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

Publisher: Blackwell Science Country of Publication: Australia NLM ID: 9615568 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1440-1797 (Electronic) Linking ISSN: 13205358 NLM ISO Abbreviation: Nephrology (Carlton) Subsets: MEDLINE

Original Publication: Carlton, Vic., Australia : Blackwell Science,

Immunosuppressive Agents*/pharmacokinetics ; Kidney Transplantation*/adverse effects ; Mycophenolic Acid*/pharmacokinetics ; Native Hawaiian or Other Pacific Islander*/ethnology ; Native Hawaiian or Other Pacific Islander*/genetics ; Tacrolimus*/pharmacokinetics ; White People*/ethnology ; White People*/genetics; Australia/epidemiology ; Bayes Theorem ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Humans ; Kidney Failure, Chronic/ethnology ; Kidney Failure, Chronic/genetics ; Kidney Failure, Chronic/therapy ; Models, Biological ; Prospective Studies ; Transplant Recipients

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/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .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.
(© 2022 Asian Pacific Society of Nephrology.)

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The Royal Australasian College of Physicians and the Australian and New Zealand Society of Nephrology; Jacquot Research Establishment Fellowship

Keywords: Aboriginal Australian; kidney transplantation; mycophenolic acid; pharmacokinetics; tacrolimus

0 (Immunosuppressive Agents)
EC 1.14.14.1 (CYP3A5 protein, human)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
HU9DX48N0T (Mycophenolic Acid)
WM0HAQ4WNM (Tacrolimus)

Date Created: 20220621 Date Completed: 20220818 Latest Revision: 20221207

20221213

10.1111/nep.14080

35727904