Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients

Kim, Jae Hyun; Han, Nayoung; Kim, Myeong Gyu; Kim, Young Won; Jang, Ha-Young; Yun, Hwi-yeol; Yu, Mi Yeon; Kim, In Wha; Kim, Yon Su; Oh, Jung Mi

doi:10.1038/s41598-019-47876-0

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…Hence, C57BL/6 Ubi-GFP recipients were treated daily with vehicle only (mock group) or 1mg/kg tacrolimus (T1 group) from day 0 to day 28 post-HTT (Figure 2a). Tacrolimus whole blood concentrations were measured using a liquid chromatography-mass spectrometry (LC-MS) assay at 3 hours post-dose (C3) (Figure 2b), and showed drug levels similar to those found in transplanted patients [21,22]. After 28 days, histological quantification of epithelial loss and lumen occlusion revealed a significant although heterogeneous effect of tacrolimus in reducing both parameters (Figure 2c-d).…”

Section: Tacrolimus Treatment Reduces Post-transplant Obliterative Lesions and Allows The Survival Of Donor-derived Myofibroblasts In Thementioning

confidence: 65%

The mononuclear phagocyte system contributes to fibrosis in post-transplant obliterans bronchiolitis

et al. 2020

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Bronchiolitis Obliterans Syndrome (BOS) is a fibrotic disease heavily responsible for high mortality rates after lung transplantation. Myofibroblasts are primary effectors of this fibrotic process, but their origin is still under debate. The purpose of this work was to identify the precursors of mesenchymal cells responsible for post-transplant airway fibro-obliteration.Lineage-tracing tools were used to track or deplete potential sources of myofibroblasts in the heterotopic tracheal transplantation model. Allografts were analysed by histology, confocal microscopy, flow cytometry or single-cell transcriptomic analysis. BOS explants were evaluated by histology and confocal microscopy.Myofibroblasts in the allografts were recipient-derived. Still, when recipient mice were treated with tacrolimus, we observed rare epithelial-to-mesenchymal transition phenomena and an overall increase in donor-derived myofibroblasts (p=0.0467), but the proportion of these cells remained low (7%). Hematopoietic cells, and specifically the mononuclear phagocyte system, gave rise to the majority of myofibroblasts found in occluded airways. Ablation of Cx3cR1+ cells decreased fibro-obliteration (p=0.0151) and myofibroblasts accumulation (p=0.0020). Single-cell RNA-sequencing unveiled similarities between myeloid-derived cells from allografts and both murine and human samples of lung fibrosis. Finally, myofibroblasts expressing the macrophage marker CD68 were increased in BOS explants when compared to controls (14.4% versus 8.5% p=0.0249).Recipient-derived myeloid progenitors represent a clinically-relevant source of mesenchymal cells infiltrating the airways after allogeneic transplantation. Therefore, therapies targeting the mononuclear phagocyte system could improve long-term outcomes after lung transplantation.

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Section: Tacrolimus Treatment Reduces Post-transplant Obliterative Lesions and Allows The Survival Of Donor-derived Myofibroblasts In Thementioning

confidence: 65%

The mononuclear phagocyte system contributes to fibrosis in post-transplant obliterans bronchiolitis

et al. 2020

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“…363,366,367,399 One population pharmacokinetic study did report lower MPA clearance in SLCO1B1 c.388A.G variant (SLCO1B1*1B; rs2306283, p.Asn130Asp) carriers, 377 whereas 2 others reported no effect from any of the SLCO1B1 variants c.388A.G, SLCO1B1*5 (rs4149056, c.521T.C, p.Val174Ala), SLCO1B1*15 (rs2306283, c.388A.G, p.Asn130Asp/rs4149056, c.521T.C, pVal174Ala), (rs2291073, c.226+89T.G), (rs2291075, c.597C.T, p.Phe199=), (rs2417955, 1883T.A, intronic), (rs3829306, c.-61-2168C.T), (rs4149026, 10169A.C, intronic), or (rs4149058, c.727+1260A.G) on MPA PK. 383,395 In another study, SLCO1B1*15 (rs2306283/ rs4149056) carriers displayed lower MPAG concentrations than noncarriers. 400 Regarding SLCO1B3, 2 studies reported reduced MPA exposure in SLCO1B3 c.334 G (rs4149117) carriers as compared to noncarriers, 363,381 whereas 2 other studies found no associations between SLCO1B3 variants and MPA PK.…”

Section: Pg-pk Relationshipsmentioning

confidence: 94%

“…Similarly, one population pharmacokinetic study in 65 KTR reported ABCC2 variants to affect MPA absorption and clearance, 392 whereas others found no associations between ABCC2 variants and MPA PK. [368][369][370]377,383,384,[393][394][395][396] Of note, the interpretation of associative studies on ABCC2 variants and MPA PK may be complicated in patients receiving concomitant immunosuppressive therapy with cyclosporine A, which is not uncommon in the population receiving MPA. Cyclosporine A exhibits extensive inhibition of ABCC2, which likely masks any impact of ABCC2 variants on MPA PK.…”

Section: Pg-pk Relationshipsmentioning

confidence: 99%

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Bergan¹,

Brunet²,

Hesselink³

et al. 2021

Therapeutic Drug Monitoring

133

237

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When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and

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“…The research shows that low tacrolimus dosing that does not correspond to the therapeutic range is associated with an increased risk of organ rejection [20] As the concentration of tacrolimus is closely related to graft survival [30,31], it is important to understand the relevant factors, including concomitant drug administration, which influence the variability of tacrolimus and to quantify their effects on the concentration of tacrolimus to assist in drug dosage decisions in patients [32]. M.A.…”

Section: Discussionmentioning

confidence: 99%

Analyses of AUC(0–12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus

Radzevičienė

Marquet

Maslauskienė

et al. 2020

JCM

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The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0–12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0–12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0–12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of patients receiving only tacrolimus and for 25.0–31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1–5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0–12) exposure value. This indicates good compatibility of the dosage and the AUC(0–12) method. The Bland–Altman plot demonstrated that C0 and AUC(0–12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0–12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576–0.736), p < 0.01. Moreover, AUC(0–12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0–12) might influence the results.

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Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients

Cited by 8 publications

References 47 publications

The mononuclear phagocyte system contributes to fibrosis in post-transplant obliterans bronchiolitis

The mononuclear phagocyte system contributes to fibrosis in post-transplant obliterans bronchiolitis

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Analyses of AUC(0–12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus

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