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American Journal of Kidney Diseases

Tacrolimus Formulations and African American Kidney Transplant Recipients: When Do Details Matter?

  • Dirk R.J. Kuypers
    Correspondence
    Address for Correspondence: Dirk R.J. Kuypers, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
    Affiliations
    Department of Nephrology and Renal Transplantation, University Hospitals Leuven; and Department of Microbiology and Immunology, KU Leuven – University of Leuven, Leuven, Belgium
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      Related Article, p. 315
      Poorer outcomes after kidney transplantation in African Americans compared with other ethnicities have been attributed to clinical (eg, cardiovascular disease), genetic (eg, APOL1 gene variants), and socioeconomic (eg, financial) factors.
      • Palanisamy A.P.
      • Schiltz 3rd, C.E.
      • Pilch N.A.
      • et al.
      Cardiovascular risk factors contribute to disparities in graft outcomes in African American renal transplant recipients: a retrospective analysis.
      • Newell K.A.
      • Formica R.N.
      • Gill J.S.
      • et al.
      Integrating APOL1 gene variants into renal transplantation: considerations arising from the American Society of Transplantation Expert Conference.
      • Taber D.J.
      • Hamedi M.
      • Rodrigue J.R.
      • et al.
      Quantifying the race stratified impact of socioeconomics on graft outcomes in kidney transplant recipients.
      Better understanding of the causes underlying these disparities has led to several initiatives striving to improve outcomes in African American kidney transplant recipients (KTRs).
      • Strigo T.S.
      • Ephraim P.L.
      • Pounds I.
      • et al.
      The TALKS study to improve communication, logistical, and financial barriers to live donor kidney transplantation in African Americans: protocol of a randomized clinical trial.
      • Rodrigue J.R.
      • Kazley A.S.
      • Mandelbrot D.A.
      • Hays R.
      • LaPointe Rudow D.
      • Baliga P.
      American Society of Transplantation
      Living donor kidney transplantation. Overcoming disparities in live kidney donation in the US–recommendations from a consensus conference.
      The CYP3A5*1 allele, known to confer faster metabolism of tacrolimus in KTRs and predominantly present in individuals of sub-Saharan African ancestry, has been shown to cause subtherapeutic exposure in African Americans, a group having higher acute rejection rates and inferior graft outcomes.
      • Jacobson P.A.
      • Oetting W.S.
      • Brearley A.M.
      • et al.
      DeKAF Investigators
      Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium.
      • Taber D.J.
      • Gebregziabher M.G.
      • Srinivas T.R.
      • Chavin K.D.
      • Baliga P.K.
      • Egede L.E.
      African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients.
      The effects of CYP3A5 on conventional twice-daily tacrolimus (IR-Tac [Prograf; Astellas Pharma US, Inc]) and extended-release once-daily tacrolimus (ER-Tac [Astagraf XL; Astellas Pharma US, Inc]) formulations in terms of exposure, dose requirements, and dose conversion ratios are well established in whites.
      • Stifft F.
      • Stolk L.M.
      • Undre N.
      • van Hooff J.P.
      • Christiaans M.H.
      Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation.
      • Glowacki F.
      • Lionet A.
      • Hammelin J.P.
      • et al.
      Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients.
      A randomized prospective study in which most participants were white demonstrated no clinical benefit of CYP3A5 genotype–based IR-Tac dosing in de novo kidney transplantation.
      • Shuker N.
      • Bouamar R.
      • van Schaik R.H.
      • et al.
      A randomized controlled trial comparing the efficacy of Cyp3a5 genotype-based with body-weight-based tacrolimus dosing after living donor kidney transplantation.
      The once-daily tacrolimus formulation referred to as LCPT (Envarsus XR; Veloxis Pharmaceuticals) has higher bioavailability by design (using the Veloxis MeltDose drug delivery technology) than IR-Tac and ER-Tac in whites, with ratios of the geometric mean values of the 24-hour area under the curve (AUC0-24h) of 117% (90% confidence interval [CI], 107.9%-127%) and 125.7% (90% CI, 114.1%-138.5%), respectively.
      • Tremblay S.
      • Nigro V.
      • Weinberg J.
      • Woodle E.S.
      • Alloway R.R.
      A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study.
      The bioavailability of the different tacrolimus formulations has not been formally evaluated in African American KTRs, although the majority are carriers of at least 1 CYP3A5*1 allele.
      • Tremblay S.
      • Nigro V.
      • Weinberg J.
      • Woodle E.S.
      • Alloway R.R.
      A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study.
      Hypothetically, a tacrolimus formulation with higher oral bioavailability could benefit patients who constitutionally (ie, genetically) have higher dose requirements because this phenotype has been associated with both nephrotoxicity and subtherapeutic exposure leading to acute rejection.
      • Taber D.J.
      • Gebregziabher M.G.
      • Srinivas T.R.
      • Chavin K.D.
      • Baliga P.K.
      • Egede L.E.
      African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients.
      • Kuypers D.R.
      • Naesens M.
      • de Jonge H.
      • Lerut E.
      • Verbeke K.
      • Vanrenterghem Y.
      Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.
      Direct comparative prospective studies between IR-Tac and ER-Tac or LCPT have not demonstrated meaningful differences in primary clinical end points (eg, acute rejection and graft survival) or secondary end points (eg, donor-specific anti-HLA antibody formation). In this issue of AJKD, Trofe-Clark et al
      • Trofe-Clark J.
      • Brennan D.C.
      • West-Thielke P.
      • et al.
      Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African Americans kidney transplant recipients.
      showed in a prospective randomized comparative crossover pharmacokinetic study (ASERTAA [A Study of Extended Release Tacrolimus in African Americans]) that achieving therapeutic trough concentrations (C0) with IR-Tac in CYP3A5-expressing African American KTRs was accompanied by significantly higher peak concentrations (Cmax), an effect that was attenuated when using the LCPT formulation.
      • Trofe-Clark J.
      • Brennan D.C.
      • West-Thielke P.
      • et al.
      Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African Americans kidney transplant recipients.
      Among CYP3A5 expressors (76% of patients were carrying at least 1 CYP3A5*1 allele), IR-Tac weight-normalized dose requirements were, as expected, higher (0.12 ±  0.05 mg/kg/d) compared with CYP3A5 nonexpressors (0.06 ± 0.02 mg/kg/d). Interestingly, IR-Tac Cmax was significantly higher (33.9%; 90% CI, 6.2%-68.8%) in CYP3A5 expressors versus nonexpressors; this difference between CYP3A5 genotypes was not observed during LCPT treatment. The authors applied a 1 mg to 0.85 mg dose conversion factor when switching from IR-Tac to LCPT treatment in the crossover AUC0-24h measurements. This conversion ratio was based on LCPT pharmacokinetic data from comparative studies in white KTRs.
      • Bunnapradist S.
      • Ciechanowski K.
      • West-Thielke P.
      • et al.
      MELT investigators
      Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.
      • Budde K.
      • Bunnapradist S.
      • Grinyo J.M.
      • et al.
      Envarsus Study Group
      Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of phase III, double-blind, randomized trial.
      Despite the preemptive dose adaptations, LCPT AUC0-24h was still 12.2% higher than during IR-Tac treatment, while LCPT Cmax was 31.4% lower. These differences were observed only in KTRs carrying at least 1 CYP3A5*1 allele. In CYP3A5 nonexpressors, the minimum concentration (C0) was still significantly higher with LCPT than with IR-Tac, indicating that the estimated preemptive dose conversion ratio was too low. The authors found that on a milligram-to-milligram basis, LCPT oral bioavailability was 32.6% and 35.8% higher than IR-Tac in African American CYP3A5 expressors and nonexpressors, respectively.
      Recently, Tremblay et al
      • Tremblay S.
      • Nigro V.
      • Weinberg J.
      • Woodle E.S.
      • Alloway R.R.
      A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study.
      established total daily dose conversion rates between IR-Tac, ER-Tac, and LCPT based on results of a 2-sequence 3-period crossover pharmacokinetics study. Although the ER-Tac dose needed augmentation by 8% when switching from IR-Tac, the daily LCPT dose needed lowering by 30% when converting from IR-Tac and by 36% when switching from ER-Tac.
      • Tremblay S.
      • Nigro V.
      • Weinberg J.
      • Woodle E.S.
      • Alloway R.R.
      A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study.
      The authors of the current AJKD study explain the higher bioavailability (and thus lower dose requirements) of LCPT versus IR-Tac because CYP3A4/CYP3A5 concentration in the intestinal mucosa decreases from the proximal toward distal parts of the gut, leading to slower tacrolimus metabolism in the distal gut (colon), where LCPT is mainly released from its formulation.
      • Knops N.
      • Levtchenko E.
      • van den Heuvel B.
      • Kuypers D.
      From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation.
      In contrast, IR-Tac is released immediately in the proximal intestine and hence metabolized faster by intestinal CYP3A4/5.
      • Knops N.
      • Levtchenko E.
      • van den Heuvel B.
      • Kuypers D.
      From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation.
      The lower Cmax (and slower Tmax [time to Cmax]) of LCPT compared to IR-Tac fits with this hypothesis. However, in a study of healthy volunteers, when a tacrolimus solution in polyethylene glycol 400 was released at specific parts of the gastrointestinal tract (stomach, proximal and distal small bowel, and ascending colon), tacrolimus AUC0-24h and Cmax did not differ significantly between sites.
      • Tsunashima D.
      • Kawamura A.
      • Murakami M.
      • et al.
      Assessment of tacrolimus absorption from the human intestinal tract: open-label, randomized, 4-way crossover study.
      In physiologically based pharmacokinetic modeling, a controlled-release (CR) formulation of tacrolimus (which is classified as a BCS [Biopharmaceutics Classification System] class 2 drug [ie, low solubility and high permeability]) would have an expected absorption lower than its immediate-release formulation.
      • Olivares-Morales A.
      • Kamiyama Y.
      • Darwich A.S.
      • Aarons L.
      • Rostami-Hodjegan A.
      Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model.
      However, overall relative bioavailability of a CR formulation would not be affected because the fraction of the drug that escapes from first-pass metabolism in the proximal gut wall would also increase.
      • Olivares-Morales A.
      • Kamiyama Y.
      • Darwich A.S.
      • Aarons L.
      • Rostami-Hodjegan A.
      Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model.
      Most CR formulations therefore have decreased or unchanged relative bioavailability compared with their immediate-release counterparts, as is the case for ER-Tac. What makes LCPT different? Most likely, the biopharmaceutical characteristics of the formulation (MeltDose drug delivery technology) enable tacrolimus to very effectively circumvent proximal first-pass metabolism and allow for slower absorption in the distal gut.
      How should we interpret the 33.9% higher Cmax for IR-Tac in African American CYP3A5 expressors? Tacrolimus exposure has been implicated in infectious complications, neurologic symptoms, and reduced creatinine clearance, but in contrast to cyclosporine, not with arterial graft perfusion.
      • Kuypers D.R.
      • Claes K.
      • Evenepoel P.
      • Maes B.
      • Vanrenterghem Y.
      Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients.
      • Langone A.
      • Steinberg S.M.
      • Gedaly R.
      • et al.
      STRATO Investigators
      Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study.
      • Zaldzman J.S.
      A comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily cyclosporine on renal function in healthy volunteers.
      LCPT, characterized by a “flattened” AUC0-24h compared with IR-Tac and ER-Tac, seems to attenuate this pharmacogenetic effect in African Americans carrying at least 1 CYP3A5*1 allele. However, the authors failed to stratify their observations according to the presence of diabetes (54% of participants had pre-existing diabetes), which can cause slower and lower peak absorption of tacrolimus. In addition, although the IR-Tac formulations used in the study were bioequivalent, small differences in dissolution characteristics and the use of corticosteroids could have affected Cmax.
      • Bloom R.D.
      • Trofe-Clark J.
      • Wiland A.
      • Alloway R.R.
      A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.
      Whether LCPT will protect African American CYP3A5*1 carriers from the previously mentioned adverse effects and other disadvantages (eg, posttransplantation diabetes) potentially related to a higher Cmax remains to be determined in prospective studies. Second, intra- and interpatient variability of Cmax was high, irrespective of CYP3A5 genotype, which further brings into question its relevance in clinical practice. Tremor was shown to be less prevalent in patients treated with LCPT compared to IR-Tac in one study, but without notable differences in C0 (Cmax was not measured).
      • Langone A.
      • Steinberg S.M.
      • Gedaly R.
      • et al.
      STRATO Investigators
      Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study.
      Of potentially more clinical relevance are the significantly lower tacrolimus daily dose requirements for LCPT compared with IR-Tac and ER-Tac. We and others have demonstrated that high tacrolimus dose requirements in white populations are associated with histologic signs of nephrotoxicity, poor graft function, and more graft loss, even in KTRs not expressing CYP3A5.
      • Kuypers D.R.
      • Naesens M.
      • de Jonge H.
      • Lerut E.
      • Verbeke K.
      • Vanrenterghem Y.
      Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.
      • Thölking G.
      • Fortmann C.
      • Koch R.
      • et al.
      The tacrolimus metabolism rate influences renal function after kidney transplantation.
      Although other variants such as CYP3A5*6 and CYP3A5*7 also play a role, the CYP3A5*1 allele still confers the largest effect on tacrolimus dose requirements in African American KTRs.
      • Oetting W.S.
      • Schladt D.P.
      • Guan W.
      • et al.
      DeKAF Investigators
      Genomewide association study of tacrolimus concentrations in African American kidney transplant recipients identifies multiple CYP3A5 alleles.
      In contrast to whites, African American KTRs are less likely to achieve therapeutic target concentrations and have higher risk for acute rejection, but exhibit a slightly lower propensity to develop interstitial fibrosis and tubular atrophy.
      • Taber D.J.
      • Gebregziabher M.G.
      • Srinivas T.R.
      • Chavin K.D.
      • Baliga P.K.
      • Egede L.E.
      African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients.
      Thus, it seems that ethnicity also determines, at least to a certain extent, the repercussions of high tacrolimus dose requirements for the graft beyond the pure pharmacogenetic effects of CYP3A5 on drug disposition.
      Intrapatient variability (IPV) in tacrolimus exposure has emerged as a very important modifiable clinical determinant of graft (dys)function, (late) acute rejection, and graft loss.
      • Shuker N.
      • Shuker L.
      • van Rosmalen J.
      • et al.
      A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.
      High tacrolimus IPV has recently also been associated with the development of donor-specific anti-HLA antibodies and the progression of graft fibrosis.
      • Rodrigo E.
      • Segundo D.S.
      • Fernández-Fresnedo G.
      • et al.
      Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development.
      • Vanhove T.
      • Vermeulen T.
      • Annaert P.
      • Lerut E.
      • Kuypers D.R.J.
      High intrapatient variability of tacrolimus concentrations predicts accelerated progression of chronic histologic lesions in renal recipients.
      IPV is a cumulative index of many variables, including medication (non)adherence, drug-drug interactions, food effects, chronobiology, gastrointestinal function, etc.
      • Shuker N.
      • van Gelder T.
      • Hesselink D.A.
      Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management.
      In a recent observational study by Taber et al,
      • Taber D.J.
      • Su Z.
      • Fleming J.N.
      • et al.
      Tacrolimus trough concentration variability and disparities in African American kidney transplantation.
      tacrolimus IPV was not only shown to be higher in African American versus non–African American KTRs, but also a 10% increase in IPV augmented the risk for acute rejection by 20% in only the former. CR formulations are often developed to achieve lower peak-to-trough fluctuations and allow once-daily dosing, which can translate into better side-effect profiles and better adherence. A tacrolimus formulation that could significantly lower IPV could provide an important additional clinical benefit for patients, especially African American KTRs. For ER-Tac, small improvements in AUC0-24h IPV (−3.2%) have been demonstrated under controlled study conditions by Stifft et al,
      • Stifft F.
      • Stolk L.M.
      • Undre N.
      • van Hooff J.P.
      • Christiaans M.H.
      Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation.
      but without changes in the concurrent IPV of corresponding C0 values. Although Trofe-Clark et al
      • Trofe-Clark J.
      • Brennan D.C.
      • West-Thielke P.
      • et al.
      Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African Americans kidney transplant recipients.
      report that estimated intrapatient coefficients of variation for AUC0-24h, C0, and Cmax for LCPT and IR-Tac were all <30%, comparative data between formulations, stratified per CYP3A5 genotype, were not shown. One can deduce from the results of recent large studies, including data from African American KTRs, that tacrolimus IPV in real-life settings is even higher than observed during pharmacokinetic studies.
      • Rodrigo E.
      • Segundo D.S.
      • Fernández-Fresnedo G.
      • et al.
      Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development.
      • Vanhove T.
      • Bouwsma H.
      • Hilbrands L.
      • et al.
      Determinants of the magnitude of interaction between tacrolimus and voriconazole/posaconazole in solid organ recipients.
      It will be interesting to see how the LCPT formulation performs in terms of IPV compared with IR-Tac and ER-Tac, especially because the reported differences in percent peak-to-trough fluctuation and swing have not been linked to a better clinical profile.
      • Trofe-Clark J.
      • Brennan D.C.
      • West-Thielke P.
      • et al.
      Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African Americans kidney transplant recipients.
      Another unanswered question is the susceptibility of the different tacrolimus formulations to drug-drug interactions with potent CYP3A inhibitors such as azole antifungals. Theoretically, one could assume that LCPT, being absorbed in more distal parts of the gastrointestinal tract, would be less affected by CYP3A inhibitors, which act mainly in the upper parts of the gut, where CYP3A4 (and CYP3A5) are abundantly expressed and involved in first-pass metabolism.
      • Knops N.
      • Levtchenko E.
      • van den Heuvel B.
      • Kuypers D.
      From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation.
      Because CYP3A5 expressors are already less susceptible for the effects of CYP3A inhibitors, LCPT could potentially be of interest for KTRs not carrying a CYP3A5*1 allele and treated with CYP3A inhibitors.
      • Vanhove T.
      • Bouwsma H.
      • Hilbrands L.
      • et al.
      Determinants of the magnitude of interaction between tacrolimus and voriconazole/posaconazole in solid organ recipients.
      Trofe-Clark et al
      • Trofe-Clark J.
      • Brennan D.C.
      • West-Thielke P.
      • et al.
      Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African Americans kidney transplant recipients.
      have set the stage for more in-depth research into the optimal tacrolimus formulation for African American KTRs in the quest for personalized immunosuppression.

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      Linked Article

      • Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients
        American Journal of Kidney DiseasesVol. 71Issue 3
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          Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile.
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