Sean Oosterholt (1), Jacek Rubik (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom, (2) Children’s Memorial Health Institute, Warsaw, Poland
Objectives: Epidemiological data suggests that the global burden of patients with renal failure who receive renal replacement therapy is more than 1.4 million and that this number is growing by 8% a year. Once transplanted kidney survival is roughly estimated as 95% for the first year, 85-90% for 5 years and about 75% survive 10 years. Many factors influence the clinical outcome of kidney graft, such as, whether the kidney is from a living donor, match in terms of blood group and tissue type, graft quality, surgical complications, kidney disease and overall health of the patient receiving the transplant. Most importantly is an adequate immunosuppressive treatment directly following transplantation. Adequate Immunosuppression in a patient depends on various factors, including the choice of immunosuppressant and the dose regimen. This is a problematic area for paediatric patients where information is limited compared to adults and dosing is often empirically based on body weight. This in turn can lead to complications such as overexposure. The aim of the project was to investigate the impact of current dosing and dose adjustment strategies for paediatric patients undergoing kidney transplantation, taking into account the therapeutic target levels and key covariate factors such as age, weight, co-medication, kidney function and donor status.
Methods: Clinical data from 46 paediatric kidney transplant patients (age range: 2-18 years old) were used to retrospectively characterize the pharmacokinetics and investigate the relationship between dose and systemic exposure to tacrolimus. Due to most patients only having trough samples (C0), individual pharmacokinetic parameters were described using prior information from a previously published PK model [1] with $PRIOR in NONMEM. Tacrolimus dose optimization was then evaluated through 1) clinical trials simulations including different dose adjustment scenarios and 2) comparison of a model-based dosing algorithm with dose adjustment based on therapeutic drug monitoring.
Results: The paediatric data were fitted by a two-compartment model with first order absorption and elimination, with IIV on Ka, V1, CL and Q. Due to the sampling scheme of only trough concentrations none of the parameter estimates changed more than 5% relative to the prior values. Of the investigated covariate effects prednisolone had a positive statistically and clinically significant effect on clearance (Emax model with an ED50 of 35 mg and a maximum increase of clearance of 249%). Additionally, the patients who were prescribed omeprazole had an average decrease in clearance of 10%. Age, haematocrit, donor status and GFR were found to have no significant effect on any of the PK parameters. Dose optimization based on weight bins increased the proportion of patients within the target range (trough concentration between 5-10 ng/ml) after the first dose more than 75% compared to the 0.1 mg/kg recommended dose: <10kg (0.4 mg/kg), 11-20kg (0.2 mg/kg), 21-30kg (0.15 mg/kg), 31-50kg (0.1 mg/kg), 51-60kg (0.08 mg/kg), 61-70kg (0.07 mg/kg), >70kg (0.06 mg/kg). Combining a model-based algorithm with the standard therapeutic drug monitoring allowed for further increase of the number of patients with drug exposure within the target therapeutic range (>99% of the patients).
Conclusion: The use of priors allowed for the characterization of PK parameters and covariate effects in sparsely sampled paediatric data. Subsequent simulations showed possible points of improvement in current practice, such as weight-banded dosing regimen, which greatly increase the probability of achieving a target therapeutic range. Moreover, unlike current practice, our analysis shows that one does not need to wait for steady state levels to confirm individual exposure if TDM is applied in combination with the proposed model-based dosing algorithm.
References:
[1] W. Zhao et. al, Population Pharmacokinetics and Pharmacogenetics of Tacrolimus in De Novo Pediatric Kidney Transplant Recipients, Clinical pharmacology & Therapeutics, 2009, 609-618
Reference: PAGE 27 (2018) Abstr 8756 [www.page-meeting.org/?abstract=8756]
Poster: Drug/Disease Modelling - Paediatrics