Pharmacokinetics, pharmacodynamics and pharmacogenomics of busulphan and other agents used in blood or marrow transplantation

By examining the pharmacokinetics (PK, dose versus concentration relationship), pharmacodynamics (PD, concentration versus effect relationship) and pharmacogenomics (genetic influences on PK and PD) of drugs used in blood or marrow transplantation, it may be possible to individualise the dose to enhance therapeutic efficacy, reduce toxicity and maximise the chance of disease control. The aims of this project are to: 1. Examine the pharmacokinetics of busulphan and other drugs used in BMT conditioning and to identify sources of variability in the pharmacokinetic parameters 2. To examine whether there is an association between exposure to busulphan and other drugs and toxicity and/or outcome following BMT (pharmacodynamics) 3. To examine the influence of genetic factors on the pharmacokinetics of busulphan and other drugs and outcome following BMT. Outcome endpoints include frequency of servious (Grade 3 +) toxicity, as well as survival endpoints. 4. To investigate whether patients who get veno-occlusive disease of the liver (VOD) following busulphan-based conditioning use different metabolic pathways than those who do not. The target population are patients scheduled to receive busulphan or other agents prior to autologous or allogeneic bone marrow transplantation. The required blood and urine sampling will depend on the level of participation of the institution. Each institution can participate in any or all of four levels and this will be determined by the Principal Investigator, who will make this decision at their own discretion based on factors including (1) the characteristics of the local patient population and the common toxicities seen at the site and (2) the availability of resources for trial participation Additionally, participants are also able to accept or decline certain levels of participation. on the consent form. Level 1 involves the collection of clinical data in patients having busulphan concentrations measured for routine pharmacokinetic assessment. Level 2 involves the collection of additional bloods to analyse the pharmacokinetics of BMT drugs other than busulphan. The actual drugs being studied will depend on the protocols being used. Random urine samples will also be collected before and on the last day of busulphan dosing to investigate differences in busulphan metabolism. Level 3 involves the collection of a single EDTA blood sample prior to BMT conditioning for pharmacogenomics tests. Level 4 involves the weekly collection of blood for metabolomics studies to investigate the pathogenesis of VOD. These bloods can be retrieved from Pathology following routine Biochemical tests. Drug concentrations will be measured using the chromatographic equipment in the Department of Biochemistry at The Children’s Hospital at Westmead. Pharmacokinetic software (including Kinetica4.0 and NONMEM7.3) will be used to calculate the pharmacokinetic parameters for each patient, and to identify sources of pharmacokinetic variability (e.g .body size, patient age, diagnosis, concomitant medication, prior medication, renal function and pharmacogenomics traits). Statistical tests including logistic regression and multivariate cox proportional hazards regression will be used to identify whether drug exposure and other factors are significant contributors to toxicity and outcome after BMT. Patient outcome will be followed up to 5 years post transplant. This information is important for developing optimal dosing strategies for BMT drugs and has the potential to reduce toxicity and improve outcomes following BMT.