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

• Published in: Nephrology (Carlton, Vic.) Vol. 27; no. 9; pp. 771 - 779
• Main Authors: Barraclough, Katherine A., Metz, David, Staatz, Christine E., Gorham, Gillian, Carroll, Robert, Majoni, Sandawana William, Cherian, Sajiv, Swaminathan, Ramyasuda, Holford, Nick
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01.09.2022; Wiley Subscription Services, Inc
• Subjects: Aboriginal Australian; Australia - epidemiology; Bayes Theorem; Bayesian analysis; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Dosage; Humans; Immunosuppressive Agents - pharmacokinetics; Kidney Failure, Chronic - ethnology; Kidney Failure, Chronic - genetics; Kidney Failure, Chronic - therapy; Kidney transplantation; Kidney Transplantation - adverse effects; Kidney transplants; Mathematical models; Models, Biological; Mycophenolic acid; Mycophenolic Acid - pharmacokinetics; Native peoples; Pharmacokinetics; Prospective Studies; Tacrolimus; Tacrolimus - pharmacokinetics; Transplant Recipients; White people; White People - ethnology; White People - genetics; Australia; pharmacokinetics; Aboriginal Australian; tacrolimus; kidney transplantation; mycophenolic acid
• ISSN: 1320-5358; 1440-1797; 1440-1797
• DOI: 10.1111/nep.14080

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. Summary at a glance This prospective observational study examined for differences in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian Australian kidney transplant recipients. No differences were found, arguing against differential drug exposure as a contributor to the poorer transplant outcomes experienced by Aboriginal Australians.