Impact of
            <i>CYP3A4/5</i>
            and
            <i>ABCB1</i>
            Polymorphisms on Tacrolimus Exposure and Response in Pediatric Primary Nephrotic Syndrome

Huang, Lingfei; Wang, Junyan; Yang, Jufei; Zhang, Huifen; Ni, Yuan; Zhu, Zhengyi; Wang, Huijuan; Gao, Peng; Wu, Yuanyuan; Mao, Jianhua; Fang, Luo

doi:10.2217/pgs-2019-0090

Cited by 16 publications

(22 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(Miyasaka et al, 2009;Hannah et al, 2016) In patients with SLE, tacrolimus can result in infections, nephrotoxicity, liver function disorders, nausea, hypertension, anemia, leukopenia, tremors, and itching. (Huang et al, 2019) Furthermore, blood concentrations of tacrolimus appear to be related to acute nephrotoxicity, neurotoxicity, diabetogenicity, and infections in the treatment of lupus nephritis. (Mok, 2017b;Chen et al, 2020) Thus, TDM of tacrolimus is important to reduce adverse effects and ensure adequate drug exposure.…”

Section: Introductionmentioning

confidence: 99%

Predicting Blood Concentration of Tacrolimus in Patients With Autoimmune Diseases Using Machine Learning Techniques Based on Real-World Evidence

Zheng

Yu²,

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Tacrolimus is a widely used immunosuppressive drug in patients with autoimmune diseases. It has a narrow therapeutic window, thus requiring therapeutic drug monitoring (TDM) to guide the clinical regimen. This study included 193 cases of tacrolimus TDM data in patients with autoimmune diseases at Southern Medical University Nanfang Hospital from June 7, 2018, to December 31, 2020. The study identified nine important variables for tacrolimus concentration using sequential forward selection, including height, tacrolimus daily dose, other immunosuppressants, low-density lipoprotein cholesterol, mean corpuscular volume, mean corpuscular hemoglobin, white blood cell count, direct bilirubin, and hematocrit. The prediction abilities of 14 models based on regression analysis or machine learning algorithms were compared. Ultimately, a prediction model of tacrolimus concentration was established through eXtreme Gradient Boosting (XGBoost) algorithm with the best predictive ability (R2 = 0.54, mean absolute error = 0.25, and root mean square error = 0.33). Then, SHapley Additive exPlanations was used to visually interpret the variable’s impacts on tacrolimus concentration. In conclusion, the XGBoost model for predicting blood concentration of tacrolimus on the basis of real-world evidence has good predictive performance, providing guidance for the adjustment of regimen in clinical practice.

show abstract

Section: Introductionmentioning

confidence: 99%

Predicting Blood Concentration of Tacrolimus in Patients With Autoimmune Diseases Using Machine Learning Techniques Based on Real-World Evidence

Zheng

Yu²,

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Meanwhile, due to the retrospective nature of the previously published study (Wang et al, 2020), some factors partly decided blood level of TAC, such as genotype of cytochrome P-450 system (CYP3A) family (Huang et al, 2020) and co-therapy medications of cost-saving agents (CYP3A inhibitors such as fluconazole, diltiazem, and Schisandra extract) prolonged TAC elimination (Zhao et al, 2016;Vanhove et al, 2017;Huang et al, 2019;Wang et al, 2021), were not involved. Furthermore, age (ontogeny) sometimes dominates the enzymatic functions (phenotype) in pediatric patients (Sun, et al, 2018), and the age-related pattern in CYP3A expression and activity is worth exploring.…”

Section: Introductionmentioning

confidence: 99%

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

et al. 2022

Self Cite

View full text Add to dashboard Cite

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown.Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5–10 ng/ml.Results: We found that 32 and 68% of samples were respectively collected early (2–180 min) and delayed (4–315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5–1, 1–2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml.Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

show abstract

“…CL/F=6.57×(WT/70) 0.75 ×1.61 CYP3A5 × (1-0.108×WZ) [7] V/F=77.6×(WT/70) [8] Where WT, CYP3A5, and WZ represents weight, recipient CYP3A5 genotype, and co-administration of WZ, respectively. For patients who were CYP3A5*3/*3, the CYP3A5 value =0; for patients with a CYP3A5*1 allele, the CYP3A5 value =1; and for patients co-administered WZ, the WZ value =1, otherwise WZ value =0.…”

Section: Modelingmentioning

confidence: 99%

“…Since 1994, tacrolimus has been approved as a prophylactic for organ rejection following a liver transplant in the United States (1). At present, in addition to preventing graft rejection during renal transplant (2), heart transplant (3), lung transplant (4), hematopoietic stem cell transplant (5) and other types of transplants, tacrolimus has also been used to treat a variety of diseases, which include systemic onset juvenile idiopathic arthritis (6), nephrotic syndrome (7), myasthenia gravis (8), ulcerative colitis (9), systemic lupus erythematosus (10), lupus nephritis (11) and autoimmune hepatitis (12). However, with a narrow treatment window and considerable pharmacokinetic variability between individuals, it is difficult to determine the optimal tacrolimus concentration within the window of treatment (13).…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation

Chen

Wang

et al. 2020

Transl Pediatr

View full text Add to dashboard Cite

Background: In order to improve the precision of treatment with tacrolimus in Chinese patients undergoing pediatric liver transplantation, the optimum initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics.Methods: Demographic data, clinical parameters, drug combinations and pharmacogenomics were integrated to build a population pharmacokinetic model using NONMEM. Additionally, Monte Carlo simulations were used to optimize the recommended initial dose.Results: Weight, patient cytochrome 450 3A (CYP3A)5 genotype, and co-administration with wuzhicapsule (WZ) were incorporated into the final model. For children with a CYP3A5*3/*3 genotype not co-administered WZ, 0.10 mg/kg/day split into two doses was recommended for patients weighing 5-17 kg, and 0.05 mg/kg/day split into two doses was recommended for patients weighing 17-60 kg. For children with a CYP3A5*1 allele not co-administered WZ, 0.25 mg/kg/day for patients weighing 5-10 kg, 0.20 mg/kg/day for patients weighing 10-17 kg, 0.15 mg/kg/day for patients weighing 17-36 kg, and 0.10 mg/kg/day for patients weighing 36-60 kg; all split into two doses was recommended. For children with a CYP3A5*3/*3 genotype co-administered WZ, 0.10 mg/kg/day for patients weighing 5-11 kg, and 0.05 mg/kg/day for patients weighing 11-60 kg; both split into two doses was recommended. For children with a CYP3A5*1 allele who were co-administered WZ, 0.20 mg/kg/day for patients weighing 5-10 kg, 0.15 mg/kg/day for patients weighing 10-22 kg, and 0.10 mg/kg/day for patients weighing 22-60 kg all split into two doses was recommended. Conclusions:The optimal initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics in Chinese patients undergoing pediatric liver transplantation.

show abstract

Impact of CYP3A4/5 and ABCB1 Polymorphisms on Tacrolimus Exposure and Response in Pediatric Primary Nephrotic Syndrome

Cited by 16 publications

References 43 publications

Predicting Blood Concentration of Tacrolimus in Patients With Autoimmune Diseases Using Machine Learning Techniques Based on Real-World Evidence

Predicting Blood Concentration of Tacrolimus in Patients With Autoimmune Diseases Using Machine Learning Techniques Based on Real-World Evidence

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation

Contact Info

Product

Resources

About