Abstract
Our aim in this chapter is to present the state of the art, including our own group research, in the field of immunosuppressant pharmacogenetics in the four main types of solid organ transplantation: kidney, heart, lung, and liver. The main focus will be on those findings in the field that have been widely investigated and then in those that are close to clinical implementation, mainly CYP3A5 genotyping for the adjustment of the initial tacrolimus dose. This recommendation will be discussed in more detail, explaining its clinical potential as well as its limitations. To end, a short opinion about the feasibility of implementation in the health systems as well as discussion about private companies selling pharmacogenetic tests will be presented.
Keywords
- SNP
- tacrolimus
- pharmacogenetic-guided therapy
- CYP3A5
- ABCB1
- precision medicine
1. Introduction
Since the first successful kidney transplantation was performed in the 1950s, great advances have been achieved in the control of immunosuppression and graft outcome, improving drastically patient survival. Nowadays, the most common immunosupressant regimens in solid organ transplantation consist of a combination of a calcineurin inhibitor (CNI: cyclosporine [Cs] or tacrolimus [TAC]) with an antiproliferative agent such as mycophenolic acid (MPA: mycophenolate mofetil or mycophenolate sodium) or the less used azathioprine. Corticosteroids are also widely employed. Also, mTOR inhibitors [sirolimus (SIR) and everolimus (EVE)] have become common drugs in the prophylaxis of rejection after transplantation [1, 2]. Immunosuppressive agents have a narrow therapeutic index and substantial inter-patient variability, so achieving the optimal equilibrium between efficacy and an acceptable grade of toxicity is essential for the success of the treatment, and individualizing drug therapy has become an important goal.
Therapeutic drug monitoring (TDM) is indispensable for immunosuppressive agents dosing and reduces the pharmacokinetic component of variability by controlling drug blood concentrations. However, TDM is only possible after the drug is administered and steady state and patient’s compliance are achieved; thus, complementary strategies are needed. The intra- and inter‐patient differences in immunosuppressant dosage requirements and pharmacokinetics are attributable to several factors, such as kidney function, ethnicity, concomitant use of other drugs [3], and qualitative and quantitative changes of proteins whose activity plays key roles in the absorption, distribution, metabolism, and function of these drugs. In these last mentioned protein changes is where pharmacogenetics plays a crucial role: Functional changes of these proteins (transporters, metabolizing enzymes, target proteins, etc.) have been attributed to polymorphism in their coding genes [4, 5]. Single-nucleotide polymorphisms (SNPs) are the main type of polymorphisms involved in human genome variation. These are different alleles or variants that naturally occur at a determined position of a gene, the frequency of the less common allele in the population being not higher than 1%. For instance, in a concrete point of a determined gene, part of the population, let’s say 80%, could have an adenine (A) or AA, and this would be the most frequent genotype at that genomic position, while 5% would have a thymine, being the variant and less frequent allele (TT genotype), and the rest 15% of the mentioned population would be heterozygous for the variant, AT genotype. Pharmacogenetics aims to determine the effect of those genetic variants regarding the efficacy and toxicity of drugs, and therefore, it may be able to predict patients’ response to them. These genetic characteristics can be known for each single patient before the drug is administered, allowing the design of the best strategy to treat the patient, what we nowadays know as precision medicine.
In this scenario, it is also very important to take into account that in transplantation each patient actually contains two different genetic entities: the donor and the recipient. Therefore, the drugs administered to the recipient will be metabolized or excreted by the transplanted organ from the donor when we are talking about liver or kidney transplantation, respectively. But also in heart- or lung-transplanted patients, the effect of the donors’ genotype could be seen if we find toxicities and/or efficacies directly related to these organs. This is the reason why more and more studies in transplantation pharmacogenetics consider both the donor and recipient genotypes to evaluate the response to treatment [6–9].
2. The genes related to the immunosuppressants
Cs and TAC are metabolized by CYP3A subfamily in both enterocytes and hepatocytes. Cs is primarily metabolized by
The
Following administration, mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium is hydrolyzed to MPA, the active metabolite. MPA is metabolized in the liver, gastrointestinal tract, and kidney by uridine diphosphate gluconosyltransferases (UGTs). MPAG, the main metabolite, is a phenolic glucuronide, which has no pharmacological activity and is excreted into the urine via active tubular secretion and into the bile by multidrug resistance protein 2 (
Azathioprine is employed in patients with intolerance to mycophenolate as an alternative antimetabolite. This prodrug is activated to 6-mercaptopurine in the erythrocytes, and thiopurine methyltransferase (
Information about genetic variations affecting SIR and EVE response is still scarce. Both drugs are metabolized via
Glucocorticoid-induced osteonecrosis is an important adverse event affecting transplant patients, leading to severe joint pain and limitations on physical activity. Numerous studies have reported that
Other clinical consequences, mainly long term, of immunosuppressants are being subject to really interesting pharmacogenetic studies: tumor development, fertility impairment, or hypertension [33–35].
3. Kidney transplantation
3.1. Calcineurin inhibitors
The expression of
In the meta-analysis conducted by Terrazzino et al. [41], no evidence of an effect of the
A polymorphism in intron 3 of
The first studies about the relationship between
The first prospective randomized-controlled trial (by Thervet et al.) to compare the pharmacokinetic characteristics of TAC in patients receiving a fixed dose of the drug or a dose adapted according to the patient’s
Other authors have studied the influence of donors’ genotype. Opposite to liver transplantation, donors’
Several meta-analyses have been performed. The results of a meta-analysis performed by our group suggest a significantly lower TAC dose-normalized Cmin among
Regarding
Transplant patients receive a large number of drugs and the effect of concomitant drugs is important. Gastric protection is very common in transplant recipients. We conducted a study in 75 renal transplant recipients treated with TAC and omeprazole. This drug is mainly metabolized via
3.2. mTOR inhibitors
A study also showed that
3.3. Mycophenolic acid
Several studies have reported the role of SNPs in the promoter region of
Regarding
MPA is also substrate of organic anion-transporting polypeptides (OATPs), which are responsible for the entrance of MPA and MAPG into hepatocytes. This has been observed in vitro [85], but in vivo results are still contradictory [85–87]. Picard et al. [85] observed that the pharmacokinetics of both MPA and MPAG were significantly influenced by the
The association of SNPs in IMPDH with MPA is not clear.
4. Heart transplantation
Heart transplantation has experienced a great improvement in the last years. Survival among cardiac transplant recipients is estimated to be 83% 5 years posttransplantation as a result of improvements in immunosuppressant treatments, surgical technique, and reduction of adverse events [91, 92]. Nevertheless, still a considerable number of patients experience morbidity and mortality after transplantation. These outcomes could be related to genetic variability in genes that encodes transporters, metabolizers, or molecular targets of immunosuppressant therapy.
4.1. Calcineurin inhibitors
Most of the published studies analyzed the relationship between
High CNI levels are related to the appearance of nephrotoxicity. Most of the studies did not detect association between
The differences in TAC blood levels regarding the already explained CYP3A5 variants *1 or *3 were clearly observed in adult heart transplantation [95, 96, 98, 109, 110] and also in children [93, 94, 111]. However with Cs it was only described in our small cohort of 25 adult heart transplant patients, in which the CYP3A5*3/3* variant was associated to an increase in trough blood levels corrected by dose and body weight [98]. These results were not reproduced in two other similar studies (30 and 45 adult heart recipients) [96, 99].
Age and
A study in 60 pediatric heart transplant recipients investigated the combined effect of
Other different CYP enzymes were studied in heart transplantation.
4.2. mTor inhibitors
A report in adult heart recipients suggested that EVE blood levels were not related to
4.3. Mycophenolic acid
In pediatric heart transplantation, the gastrointestinal intolerance was reproduced with variant allele of
Regarding serum levels of MPA and their metabolites, a study did not obtain significant relationships with
The influence of
The presence of polymorphisms in IMPDH1 and IMPDH2 genes does not result in lower activity in all cases [121]. In a cohort of 59 pediatric cardiac transplant, two variants of IMPDH1 (rs2278294 and rs2228075) were associated to greater gastrointestinal toxicity [122]. On the other hand, this study also found that variant G of IMPDH2 (rs11706052) polymorphism was related to neutropenia that required dose holding. A posterior haplotype analysis repeated the association of IMPDH1 to gastrointestinal intolerance but this was not greater than individual IMPDH1 polymorphisms [122].
4.4. Azathioprine
In heart transplantation, heterozygotes for TPMT SNPs (rs1142345, rs1800460, rs1800462) were shown lower enzyme activity and earlier and higher rejection than wild-type genotypes, although without changes in leukopenia incidence [123].
4.5. Other genes: the immunomodulatory pathway
The immune response and acute transplant rejection could be influenced by cytokines and growth factors; hence regulating cytokine production is a strategy to minimize rejection. Of these, the most studied in heart transplantation is the transforming growth factor- ß1 (
Polymorphisms in cytokine genes (
The nucleotide-binding oligomerization domain containing 2 (
A new gene that was studied in heart transplantation was the connective tissue growth factor (
5. Lung transplantation
Lung transplantation has become an alternative option for a variety of end-stage pulmonary diseases, including cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, bronchiolitis, or advanced chronic obstructive pulmonary disease. Hardy performed the first human lung transplantation in 1963 but the recipient survived only 18 days. In the 1980s, the introduction of Cs generated renewed interest in this area, and in 1986, Dr Joel Cooper reported the first successful single lung transplant. Since the early 1990s, more than 30,000 lung transplants have been performed around the world.
The increasing success of thoracic transplantation is largely attributable to the development of effective immunosuppressive regimens. However, it remains as one of the solid organ transplant with the worst outcomes, with less than 80% 1-year survival and less than 70% after 3 years [129]. Several reasons for these poor results have been identified; some of them are shared with other solid organ transplants, including acute rejection and drug treatment toxicity. Lung-transplanted patients are a particularly difficult group to study: Immunosuppressive treatment variations and the way they are administered (intravenous and oral) during the first weeks post transplantation make changes in blood concentration difficult to evaluate. On the other hand, patients with cystic fibrosis, one of the main groups of lung transplantation patients, present high absorption variability, leading to lower immunosuppressive drugs blood levels [130]. It should be noticed that most of the lung transplant studies have not considered this variable in their analyses, potentially leading to erroneous results. This complexity has made this group of patients less studied than other groups such as heart, liver, or kidney transplantation. However, some relevant findings have been published.
Contradictory results have been reported regarding the effect of
Initial studies have demonstrated a positive association between TAC dosing and the CYP3A5 gene polymorphism in heart and adult lung transplant patients [5, 131]. The CYP3A5 *3/*3 nonexpresser patients have a higher TAC level/dose than the CYP3A5 *1/*1 or *1/*3 enzyme expressers. Several authors have recommended that CYP3A5 expressers should initially get double dose of TAC than the administered to CYP3A5 nonexpressers [44], but this proposal should be tested thoroughly in lung transplantation before initiation in clinical practice.
No relevant information related to SNP variations and MPA concentrations in lung transplantation has been published. In a 51 patients study, we found that those patients with heterozygous at
Schoeppler et al. [134] in 65 lung transplant recipients did not find associations between several polymorphisms, in genes including
The process of chronic rejection is a pathologic process very different to acute rejection, and almost all lung transplant patients at 4 years posttransplantation have some evidence of chronic rejection [137]. Whether the chronic rejection process either directly or indirectly involves P-gp is unknown but is a possibility worth to be explored.
Budding et al. [138] found an association between complement regulatory gene
6. Liver transplantation
The concept that a single gene polymorphism could affect patient survival in a complex patient population is difficult to conceive. However, a study by Hashida et al. [142] suggested that patients who had high amounts of
In summary, there is not sufficient information to support prospective clinical trials about TAC dosing based only in these polymorphisms, but they may be good candidates for combined analyses of polymorphisms affecting the inter-individual variability in TAC pharmacokinetics among
6.1. Influence of donor versus recipient genotype
Pharmacokinetic studies in liver transplant recipients are complex due to the fact that the recipient’s intestinal genotype and the donor liver genotype may act together influencing the overall drug disposition. Several studies have evaluated the effect of donors and recipients
In view of this and many more studies published through the years, there is enough evidence to carry out studies to assess the prescription of TAC based on both the donor and the recipient
Regarding
Influence of the
Influence of ABCB1 3435C> T, 1236C> T, and 2677G> T/ A SNPs on the pharmacokinetics of Cs remains uncertain, with inconsistent results to date. Higher Cs exposure at a given dose was found in liver transplant recipients with the 3435CT heterozygous variant genotype compared with the 3435CC wild-type genotype [155]. However, other studies reported contradictory results. Jiang et al. [156] conducted a meta-analysis and they failed to demonstrate a correlation between
Respect to the combined effect of CYP3A5 and ABCB1 polymorphism in donors and recipients regarding Cs, there are no studies published to date.
No relevant studies regarding mTor inhibitors or mycophenolate pharmacogenetics in liver transplantation have been found either.
6.2. Impact of pharmacogenetics on clinical outcomes
Acute rejection: Acute cellular rejection occurs in 20 to 35% patients during the first 2 weeks after liver transplantation. The impact of SNPs of drug transporter proteins and metabolizing enzymes needs to be further analyzed, as studies about the impact of
Acute nephrotoxicity occurs in 30 to 90% patients. It is due to vasoconstriction of the afferent arterioles, a dose-dependent and reversible effect. Its etiology had been associated with relatively higher systemic exposure to CIs, but recent studies could not confirm this association, which could explain why the evidence does not support an effect of
The improvement of the outcome and survival of liver transplant patients has been associated with the occurrence of long-term chronic complication. One of them is chronic nephropathy, whose frequency is higher than in other solid organ transplants (5-year cumulative incidence of 20–37%) [160]. The main cause is local renal exposure of CNIs or their metabolites in kidney tissue, which is not necessarily associated to the CNI blood level [161]. Some studies have linked the inter-individual variability in kidney accumulation of CNIs to
Respect to
7. So, what can we actually do in the clinical practice?
After reviewing the state of the art with the most recent works published in each type of solid organ transplantation, which of all those findings does really have evidence enough to be implemented in the clinic? Currently, CYP3A5 association related to TAC dosage and metabolism is the only one classified with a level of evidence 1A by PharmGKB consortium (www.pharmgkb.org), with an actionable consequence: a dosing guideline proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) [167]. The authors of this guideline underline that “…we are not recommending whether or not to test for CYP3A5 genotype in transplant, but we are providing recommendations on how to use CYP3A5 genotype information if it is known. Since it is typical clinical practice to achieve target blood concentrations as quickly as possible, we do recommend if CYP3A5 genotype is known, to individualize initial tacrolimus treatment using CYP3A5 genotype to guide tacrolimus dosing…” and also “Thus at present, there is no definitive evidence to indicate that genotype-guided dosing for tacrolimus affects long term clinical outcomes. However there is strong evidence to support its effect on achieving target trough whole blood concentrations, which is routine clinical practice for most centers….”
This considers that patients with at least one *1 allele (genotype GA or AA) being recipients of a kidney, heart, lung, or hematopoietic stem cell transplant and liver transplant patients where the donor and the recipient genotypes are identical, who are treated with TAC, would present lower dose-adjusted trough concentrations and decreased chance of achieving target concentrations, so they recommend to increase the starting dose 1.5 to 2 times the initially recommended starting dose (weight guided), not exceeding 0.3mg/kg/day, and then to use TDM to guide following dose adjustments. The same would apply for children and adolescents. Of course, other clinical factors influencing the treatment must be considered.
The association of
7.1. And how can we have these analyses performed?
As in any field of knowledge that directly affects the improvement of health, even more if it deals with drug use, clinical applications arising from pharmacogenetics should be well regulated and should be given proper use. Both the patient and the doctor should be well informed of the scope and meaning of the data to be obtained. It is vital to know what we expect from pharmacogenetic analysis realistically, without creating false hopes.
In the last years, many private companies have developed “direct to consumer genetic analyses.” Many of them analyze tens to hundreds of genetic variants and it seems like “the more, the better,” but what can we do with that large amount of information? How do we interpret all those results? Is there enough knowledge about which is the biological meaning of each variant? And least but not last, what level of evidence does that knowledge have?
Regulatory agencies, academia, and industry agree in their worry about the alarm with regard to some proposals, which are clearly misleading for the consumer. Just a quick search on the Internet to realize that consumers can buy genotyping kits that offer scientifically implausible predictions, such as predicting vulnerability to sudden death in athletes, obesity, the ability to succeed in school, etc. The US committee SACGHS (the Secretary's Advisory Committee on Genetics, Health and Society) has issued several reports concerning this point, stressing the need to regulate this area of biomedicine to protect consumers. There are two excellent publications about Dr. J.P. Evans, illustrating the problem [168, 169].
Therefore, researchers still have a huge amount of work to do, to validate the associations proposed between certain SNPs and drug efficacy and toxicity and to discover new ones. These studies should finally be prospective and well designed and include the whole steps of the drug fate inside the organism, interactions, etc. and of course include accurate biostatistical and bioinformatic tools. The development of informatic tools to make pharmacogenetic results accessible and easy to interpret for clinicians is also a hot point. Only those associations with the highest level of evidence should be implemented in the clinical practice, as in our case
8. Conclusions
The variability in solid organ transplantation therapy outcomes cannot be predicted only by clinical factors. Pharmacogenetics will help to implement personalized medicine based on patient data, clinical parameters, and genotypes. Evidences of the role of polymorphisms in some candidate genes have been established, as
Certainly pharmacogenetics is already a reality in clinical application. To know about it and to understand its limits are unavoidable challenges that must be confronted by those who are responsible for the health of the population. Likewise, to establish the frames of cost-effectiveness for a feasible implementation is crucial for its real use in the clinical setting, in order to be used correctly and in a sustainable manner.
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