. However, often high bosentan concentrations are used […]

Introduction Sildenafil is a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect on vascular smooth muscle cells [1]. Prenatal therapy with sildenafil has been studied for multiple indications in different animal models [2–4]. In pregnant sheep however, transplacental transfer of sildenafil is extremely low, which complicates the study of its effect on the fetus. […]

Introduction: Valproic acid (VPA) is a narrow therapeutic index drug widely prescribed for the treatment of epilepsy, psychiatric disorders, and migraine. First available as an enteric-coated immediate release formulation (IR), its fast absorption profile and short half-life motivated the development of extended-release formulations (ER) to reduce both daily administrations and pharmacokinetic peak-to-trough fluctuation (PTF). A […]

Introduction The coagulation network model is used to describe the relationship between an anticoagulant, or pro-coagulant, and a clotting test outcome [1]. The system consists of an in-vivo (62 ODEs and 184 parameters) and in-vitro (62 ODEs and 182 parameters) modules. These two modules are linked by a discontinuous interface with the whole function not being […]

Background: Optimization of drug specific parameters in complex models, such as whole body physiologically-based pharmacokinetic (WBPBPK) models, by model fitting to observed data is challenging. This process is time-consuming and models are often unidentifiable/over-parameterized due to the large number of parameters and availability of data which are mostly limited to observations from plasma [1]. The […]

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability %) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) […]

Viral kinetics models have been successfully developed for infection diseases such as influenza A. The aim of this work is to adopt the rationale for the viral kinetics of SARS-CoV-2, while incorporating pharmacodynamic effects of Remdesivir, the only FDA-approved drug for Covid-19 at this stage. The model consists of a system of differential equations where […]

Background This study implements a PBPK modelling approach to investigate inter-ethnic differences in imatinib dosing regimens. Methods A PBPK model of imatinib was built in the Simcyp Simulator (v.17) integrating in vitro metabolism and clinical pharmacokinetic data and accounting for ethnic differences in body size and expression of CYP enzymes and proteins involved in imatinib […]

Introduction Quantitative systems pharmacology (QSP) models describe the clinical pharmacological properties of a drug.  They are typically described as systems of linear mass-balance and nonlinear mass-action of drugs.  One of the purposes of QSP models is to simulate potential outcomes from virtual clinical trials. This approach is predicated on generating virtual populations of patients (a […]