Dr. Deirdre D'Arcy

Summary

Teicoplanin is a glycopeptide antibiotic that has bactericidal activity against aerobic and anaerobic Gram-positive bacteria including multi-resistant staphylococci. Along with vancomycin, it has become one of the treatments of choice for Gram-positive sepsis, including infections caused by meticillin-resistant Staphylococcus aureus. Teicoplanin has a structure and spectrum of activity similar to that of vancomycin but its pharmacokinetic properties are quite distinct. For these reasons, teicoplanin is often the preferred choice over vancomycin for the treatment of Gram-positive infection in patients with haematological malignancy. Despite this, specific dosage guidelines and an appropriate target trough level for this patient group have not been determined. Higher doses have been suggested for patients with haematological malignancy, but increasing the dose not only increases the risk of adverse effects but also reduces the cost-effectiveness when compared to vancomycin. Therefore, most patients with haematological malignancy continue to receive standard doses of teicoplanin and therapeutic drug monitoring is not widely practised. As patients with haematological malignancy are at high risk for developing severe Gram-positive infections, underdosing of teicoplanin is of great concern. The aims of this project are to determine current teicoplanin prescribing practices, to investigate whether certain clinical or patient factors contribute to efficacy or toxicity of teicoplanin or to trough levels attained, and to conduct a prospective trial to determine pharmacokinetic characteristics of teicoplanin in patients with haematological malignancy. Phase 1, a survey of teicoplanin practice in all Irish/UK haematology services, was completed in June 2013. Findings revealed that the majority of hospitals rely on the manufacturer's standard dosage regimen rather than therapeutic drug monitoring as an indicator for therapeutic dosing and that local practices lack a clear evidence base. Data gathering for Phase 2, a retrospective study of teicoplanin dosage and clinical outcomes in teicoplanin-treated patients with haematological malignancy at Tallaght Hospital, was completed in November 2013. Results suggested a positive relationship between teicoplanin concentration and treatment outcome. Findings also suggested a risk of underexposure if conventional doses of teicoplanin are used in patients with haematological malignancy. A model was developed for dosage optimisation of teicoplanin in patients with haematological malignancy. Nephrotoxicity analysis suggested that teicoplanin is well tolerated at the renal level. Phase 3, a clinical trial to determine the pharmacokinetics and pharmacodynamics of teicoplanin in patients with haematological malignancy, was commenced in subjects in March 2014.

Funding Agency

Meath Foundation (In collaboration with Tallaght hospital Haematology and PHarmacy departments).

Programme

PhD

Project Type

PhD

Summary

This project involves the development of software code which allows generation of a simulated profile of particles dissolving over time. It includes simulation of dissolution under a range of pharmaceutical industry-standard test conditions. Dissolution testing is a routine testing process in the pharmaceutical industry. Both instrumentation and operational characteristics of the dissolution test are rigidly defined. It is a recognised problem that dissolution results can fall out of specification,suggesting that a drug is being released too slowly or too quickly. These out of specification results could be due to (unintentional) changes in many stages of the manufacturing process, or could be as a result of a change in the operation or specifications of the dissolution testing apparatus itself. Existing solutions concern either running experimental tests, or use of certain dissolution theory and models, which do not always take the detailed operational characteristics of the test procedure into account. This technology allows insight into effects of the testing conditions on the dissolution rate, without having to run real-time dissolution tests to check each effect.

Project Type

MSc plus continuing PI research

Summary

Amphotericin B lipid complex (ABLC) has been used extensively to treat proven or suspected severe fungal infections. In this project, the effect of continuous renal replacement therapy - continuous veno-venous haemodiafiltration (CVVHDF) on the pharamcokinetics of ABLC in critically ill patients was examined. Sixteen patients (21 profiles) were recruited to the study; 9 profiles undergoing CVVHDF and 12 profiles not undergoing CVVHDF, during their ABLC treatment. Non compartmental analysis was performed to calculate the following PK parameters of AMB: clearance (Cl), volume of distribution at steady state (Vss) and half life (t1/2). In the current study, wide variability was observed in both intra- and inter-patient PK of AMB, after the administration of ABLC. Multiexponential kinetics of AMB, after the administration of ABLC, were also observed. The median values of Cl, Vss and t1/2 calculated within a sampling interval of AMB were determined to be 27 L/h and 44 L/h, 1500 L and 2000 L, 34 hours and 33 hours for patients undergoing CVVHDF and not undergoing CVVHDF respectively. No statistical difference was found between PK parameters of AMB in patients undergoing and not undergoing CVVHDF. Also, the maximum amount cleared by CVVHDF was less than 1% of ABLC dose. Statistically significant relationships were observed between Vss and albumin and C reactive protein (CRP), where a decrease in albumin and an increase in CRP levels were related to an increase in Vss. In addition, a trend effect was demonstrated where an increase in the daily dose of noradrenaline administered was related to an increase in plasma AMB concentrations.

Funding Agency

In collaboration with the ICU, Tallaght hospital (part funded by Cephalon Ireland Ltd).

Programme

PhD

Summary

The dissolution rates of model compounds of low- to intermediate-solubility were examined under conditions of no forced convection (natural convection) and at low flow rates in the USP 4 dissolution apparatus (Flow-through apparatus). The hydrodynamics of the flow-through apparatus were simulated using the CFD software, Fluent. The effect of low, time-dependent fluid velocities on dissolution was being examined, in particular with relevance to the estimated magnitude of fluid velocities in the GI tract. The effect of natural convection was found to have a signfiicant impact on dissolution rate under low velocity conditions.

Funding Agency

IRCSET

Programme

Post-graduate scholarship