ISoP Lecture 2013: “Broadening the Impact” – Identifying Some Novel Clinical Applications of Pharmacometrics Research

The background, approach and challenges to conducting pharmacometrics research in four novel therapeutic scenarios are described all of which are currently being investigated by the presenter’s research team: “Therapeutic Hypothermia and Anticonvulsant Pharmacokinetics in Newborn Infants with Hypoxic Ischemic Encephalopathy HIE)”, “Melatonin Pharmacokinetics in Tetraplegia”, “Modeling Fetal Drug Exposure”, “A Thymine-Based PK Screening Test for […]

Semi-mechanistic PKPD model of thrombocytopenia characterizing the effect of a new histone deacetylase inhibitor (HDACi) in development, in co-administration with doxorubicin.

Objective: Recent studies [1, 2] demonstrated that the combination of an HDAC inhibitor and DNA-damaging agents has synergistic effects to induce apoptosis. This observation is of potential clinical applicability although several dose-limiting toxicities need to be pre-assessed before dose optimization. The study aim was to develop a PKPD model of thrombocytopenia that considered the PK […]

Application of Item Response Theory to ADAS-cog Scores Modelling in Alzheimer’s Disease

Background: The challenges in the development of new therapeutic agents for Alzheimer’s Disease (AD) become apparent through the high number of failed late phase trials. Despite an increasing interest in biomarkers, cognition remains the primary regulatory accepted clinical outcome. The most frequently used test, ADAS-cog, consists of a broad spectrum of tasks that test different […]

Weight-HbA1c-Insulin-Glucose (WHIG) Model for long term disease progression of Type 2 Diabetes

Background: A previously developed semi-mechanistic model [1] linked fasting serum insulin (FSI), fasting plasma glucose (FPG), and glycosylated haemoglobin (HbA1c) to characterise the disease progression of newly diagnosed type 2 diabetic (T2DM) patients. To build upon the model, weight change (DWT) as an effector to the FSI-FPG-HbA1c relationship was implemented in the present study. Methods: […]

Modelling analgesia-concentration relationships for morphine in an experimental pain setting

Aims: To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model describing the concentration-effect relationships for morphine on experimental pain caused by skin heat and muscle pressure. Methods: Data were analysed from a study of 39 healthy volunteers who received 30 mg oral morphine, or placebo. Blood samples were collected up to 150 min post-dose, while experimental skin […]

Pharmacokinetics of Phenobarbitone in Neonates – A Population Model Based on Routine Therapeutic Drug Monitoring Data

Background: Phenobarbitone is a commonly used first-line agent for treatment of neonatal seizures of varying causes. A significant proportion of neonatal seizures are due to Hypoxic-Ischaemic Encephalopathy (HIE). Babies with HIE who are treated with 72 hours of therapeutic hypothermia have an improved chance of survival without major disability. However, there is limited information regarding […]

Can literature models describe the neutropenic time course produced by hyper-CVAD chemotherapy in non-Hodgkin lymphoma?

Background: Cytotoxic anticancer drugs methotrexate and cytarabine are incorporated into various high-dose multi-agent chemotherapy regimens (e.g. hyper-CVAD) for aggressive non-Hodgkin lymphoma (NHL). Methotrexate and cytarabine have narrow therapeutic windows and display large inter-patient variability on pharmacokinetic (PK) parameters thus creating difficulty in standardising doses within a population. Studies have shown that neutropenic events after chemotherapy […]

Exposure-Response Relationship to Assess the Risk of Neutropenia in Patients With Hepatocellular Carcinoma Treated with Tivantinib

Background: Tivantinib is a selective MET inhibitor that is extensively metabolized in the liver. In a randomized, placebo-controlled phase 2 study in patients with advanced HCC, tivantinib monotherapy improved time to progression by 56%. However, in that study at the standard phase 2 dose of 360 mg twice-daily (BID), tivantinib exposure was increased, and the […]

Voriconazole Population Pharmacokinetics

Background: Voriconazole is widely used in the treatment of life-threatening invasive fungal infections (IFIs). The use of voriconazole is problematic due to its highly variable pharmacokinetics and narrow therapeutic index which complicate dosage selection and adjustment; few population pharmacokinetic data are available. Aim: This study aimed to develop a voriconazole population model incorporating data from […]

Application of Population Modelling to Improve the Estimation of Drug Withdrawal Times in Racehorses

Background: The rules of racing state that an animal may not be treated on the day of a race and must be presented at the racetrack as “drug-free”. Drug treatment needs to be stopped prior to ensure compliance with these rules. Many factors influence the drug withdrawal time including, but not limited to, the pharmacokinetics […]