Internal Deterministic Identifiability of PK and PKPD Models

Introduction: Identifiability analysis is an important aspect of the PKPD modelling framework and is divided into structural and deterministic identifiability. Structural identifiability (SI) relates to the uniqueness of outputs to parameters and inputs. Deterministic identifiability (DI) relates to the precision of parameter estimates. Here we introduce two subcategories of DI: (1) external deterministic identifiability (EDI) […]

Solutions for nonlinear ordinary differential equations in pharmacokinetic-pharmacodynamic systems

Background: Pharmacokinetic-Pharmacodynamic systems are often expressed with nonlinear ordinary differential equations (ODEs). While there are numerous methods to solve such ODEs these methods generally rely on time-stepping solutions (e.g. Runge–Kutta) which need to be matched to the characteristics of the problem at hand.  Aims: To explore l  the performance of an inductive approximation which iteratively converts […]

Population pharmacokinetic and pharmacodynamic properties of OZ439 in healthy volunteers and patients with falciparum and vivax malaria

Background: Increased deployment of artemisinin-based combination therapies (ACTs) has been an important contributor to the recent reductions in malaria, but control and elimination goals are now threatened by the emergence of artemisinin resistance in the Greater Mekong sub-region [1]. New drugs with efficacy and safety profiles which are comparable to the ACTs are needed. OZ439 […]

NextDose – A web based dosing tool – Development version 2017

Background: NextDose is a web based Bayesian dosing tool (1, 2). Dosing guidance is currently offered for intravenous busulfan, intravenous methotrexate and oral tacrolimus. It has been used at Auckland Starship Hospital and Auckland City Hospital to guide dosing of busulfan since 2012 (3). Objectives: 1. To describe the features of a new release of […]

Systems Pharmacology – Learning from GAVamycin

Background: “Systems pharmacology is the application of systems biology principles to the field of pharmacology.”(1). The pharmacokinetics of gentamicin (G), amikacin (A) and vancomycin (V) have been widely described including models with common features for each drug (2, 3) and a proposal to predict glomerular filtration rate (GFR) from drug clearance (CL). A reverse systems […]

Performance of estimation methods in modelling the kinetics of respiratory virus infection

Background: Viral kinetic (VK) models are progressively being used to support the dose justification of drugs used to treat influenza and Respiratory Syncytial Virus infection 1-2. However, study design considerations and data limitations often present challenges when developing models that describe the VK following placebo and drug treatment. We explore the performance of estimation methods […]

Identifiability analysis of empirical models used for quantifying “biased” ligands

Background: Model identifiability is an important attribute that a model must satisfy in order to derive the meaningful interpretation of estimated parameters.  In general, there are two types of identifiability: structural and deterministic.  Structural identifiability is rooted in the underlying mathematical structure of model.  Deterministic identifiability is concerned with the study design and its execution. […]

Population in vitro-in vivo correlation model linking gastrointestinal transit time, pH with the in vivo disposition kinetics of itraconazole

Background Sporanox and SUBA-itraconazole are oral capsule formulations of itraconazole with characteristically different pH-dissolution profiles. Oral administration of itraconazole is associated with marked inter-subject and intra‑subject pharmacokinetic variability due, in part, to variability in the drug’s absorption from the GI tract [1]. Objectives The objectives of this work were to : (1) Establish an in vitro-in […]

Assessing the predictive performance of an interactive application to dose adjust voriconazole

Aims Voriconazole is a broad spectrum triazole antifungal used as first line therapy for invasive infections. Pharmacokinetic (PK) studies have indicated large between subject variability between dose and exposure, which has prompted the use of therapeutic drug monitoring (TDM) to optimise dosing [1].  Voriconazole also exhibits large within subject variability, potentially limiting the utility of […]

Development of an Interactive Tool to Explore Doses & Sample for Paediatric Trials

Aims: The aim of this work was to develop an interactive tool that allows users to (1) explore paediatric dose levels that provide a similar exposure as predicted for an adult reference population, and (2) calculate the sample size required for a pharmacokinetic (PK) study in paediatrics based on FDA guidance [1,2]. Methods: A virtual […]