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