• There is a shortage of transplant organ donors in China, and the ratio of kidney transplant supply to demand in China is only 1:55. The use of immunosuppressive drugs directly affects the long-term survival of transplant recipients and grafts.
• The American Society of Transplantation, the International Society for Heart and Lung Transplantation, and the Kidney Disease Improvement Global Organization (KDIGO), among others, recommend caution and strict management when switching from narrow therapeutic index drugs, and not to switch easily.
• The immunosuppressant mescaline is a narrow therapeutic index drug, and small changes in dose or blood levels can lead to treatment failure and/or serious adverse effects that can be life-threatening, and clinical use requires strict monitoring of blood levels.

From the first successful kidney transplantation in 1954 to the present, despite rapid technological development, the ten-year survival rate of post-transplant grafts has been hovering around 60%, and the main problem still lies in immunosuppressive drugs, the use of which directly affects the success or failure of transplantation. In

2020, the Shanghai Pharmaceutical Industry Association published in the narrow therapeutic index literature compilation, which included drugs such as morte-macrolimus in the narrow therapeutic index drugs and called for a cautious attitude towards the replacement of different brands of narrow therapeutic index immunosuppressive drugs such as morte-macrolimus [1]. Experts also point out that organ transplant surgeons should be particularly careful when using narrow therapeutic index drugs drugs.

If a patient is on a drug that is already very stable in control, but if he hears of a cheaper drug, he asks, "Is it time to switch?" The doctor's answer is, "You've been stable for ten years, you don't want to change the drug." Then is it possible to change the manufacturer? The doctor's answer is still, "You've been stable, and you don't want to change manufacturers. If you change your medication, you don't know the risks involved."

The use of immunosuppressants directly affects the long-term survival of transplant recipients and grafts

At this stage, about 550,000 dialysis patients need kidney transplants, yet only about 10,000 patients can be satisfied by donors each year. A hard-won organ can be used for transplantation only after it has been thoroughly examined and qualified. For the transplant recipient, the transplanted organ is precious and the transplant is equivalent to a "new life". Almost all transplant recipients are required to take immunosuppressive drugs for the rest of their lives. The efficacy and safety of post-operative immunosuppressive drugs and their proper use are related to the long-term survival of the transplant recipient and the graft, therefore, the scientific and reasonable use of immunosuppressive drugs is required. If graft failure occurs after transplantation due to improper adjustment of immunosuppressive agents, it will be a heavy blow to the patient, his family, and the whole society, and the resulting huge burden of medical expenses should not be underestimated.

For renal transplant recipients, postoperative immunosuppression is mostly a triplet of basic medications, including morte-macrolimus, calcium-modulated neurophosphatase inhibitors, and glucocorticoids [2]. In the United States, 92.4% of organ transplant patients are on an immunosuppressive regimen that includes morte-macrolimus.

The first mortifamolates were approved in China in 1997 for the prevention of organ rejection in patients receiving allogeneic kidney transplants and have accompanied more than 160,000 patients after liver and kidney organ transplantation.

Transplantation anti-rejection basic immunosuppressive drug morte-mescaline is a narrow therapeutic index drug

The American medical community as well as the European Transplantation Society have recommended morte-mescaline to be included in the narrow therapeutic index drug list [3,4], and Canada has included morte-mescaline in this list [5]. In addition, the European Transplantation Society considers morte-mescaline as a narrow therapeutic index drug, along with cyclosporine, tacrolimus, sirolimus and everolimus. Classified by the World Health Organization's ATC code into 31 categories, there are 6 immunosuppressive drugs, including mortifamolates. Chinese scholars published academic articles in 2018 morte-macrolimus esters are also listed as NTIDs [6]. 2020 Shanghai Pharmaceutical Industry Association included morte-macrolimus esters and other drugs in the narrow therapeutic index drugs [1].

Authoritative domestic and international guidelines and consensus agree that therapeutic drug concentration monitoring should be performed for morte-mescaline: the 2008 Rome consensus [7] addresses the problem of large inter-individual variation in morte-mescaline drugs and calls for good blood concentration monitoring for some specific patients when using this drug. In addition, the KDIGO guidelines [8] and the Chinese guidelines for immunosuppressive therapy in kidney transplantation recommend morte-mescaline plasma concentration monitoring in transplant patients [9].

Mortimerate concentration is closely related to efficacy and safety: the Rome consensus recommends a therapeutic window of 30-60 mg-h/L for morte-mescaline [7], beyond which the risk of adverse effects such as anemia, leukopenia, morte-mescaline-associated diarrhea, viral infection, and acute rejection increases with each 1 mg/L increase in morte-mescaline plasma concentration. Therefore, the clinical use of morte-mescaline requires strict blood level control. Relevant guidelines from the

International Association recommend that careful substitution should be made between different brands of immunosuppressive agents

Drug substitution may appear to save money, but due to the potential for adverse prognosis and increased costs for additional concentration monitoring associated with substitution. Interindividual variation in immunosuppressant exposure can lead to serious consequences, including an increased incidence of acute exclusion and graft loss, and substitution between immunosuppressive agents may amplify this causal relationship. Patient medical adherence is associated with drug brand and patient trust, and poor adherence may lead to an increased risk of rejection due to inadequate immunosuppression.

Organ transplant recipients are taking multiple medications including immunosuppressants at the same time, and the immunosuppressive regimen has been determined to stabilize the recipient with medications and doses after individual treatment and monitoring after surgery, in which case this stability would be disrupted if medication switching between each other is performed. Therefore, different trade name drugs cannot be easily switched without the potential for increased treatment risk and monitoring costs.

For this reason, the American Society for Transplantation [10], the International Society for Heart and Lung Transplantation [11], and KDIGO [12], among others, have stated that caution and strict management should be exercised when switching immunosuppressive drugs and that drug switching should not be done lightly.

Mortimecrolate brand switching should not lose sight of this, and real cases show that patients' disease states are not maintained stable after switching

A Japanese study in 2018 showed that after switching five transplant patients who were using the original morte-mecrolate drug to generic morte-mecrolate, unstable blood concentration levels occurred in four cases, and in one case, the lower post-conversion blood levels after conversion may have led to rejection [6]. Therefore, brand switching of medical morte-malcophenolate must be done with caution.

Mortimefloxyprost is a narrow therapeutic index drug and a special drug for a special patient population, both of which determine that causing its improper replacement may lead to more serious clinical consequences. Therefore, it is important to have very good monitoring of mortyl mescaline and not to replace brands easily in patients using mortyl mescaline to reduce the risk of graft failure.

References:

[1] Compendium of Literature on Narrow Therapeutic Window Drugs Shanghai Medicine 2020, Vol. 41 Supplement-2

[2] Technical Specification for Clinical Application of Immunosuppressants in Organ Transplantation (2019 Edition). Organ Transplantation, 2019, 010(003):213-226.

[3] Pharmacometric Approach To Define Narrow Therapeutic Index (NTI) Drugs & Evaluate Bioequivalence (BE) Criteria for NTI Drugs (https://www.fda.gov/media/108490/download)

[4] Teun van Gelder et al. Transpl Int. 2011 Dec;24(12):1135-41.

[ 5] https://go.drugbank.com/categories/DBCAT003972

[6] Li X X , et al. FroNTIDsers in Pharmacology, 2018, 9.

[7] Y. Le Meur et al. Transplantation Reviews 25 (2011) 58-64.

[8] KDIGO Transplant Work Group. American Journal of Transplantation 2009; 9 (Suppl 3): S1-S157.

[9] Shi B.Y., et al. Organ Transplantation, 2016, 7(5):327-331.

[10] Rita R. Allowaya, et al. American Journal of Transplantation. 2003; 3: 1211-1215.

[11] Patricia A. The Journal of Heart and Lung Transplantation. 2009 Jul: 655-660.

[12] Bertram L. Kasiske, et al. Kidney International (2010) 77, 299-311.