ANZDATA: Pharmacology based time to event analysis for death and renal transplant failure

Posted on by Nick Holford

Background: The ANZDATA registry (http://www.anzdata.org.au/v1) has collected data on all patients receiving a renal transplant in Australia or New Zealand since 1977 

Objective: To describe the effect of immunosuppressant medicines on time to death and time to renal transplant failure

Methods: Demographic data and the daily dose of medicines used as immunosuppressants were extracted from the ANZDATA database. Renal function (RF) was calculated from creatinine clearance and weight and age predicted glomerular filtration rate (1-2). The time to death and time to each transplant failure was noted along with times of censored events. Average steady state concentrations (Css) of cyclosporine, mycophenolic acid, tacrolimus and prednisolone were calculated from the daily dose and allometrically scaled clearance. The hazard of each event was modelled as a function of demographic covariates and the time course of treatment (yes/no) or Css (3). Parameters were estimated using NONMEM 7.4.1.

Results: Race was a predictor of both increased (e.g. Australian aborigine, Maori) and decreased (e.g. Filipino, Vietnamese) hazard of death relative to Caucasians. Increase in RF had a stronger effect on reducing the hazard of transplant failure than death. Css concentration was a better predictor of reduction in hazard than treatment alone. Higher concentrations were required to reduce the hazard of transplant failure by 50% than the hazard of death.

Conclusion: A pharmacological approach to describing the hazard of death and transplant failure provides insights for target concentration based dose individualization.

References:

  1. Matthews I, Kirkpatrick C, Holford N. Quantitative justification for target concentration intervention–parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. Br J Clin Pharmacol. 2004;58(1):8-19.
  2. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67-76.
  3. Holford N. A Time to Event Tutorial for Pharmacometricians. CPT: pharmacomet syst pharmacol. 2013;2:e43 doi:10.1038/psp.2013.18.
2018