Kidney transplantation is the best treatment for children with end-stage kidney disease. However, the typical transplanted kidney fails substantially short of recipient life expectancy, due largely to chronic rejection. At the same time, the immunosuppressant drugs needed to prevent rejection sometimes cause morbidity and even mortality, from infection, cardiovascular disease and malignancy. Achieving the optimal balance between rejection risk and immunosuppressant toxicity is a critical challenge. Patients vary in how they respond to immunosuppressant drugs, so it’s very hard to get it right every time.
This Grand Round will discuss advances in ‘precision dosing’ of drugs, with the example used of transplant immunosuppression. This will include explanation of why dose optimisation of anti-rejection drug mycophenolate is – wrongly – considered unnecessary, and why greater precision in dosing of the anti-rejection drug tacrolimus can improve long-term outcomes for patients. Finally, the use of ’model-informed precision dosing’ will be discussed – this involves using data from previous patients to rapidly achieve precise target concentrations in new patients. This technique has the potential to optimize effectiveness and minimize toxicities for immunosuppressants, antimicrobials, and chemotherapeutic agents.
Dr David Metz is a Paediatric Nephrologist and Clinical Pharmacologist at the Royal Children’s Hospital, Melbourne. His PhD focuses on various aspects of immunosuppressant ‘precision’, including peri-transplant dose optimisation, time to event analysis of registry data and population PK modelling of mycophenolic acid to optimise graft and patient outcomes. His research has been recognised with prizes, international and national invited talks, and he has recently authored a major review accepted for publication in the journal Transplantation.