A model for procalcitonin concentrations following birth in non infected preterm neonates

Background: Procalcitonin (PCT) may be used to monitor infection and guide antibiotic therapy (1). However its usefulness in neonates is hampered due to changes following birth and events such as surgery. Methods: PCT concentrations measured in 282 non-infected pre-term and term neonates (22 and 41 weeks gestation) were provided for analysis (2). A turnover model was […]

PBPK Modeling of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Binding, pH-dependent Solubility and Nonsink Permeation

Introduction: Vismodegib displays unique pharmacokinetic characteristics including saturable plasma protein binding to alpha-1 acid glycoprotein (AAG) and apparent time-dependent bioavailability leading to non-linear PK with dose and time, significantly faster time to steady-state and lower than predicted accumulation. Objectives: Given these unique characteristics, a PBPK model was developed to explore mechanistic insights into saturable protein […]

Matters close to the heart: adaptation of tacrolimus models to inform therapeutic drug monitoring using the PRIOR approach

Introduction. External evaluation of published tacrolimus population pharmacokinetic models (n=17) highlighted that no available model accurately describes tacrolimus disposition in heart transplant (HTX) recipients, both with and without concomitant azole antifungal therapy.1 Concomitant azole antifungal therapy alters tacrolimus disposition substantially necessitating dose adjustments. The incorporation of azole antifungal use as a covariate may improve model-predicted […]

An ex vivo study measuring antibiotic adsorption to cardiopulmonary bypass circuitry

Background: Cephazolin and vancomycin are commonly used for antibiotic prophylaxis during surgery supported by cardiopulmonary bypass (CPB). Antibiotic pharmacokinetics (PK) can be altered by CPB through haemodilution, haemofiltration, hypothermia and drug adsorption to the circuitry (1). Adsorption can contribute to decreased antibiotic concentrations with consequent reduced prophylactic effectiveness (2). Highly protein bound drugs like cephazolin […]

Saliva for TDM of antifungal drugs: voriconazole model

Aims. Therapeutic drug monitoring (TDM) is recommended for many antifungal drugs. Saliva sampling is a non-invasive alternative to plasma sampling. However, no clinically validated saliva models available. This study firstly aims to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to […]

A mathematical model of CB1 receptor allosteric modulation

Introduction: The type 1 cannabinoid receptor (CB1) is among the most abundant G-protein coupled receptors in the central nervous system.  CB1 modulates neurotransmission, and plays a vital role in both physiology and pathology.  Allosteric ligands bind to a different site on the receptor to the endogenous (orthosteric) ligand and can have effects that are unique […]

A model-based evaluation of the effect of bosentan on bile salt disposition in sandwich-cultured human hepatocytes

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 […]

Prediction of multiple-dose relative bioavailability outcome for an extended release valproic acid formulation

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 […]

A population pharmacokinetic model of sildenafil in an extra-uterine system for premature lambs

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. […]

Mechanism-based modelling of meropenem plus tobramycin combination regimens against clinical hypermutable Pseudomonas aeruginosa in the hollow-fibre infection model

Introduction: Hypermutable Pseudomonas aeruginosa (HYPa)strains are frequently associated with chronic respiratory infections in patients with cystic fibrosis leading to increased morbidity and mortality. HYPa have increased mutation rates resulting in multidrug-resistance and treatment failure. Aims: To evaluate bacterial killing and resistance suppression of clinically relevant meropenem (MER) and tobramycin (TOB) dosage regimens against two clinical […]