An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients

https://doi.org/10.1016/j.pharmthera.2006.04.006Get rights and content

Abstract

Calcineurin inhibitors, tacrolimus (FK506) and cyclosporine (ciclosporin A), are the primary immunosuppressive agents used on recipients of organ transplantations. The hepatic metabolism of these drugs by cytochrome P450 IIIA (CYP3A) subfamilies is considered a major eliminating process. The intestinal efflux-pump P-glycoprotein (Pgp) (multidrug resistance 1 [MDR1], ATP-binding cassette B1 [ABCB1]) and CYP3A4 have been demonstrated as important for the bioavailability of drugs, so called “absorptive barriers”. Recently, an important role for CYP3A5 in the intestine for the oral clearance of drugs has been identified. Both tacrolimus and cyclosporine are substrates of Pgp, CYP3A4 and CYP3A5, and therefore, these molecules are potential pharmacokinetic factors with which to establish personalized dosage regimens for these drugs. Although the effect of single nucleotide polymorphisms in the MDR1/ABCB1 and CYP3A5 genes on the pharmacokinetics of immunosuppressant has been widely examined, some contradictions have been emerged. In living-donor liver transplant (LDLT) patients, the intestinal mRNA expression level of MDR1 and CYP3A5 genotyping both in the native intestine and in the grafted liver are suggested to be potential pharmacokinetic factors for adjusting initial dosage and predicting post-operative variation in the pharmacokinetics of tacrolimus. We review the pharmacokinetic and pharmacodynamic characteristics of these drugs including the large pharmacokinetic variation and potential individualized dosage adjustments based on the genomic information of transporters and metabolic enzymes as well as classical pharmacokinetic analyses based on therapeutic drug monitoring (TDM).

Introduction

Allograft transplantation and subsequent immunosuppressive therapy form the cornerstones of treatment for end-stage failure of organs, such as the heart, lung, liver, small bowel and kidney. Two calcineurin inhibitors, tacrolimus (FK-506) and cyclosporine (ciclosporin A), play pivotal roles in most of the immunosuppressive protocols (Todo et al., 1991, Venkataramanan et al., 1991, Todo et al., 1992, Tanaka et al., 1994, Tzakis et al., 1994, Busuttil et al., 1996, Frezza et al., 1996, Kokado et al., 1999, Levy, 1999, Belitsky et al., 2000). After the introduction of cyclosporine in the early 1980s to treat recipients of renal and liver transplantations, graft survival improved markedly from ~ 60% to over 80% compared to azathioprine- or steroid-based protocols (Starzl et al., 1982, Gordon et al., 1986, Otte, 2002). In the mid-1990s, tacrolimus with a strong immunosuppressive effect was developed as an alternative to cyclosporine (McMaster, 1994, McDiarmid et al., 1995, Busuttil & Holt, 1997). Therapeutic drug monitoring (TDM) has helped to reduce the toxicity of these drugs, life-threatening infections and acute cellular rejections via “concentration-oriented therapy” rather than “dose-oriented therapy” (Grevel, 1993, Jusko, 1995, Kershner & Fitzsimmons, 1996, Levy, 1999, Armstrong & Oellerich, 2001). However, individualized dosage regimens of these immunosuppressants have not been established except for the TDM-based dosage modification, because of an extensive inter-individual variation in the pharmacokinetics of tacrolimus and cyclosporine (Grevel et al., 1993, Jusko et al., 1995, Venkataramanan et al., 1995, Cooney et al., 1997). In addition, large intra-individual variation in the pharmacokinetics is also found after liver transplantation (Yasuhara et al., 1995). Although hepatic metabolism is an important route for the elimination of these drugs, intestinal efflux via P-glycoprotein (Pgp, a product of the multidrug resistance 1 gene [MDR1] or the so called ATP-binding cassette [ABC] transporter, ABCB1) is also considered to contribute significantly to the variation in the pharmacokinetics of these drugs, especially bioavailability (Hebert et al., 1999, Fromm, 2000, Lin & Yamazaki, 2003). The 2 cytochrome P450 IIIA (CYP3A) subfamilies CYP3A4 and CYP3A5 mediate the biotransformation of tacrolimus and cyclosporine, and both enzymes are expressed in enterocytes as well as in hepatocytes (Williams et al., 2003, Kamdem et al., 2005, Thervet et al., 2005). Therefore, it is well acknowledged that intestinal MDR1 and CYP3A4/5 act in concert as an absorptive barrier to orally administered drugs including tacrolimus and cyclosporine (Zhang & Benet, 2001, Kivisto et al., 2004). The identification of new biological factors is needed to quantitatively clarify the molecular mechanisms behind the variation in the pharmacokinetics of tacrolimus and cyclosporine. For example, genomic information on the intestinal ABCB1 and CYP3A4/5 proteins in the liver and/or intestine should be taken in consideration when performing the personalized dosage adjustment of these immunosuppressants in patients receiving allograft transplantations.

This review will focus on several advances in efforts to adjust the dosage of calcineurin inhibitors including traditional TDM and recent pharmacogenomic-based strategies.

Section snippets

Therapeutic drug monitoring of tacrolimus and cyclosporine

To reduce their inherent toxicity and to lower the incidence of acute cellular rejection in the early post-transplant phase, which will also have an overall long-term clinical benefit in terms of less graft loss and improved patient survival, careful monitoring of blood concentrations of tacrolimus and cyclosporine is an essential part of patient management after organ transplantations. At first, the personalized immunosuppressive therapy by TDM is discussed.

Limitation of therapeutic drug monitoring-based dosage adjustment of immunosuppressants

Because the blood concentration of cyclosporine or tacrolimus reflects mortality, efficacy, adverse reactions and infections, pharmacokinetic studies based on TDM have been conducted for some 20 years. However, these population pharmacokinetic models were shown to have only limited predictive value with regard to explaining the variability in tacrolimus and cyclosporine exposure/drug concentrations. In addition, a fundamental limitation of traditional TDM is that it can only be started when an

Perspective

Recent pharmacogenomic/pharmacogenetic approaches have raised the possibility of personalized drug therapy, so called “tailored medicine”. Molecular and cell-biological examinations have brought the complicated mechanisms of pharmacokinetics and pharmacodynamics of drugs to light. Based on molecular examinations, the enterocyte expression level of MDR1 mRNA and the CYP3A5 genotype are suggested to be useful parameters for understanding the variability in the pharmacokinetics of tacrolimus in

Acknowledgment

This work was supported in part by a Grant-in-Aid from Japan Health Sciences Foundation “Research on Health Sciences Focusing on Drug Innovation”, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by the 21st Century COE Program “Knowledge Information Infrastructure for Genome Science”.

References (145)

  • M.F. Hebert

    Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery

    Adv Drug Deliv Rev

    (1997)
  • K. Inui et al.

    Cellular and molecular aspects of drug transport in the kidney

    Kidney Int

    (2000)
  • S. Kawasaki et al.

    Liver regeneration in recipients and donors after transplantation

    Lancet

    (1992)
  • D. Kelly et al.

    Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial

    Lancet

    (2004)
  • Y. Kokado et al.

    Low-dose tacrolimus (FK 506)-based immunosuppressive protocol in living donor renal transplantation

    Transplant Proc

    (1999)
  • A.P. Li et al.

    Substrates of human hepatic cytochrome P450 3A4

    Toxicology

    (1995)
  • A. Lopez-Montes et al.

    Treatment of tuberculosis with rifabutin in a renal transplant recipient

    Am J Kidney Dis

    (2004)
  • I.A. MacPhee et al.

    The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation

    Am J Transplant

    (2004)
  • R. Margreiter

    Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study

    Lancet

    (2002)
  • S. Masuda et al.

    Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation

    Liver Transpl

    (2003)
  • S. Masuda et al.

    Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients

    Transplant Proc

    (2005)
  • N. Morita et al.

    Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities

    Biochem Pharmacol

    (2003)
  • D. Anglicheau et al.

    Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients

    J Am Soc Nephrol

    (2003)
  • D. Anglicheau et al.

    CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation

    Clin Pharmacol Ther

    (2004)
  • Y. Armendariz et al.

    Hematocrit influences immunoassay performance for the measurement of tacrolimus in whole blood

    Ther Drug Monit

    (2005)
  • C. Balram et al.

    Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic-genotypic correlates

    Br J Clin Pharmacol

    (2003)
  • P. Belitsky et al.

    Impact of absorption profiling on efficacy and safety of cyclosporin therapy in transplant recipients

    Clin Pharmacokinet

    (2000)
  • L. Bonhomme-Faivre et al.

    MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients

    Transplantation

    (2004)
  • G.J. Burckart et al.

    Cyclosporine measurement by FPIA, PC-RIA, and HPLC following liver transplantation

    Transplant Proc

    (1990)
  • R.W. Busuttil et al.

    General guidelines for the use of tacrolimus in adult liver transplant patients

    Transplantation

    (1996)
  • B. Charpiat et al.

    A population pharmacokinetic model of cyclosporine in the early postoperative phase in patients with liver transplants, and its predictive performance with Bayesian fitting

    Ther Drug Monit

    (1998)
  • R.Y. Chenhsu et al.

    Renal allograft dysfunction associated with rifampin-tacrolimus interaction

    Ann Pharmacother

    (2000)
  • B. Chowbay et al.

    Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression

    Br J Clin Pharmacol

    (2005)
  • B. Chowbay et al.

    An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore

    Drug Metab Rev

    (2005)
  • J.L. Cogill et al.

    Evaluation of the tacrolimus II microparticle enzyme immunoassay (MEIA II) in liver and renal transplant recipients

    Clin Chem

    (1998)
  • G.F. Cooney et al.

    Cyclosporin pharmacokinetics in paediatric transplant recipients

    Clin Pharmacokinet

    (1997)
  • S. de Wildt et al.

    Cytochrome P450 3A: ontogeny and drug disposition

    Clin Pharmacokinet

    (1999)
  • A. Demetris et al.

    Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel

    Hepatology

    (2000)
  • E.E. Frezza et al.

    Small bowel transplantation: current progress and clinical application

    Hepatogastroenterology

    (1996)
  • S. Friman et al.

    A new microemulsion formulation of cyclosporin: pharmacokinetic and clinical features

    Clin Pharmacokinet

    (1996)
  • M.F. Fromm

    P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs

    Int J Clin Pharmacol Ther

    (2000)
  • S. Fukatsu et al.

    Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation

    Eur J Clin Pharmacol

    (2001)
  • M. Fukudo et al.

    Forecasting of blood tacrolimus concentrations based on the Bayesian method in adult patients receiving living-donor liver transplantation

    Clin Pharmacokinet

    (2003)
  • M. Fukudo et al.

    Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients

    Clin Pharmacol Ther

    (2005)
  • M. Fukudo et al.

    Distinct inhibitory effects of tacrolimus and cyclosporin A on calcineurin phosphatase activity

    J Pharmacol Exp Ther

    (2005)
  • M. Fukudo et al.

    Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: twice daily versus once daily dosing

    Liver Transpl

    (2006)
  • G.M. Garcia et al.

    An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: a comparison of dual vs. triple drug therapy

    Liver Transpl

    (2005)
  • M. Goto et al.

    C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation

    Pharmacogenetics

    (2002)
  • M. Goto et al.

    CYP3A51-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation

    Pharmacogenetics

    (2004)
  • M.M. Gottesman et al.

    Multidrug resistance in cancer: role of ATP-dependent transporters

    Nat Rev Cancer

    (2002)
  • Cited by (0)

    View full text