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 […]
Tag Archives | 2021
PBPK Modeling of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Binding, pH-dependent Solubility and Nonsink Permeation
January 23, 2021
Authors Michael J Dolton1, Po-Chang Chiang2, Fang Ma3, Jin Y Jin4, Yuan Chen3
Affiliations 1 Roche Products Australia, Level 8/30-34 Hickson Road, Millers Point NSW 2000 Australia. 2 Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 USA. 3 Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 USA. 4 Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 USA.
Presentation type Oral
Presenters Michael Dolton
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
January 20, 2021
Authors Ranita Kirubakaran (1,2), David W. Uster (3), Stefanie Hennig (4,5), Jane E. Carland (1,2,6), Richard O. Day (1,2), Sebastian G. Wicha (3), Sophie L. Stocker (1,2,7).
Affiliations 1. St Vincent's Clinical School, The University of New South Wales, Sydney, Australia. 2. Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital Sydney, Australia. 3. Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany. 4. Certara, Inc., Princeton, New Jersey, USA. 5. School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia. 6. Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, Australia. 7. School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Australia.
Presentation type Oral
Presenters Ranita Kirubakaran
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
January 20, 2021
Authors Conor O'Hanlon (1), Nick Holford (1), Jacqueline Hannam (1), Mark Greaves (2), Brian Anderson (2)
Affiliations 1. Department of Pharmacology and Clinical Pharmacology, University of Auckland, 2. Department of Anaesthesia, Auckland City Hospital
Presentation type Poster
Presenters Conor O'Hanlon
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
January 18, 2021
Authors Hannah Yejin Kim (1,2), Anne-Grete Märtson (3), Erwin Dreesen (4), Isabel Spriet (4,5), Sebastian G Wicha (6), Andrew J McLachlan (1), Jan-Willem Alffenaar (1,2)
Affiliations 1. The University of Sydney, 2. Westmead Hospital, 3. University of Groningen, 4. KU Leuven, 5.University Hospitals Leuven, 6. University of Hamburg
Presentation type Oral
Presenters Hannah Yejin Kim
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
January 18, 2021
Authors Liang Yang (1), Xiao Zhu (1), Hayley Green(2), David B. Finlay (2), Michelle Glass (2), Stephen B. Duffull (1)
Affiliations (1) Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand (2) Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
Presentation type Poster
Presenters Liang Yang
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
January 10, 2021
Authors Pieter Van Brantegem (1), Neel Deferm (1), Marlies Oorts (1), Axelle Cooreman (2), Mathieu Vinken (2), Erwin Dreesen (3, 4), Pieter Annaert (1)
Affiliations (1) Drug Delivery and Disposition, KU Leuven, Belgium, (2) In Vitro Toxicology and Dermato-Cosmetology, VUB, Belgium, (3) Clinical Pharmacology and Pharmacotherapy, KU Leuven, Belgium, (4) Uppsala Pharmacometrics Research Group, Uppsala University, Sweden
Presentation type Oral
Presenters Pieter Van Brantegem
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
January 10, 2021
Authors Alejandra Schiavo (1), Pietro Fagiolino (1), Marta Vázquez (1), Iñaki F. Trocóniz (2,3), Manuel Ibarra (1)
Affiliations (1) Department of Pharmaceutical Sciences. Faculty of Chemistry. Universidad de la República. Montevideo, Uruguay. (2) Pharmacometrics and Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra. Pamplona, Spain. (3) IdiSNA; Navarra Institute for Health Research, Pamplona, Spain.
Presentation type Poster
Presenters Alejandra Schiavo, Manuel Ibarra
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
January 10, 2021
Authors Pieter Van Brantegem (1), Felix De Bie (2, 3), Francesca M. Russo (2), Erwin Dreesen (4, 5), Marcus G. Davey (3), Jan Deprest (2), Alan W. Flake (3), Pieter Annaert (1)
Affiliations (1) Drug Delivery and Disposition, KU Leuven, Belgium, (2) Department of Development and Regeneration, KU Leuven, Belgium, (3) Center for Fetal Research, Children's Hospital of Philadelphia, USA, (4) Clinical Pharmacology and Pharmacotherapy, KU Leuven, Belgium, (5) Uppsala Pharmacometrics Research Group, Uppsala University, Sweden
Presentation type Poster
Presenters Pieter Van Brantegem
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
January 10, 2021
Authors Akosua A. Agyeman (1), Rajbharan Yadav (1), Kate E. Rogers (1), Vanessa E. Rees (1), Yuling Huang (1), Anton Y. Peleg (2), John D. Boyce (1), Antonio Oliver (3), Phillip J. Bergen (1), Beom Soo Shin (4), Roger L. Nation (1), Cornelia B. Landersdorfer (1)
Affiliations 1. Pharmacy and Pharmaceutical Sciences and 2. Microbiology Monash University, Melbourne, Australia, 3. Hospital Universitario Son Espases, Palma de Mallorca, Spain; 4. School of Pharmacy, Sungkyunkwan University, Korea.
Presentation type Poster
Presenters Akosua A Agyeman
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 […]