Barraclough KA

Metz D

Staatz CE

Gorham, Gillian

Carroll R

Majoni, Sandawana William

Sajiv, Cherian

Swaminathan R

Holford N

2022-06-21

AIM: To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians. METHODS: Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit. RESULTS: No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD=5.00 compared with 3.25 L/h/70kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p=0.07 and p=0.08). CONCLUSION: There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.

School of Medicine, University of Melbourne, Parkville, Victoria.

Department of Paediatrics, Monash University, Clayton, Victoria, Australia.

Department of Nephrology, Royal Children's Hospital, Victoria, Australia.

Murdoch Children's Research Institute, Parkville, Victoria, Australia.

School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.

Menzies School of Health Research, Charles Darwin University Darwin, Australia.

Central Northern Adelaide Renal Transplantation Services, Adelaide, Australia.

Clinical and Health Sciences, University of South Australia.

Northern Territory Renal Services, Darwin, Australia.

Flinders University Northern Territory Medical Program, Darwin, Australia.

Renal Services, Alice Springs Hospital, Alice Springs, Australia.

Renal Transplant Unit, Royal Perth Hospital, Perth, Australia.

Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand.

Nephrology (Carlton) . 2022 Sep;27(9):771-779. doi: 10.1111/nep.14080. Epub 2022 Jun 29.

0000-0001-9548-2310

0000-0002-4031-2514

https://pubmed.ncbi.nlm.nih.gov/35727904/?otool=iaurydwlib

https://hdl.handle.net/10137/12208

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients.

Journal Article

Publication