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Xu X, Mao X, Liu B, Sun Y, Cheng X, Wang X, Mao H. Analysis of Sirolimus Blood Concentration and Influencing Factors in Pediatric Patients: Implications for Individualized Drug Therapy. Drugs R D 2025; 25:79-88. [PMID: 40214962 PMCID: PMC12011663 DOI: 10.1007/s40268-025-00506-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND AND OBJECTIVE The purpose of this study is to investigate the status of blood concentration of sirolimus (SRL), explore the factors influencing SRL drug blood concentration, and provide guidance for the appropriate utilization of clinical medications. METHODS A single-center retrospective cohort study encompassed 1535 blood drug concentration observations obtained from 249 children from August 2018 to June 2023. Participants were categorized into four groups (A, B, C, and D) on the basis of their blood concentration levels at various time intervals. The analysis focused on identifying the factors that influenced blood concentration in the short- and long-term posttreatment. The primary endpoint was factors affecting the sirolimus blood concentration. The effect of physiopathological indicators on the corrected blood drug concentration (C/D value) was analyzed to avoid the effect of differences in the dose of SRL used in patients on SRL blood concentrations. The multiple linear regression model was used to examine the impact of factors influencing pharmacokinetics and pharmacodynamics on the C/D. RESULTS Analysis of SRL blood concentration monitoring indicated that a majority (60.43%) of patients demonstrated a trough sirolimus concentration (C0) below the level of the recommended threshold of 5 ng/mL, while approximately 17.7% of patients exceeded 15 ng/mL. The results indicated a noteworthy association between weight and body surface area (BSA) and the C/D of SRL in groups A, B, and D (P < 0.05). Additionally, aspartate transaminase (AST), alanine aminotransferase (ALT), and albumin (ALB) in group A; ALB in group B; and platelet count (PLT) in group C demonstrated a statistically significant correlation with the C/D of SRL (P < 0.05). CONCLUSIONS Clinicians should optimize medication plans by considering the child's weight, BSA, ALT, AST, PLT, ALB, and relevant factors. These findings may serve as a valuable resource for clinicians.
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Affiliation(s)
- Xiaolin Xu
- Department of Immunology, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
- School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xueting Mao
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
- Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China
| | - Bo Liu
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
- Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yixin Sun
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Xiaoling Cheng
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Xiaoling Wang
- Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
| | - Huawei Mao
- Department of Immunology, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
- Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Key Laboratory for Genetics of Birth Defects, Beijing, 100045, China.
- Department of Nephrology and Rheumatology, Children's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hospital of Beijing Children's Hospital, Xinjiang, 830000, China.
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Park YA, Park J, Yee J, Gwak HS. Effects of CYP3A5 Genetic Polymorphisms on the Weight-adjusted through Concentration of Sirolimus in Renal Transplant Recipients: A Systematic Review and Meta-analysis. Curr Pharm Des 2024; 30:3108-3115. [PMID: 39171589 DOI: 10.2174/0113816128324199240730093415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND Sirolimus, one of the immunosuppressive drugs administered to renal transplant recipients, is metabolized by cytochrome P450 (CYP) 3A5. Accordingly, CYP3A5 polymorphism is a genetic factor affecting sirolimus pharmacokinetics (PK). Therefore, we conducted a systematic review and meta-analysis on the association between sirolimus PK and CYP3A5*3 polymorphism. METHODS We searched for studies published up to 13 June 2024 from PubMed, Embase, Cochrane Library, and Web of Science. We reviewed studies on the relationship between CYP3A5*3 polymorphism and weightadjusted trough concentration/dose (C0 /D) ratio and dosage of sirolimus in renal transplant recipients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluated mean differences (MDs) and 95% confidence intervals (CIs). RESULTS A total of seven studies were included. The weight-adjusted C0 /D ratio of sirolimus was significantly higher in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD 95.27 ng/mL per mg/kg; 95% CI: 58.06, 132.47; I2 = 74%; p < 0.00001). Also, the weight-adjusted dosage of sirolimus was significantly lower in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD -2.60 × 10-3 mg/kg; 95% CI: -4.52, -0.69; I2 = 44%; p = 0.008). CONCLUSION Our meta-analysis showed a significant effect for the CYP3A5*3 genotype on weight-adjusted C0 /D ratio and dosage of sirolimus in adult renal transplant recipients.
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Affiliation(s)
- Yoon-A Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Juyeong Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Jeong Yee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, South Korea
| | - Hye Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
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A mixed blessing for liver transplantation patients - Rapamycin. Hepatobiliary Pancreat Dis Int 2023; 22:14-21. [PMID: 36328894 DOI: 10.1016/j.hbpd.2022.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/14/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.
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Gao C, Peng F, Xie X, Peng L. The Relationship Between Blood Interleukin-10 and Cardiovascular Mortality and All-Cause Mortality After Kidney Transplantation. Risk Manag Healthc Policy 2021; 14:1481-1489. [PMID: 33883954 PMCID: PMC8053705 DOI: 10.2147/rmhp.s309764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/29/2021] [Indexed: 11/23/2022] Open
Abstract
Background Circulating interleukin (IL)-10 is associated with adverse cardiovascular events in chronic kidney disease (CKD). Whether IL-10 predicts cardiovascular and all-cause mortality after kidney transplantation (KT) is unknown. Methods The association between plasma IL-10 and cardiovascular and all-cause mortality was analyzed in a prospective cohort, which included 418 stable kidney transplant recipients, at a median of 3.6 (range=1.2–8.4) years after transplantation. Multivariate Cox regression models were performed to adjusting related confounding factors. Results Median level of IL-10 in KT patient was 22.3 pg/mL. Multivariate Cox regression analysis revealed that serum levels IL-10 were significantly and independently associated with cardiovascular mortality after adjusting for age, gender, BMI, current smoker, current drinker, cause of kidney disease, systolic and diastolic BP, laboratory indexes and medication (HR=1.26, 95% CI 1.19–2.08, P-trend<0.001). The multivariate Cox analysis also suggested that serum levels IL-10 were independently associated with all-cause mortality (HR=1.25, 95% CI 1.11–1.8, P-trend=0.023) after controlling these same related confounding factors. Sensitivity and stratified analysis showed that the significant association can be affected by history of acute rejection. Conclusion Plasma IL-10 is independently and significant associated with cardiovascular and all-cause mortality after kidney transplantation. The significant association is independent of cardiovascular risk factors and other related confounding factors.
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Affiliation(s)
- Chen Gao
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Fenghua Peng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Xubiao Xie
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China
| | - Longkai Peng
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China
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Rodríguez-Jiménez C, García-Saiz M, Pérez-Tamajón L, Salido E, Torres A. Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant. Drug Metab Pers Ther 2017; 32:49-58. [PMID: 28245187 DOI: 10.1515/dmpt-2016-0040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/08/2017] [Indexed: 06/06/2023]
Abstract
BACKGROUND In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons. METHODS Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis. RESULTS CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences. CONCLUSIONS CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.
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The ABCB1 2677G>T/A polymorphism is associated with baseline blood HDL-cholesterol levels in newly diagnosed hyperlipidemic patients. Hellenic J Cardiol 2017; 59:122-126. [PMID: 28189737 DOI: 10.1016/j.hjc.2017.01.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 09/06/2016] [Indexed: 11/22/2022] Open
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Agarwal A, Prasad GVR. Post-transplant dyslipidemia: Mechanisms, diagnosis and management. World J Transplant 2016; 6:125-134. [PMID: 27011910 PMCID: PMC4801788 DOI: 10.5500/wjt.v6.i1.125] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/26/2015] [Accepted: 02/17/2016] [Indexed: 02/05/2023] Open
Abstract
Post-transplant dyslipidemia is highly prevalent and presents unique management challenges to the clinician. The two major outcomes to consider with post-transplant therapies for dyslipidemia are preserving or improving allograft function, and reducing cardiovascular risk. Although there are other cardiovascular risk factors such as graft dysfunction, hypertension, and diabetes, attention to dyslipidemia is warranted because interventions for dyslipidemia have an impact on reducing cardiac events in clinical trials specific to the transplant population. Dyslipidemia is not synonymous with hyperlipidemia. Numerous mechanisms exist for the occurrence of post-transplant dyslipidemia, including those mediated by immunosuppressive drug therapy. Statin therapy has received the most attention in all solid organ transplant recipient populations, although the effect of proper dietary advice and adjuvant pharmacological and non-pharmacological agents should not be dismissed. At all stages of treatment appropriate monitoring strategies for side effects should be implemented so that the benefits from these therapies can be achieved. Clinicians have a choice when there is a conflict between various transplant society and lipid society guidelines for therapy and targets.
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Abstract
PURPOSE OF REVIEW Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. RECENT FINDINGS Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk. SUMMARY Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.
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Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine. Int J Mol Sci 2015; 16:4281-305. [PMID: 25690039 PMCID: PMC4346957 DOI: 10.3390/ijms16024281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/04/2015] [Accepted: 02/09/2015] [Indexed: 12/25/2022] Open
Abstract
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
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