One-third of deceased donor kidney transplant recipients in the United States are of African ancestry, despite African Americans constituting 13% of the US population. Results of immunosuppression trials are often not generalizable to African American kidney transplant recipients because that patient population is often under-represented in those studies.
Compared with kidney transplant recipients of European ancestry, rates of rejection and transplant loss are greater among patients of African ancestry; those differences are due to both immunologic and nonimmunologic factors. Genetics may play a role in the disparity of outcomes as well.
The commonly used immunosuppressive drug tacrolimus is an agent for which patient genotype affects dosing. Tacrolimus pharmacokinetics are affected by sex, ethnicity, concomitant medications, and genetic polymorphisms. Tacrolimus is metabolized via CYP3A4 and CYP3A5 enzymes primarily in the gut and liver; the intrinsic tacrolimus clearance capacity of CYP3A5 predominates over CYP3A4.
Loss-of-function alleles CYP3A5*6, CYP3A5*7 are found only in individuals of African ancestry; CYP3A5*3 is present in most Americans of European ancestry and in Asians. The presence of those alleles results in marked diminution of CYP3A5 enzyme activity (CYP3A5 nonexpressers). The CYP3A5*1 allele, present predominately but not exclusively in individuals of black African descent, encodes CYP3A5 enzymes associated with rapid tacrolimus disposition (CYP3A5 expressers), leading to subtherapeutic concentrations and increased dose requirements.
Using steady-state 24-hour pharmacokinetic profiling, Jennifer Trofe-Clark, PharmD, and colleagues recently conducted a study designed to further understanding of the differences in tacrolimus exposure between African American CYP3A5 expressers and CYP3A5 nonexpressers. Results of the study were reported in the American Journal of Kidney Diseases [2018;71(3):315-326].
ASERTAA (A Study of Extended Release Tacrolimus in African Americans) was an open-label, prospective, randomized, 2-sequence, 3-period crossover, pharmacogenetics study conducted at the University of Pennsylvania, the University of Illinois, and Washington University School of Medicine (St. Louis) between November 25, 2013, and July 30, 2015. The primary outcome of interest was a comparison of steady-state pharmacokinetics of once-daily LCPT (originally LifeCycle Pharma Tacrolimus [Envarsus XR in the United States]) tablets dosed 15% lower than total daily twice-daily tacrolimus (i.e., immediate-release tacrolimus [IRT-Tac]) dose with evenly divided twice-daily IR-Tac capsules in stable African American kidney transplant recipients. Secondary outcomes included confirmation of the total daily dose reduction in the LCPT group after conversion from IR-Tac, and a comparison of the safety and short-term efficacy of the two formulations.
Using a fixed-block randomization scheme, generated by an independent statistician prior to study initiation, patients were assigned in a 1:1 ratio to one of two sequences: sequence I: patients continued their current IR-Tac dose until study day 7, then switched to LCPT; sequence II: patients started on LCPT at 15% total lower daily dose than IR-Tac until study day 7, then switched to IR-Tac at its previous twice-daily dose. Participants all received the second assigned treatment from day 8 to day 21. At days 7, 14, and 21, 24-hour pharmacokinetic profiles were obtained.
Following randomization, 27 patients were assigned to sequence I and 23 to sequence II; of those 50 patients, 46 completed the entire pharmacokinetics study of three 24-hour assessments. Of the 46 with complete data, 76% (n=35) were CYP3A5 expressers.
The two treatment sequence groups were similar in demographic and transplant characteristics; 25 had preexisting diabetes. A total of 42 participants entered the extension phase (21 in each treatment group); the extension phase was completed by 18 participants in the LCPT group and 20 in the IR-Tac group.
Among CYP3A5 expressers, LCPT peak concentration (Cmax) was 31.4% lower (P<.001) than that of IR-Tac; LCPT area under the curve from time 0 to 24 hours (AUC0-24) was 12.2% higher (P=.04) than that of IR-Tac. Among nonexpressers, Cmax and AUC0-24 were similar between IR-Tac and LCPT groups.
With IR-Tac, compared with nonexpressers, tacrolimus Cmax was 33% higher in CYP3A5 expressers (P=.04). The difference was 11% with LCPT (P=.4).
In an ad hoc analysis according to genotype, there were no statistically significant differences in adverse events. There were no reports of infectious episodes during the pharmacokinetics portion of the study.
Limitations to the study cited by the researchers included the small sample size, the pharmacokinetic design of the study (rather than a clinical efficacy study), and the short follow-up period.
“In conclusion, our study demonstrates that with the use of IR-Tac, achievement of therapeutic tacrolimus concentrations in most African Americans resulted in much higher peak concentrations, with potential for enhanced toxicity and adverse outcomes. With LCPT, the shape of the pharmacokinetics profile was not affected by CYP3A5 genotype, and tacrolimus exposure was maintained at ~80%of the IR-Tac total daily dose. Results from this study additionally indicate that the pharmacokinetics of LCPT is less influenced by CYP3A5 genotype in African Americans, and LCPT had distinctive pharmacogenetics differences compared to IR-Tac in this population. Studies are ongoing to determine whether these pharmacogenetics differences represent an opportunity for LCPT to optimize immunosuppressive management in African American patients and thereby narrow health outcome disparities in kidney transplantation.”
- Researchers conducted a randomized prospective crossover study to further understanding of the differences in tacrolimus exposure between African American CYP3A5 expressers and CYP3A5
- Approximately 80% of participants were CYP35 expressers; there were no significant differences in area under the curve from time 0 to 24 hours or in peak concentration of tacrolimus between expressers and nonexpressers during administration of either immediate-release tacrolimus (IR-Tac) or extended-release tacrolimus (LCPT).
- Peak concentration of tacrolimus with administration of IR-Tac was 33% higher in CYP3A5 expressers compared with nonexpressers; the difference was 11% with LCPT.