Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation

Fukatsu, Sachio; Yano, Ikuko; Igarashi, Takayuki; Hashida, Tohru; Takayanagi, Kazunobu; Saya, Hideyuki; Üemoto, Shinji; Kiuchi, Tetsuya; Tanaka, Kōichi; Inui, Ken Ichi

doi:10.1007/s002280100331

Cited by 80 publications

(13 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the apparent clearance of tacrolimus at 3 weeks after LDLT was approximately twice that at 1 week ( Table 2). We previously reported that the total-body clearance of tacrolimus in LDLT patients was increased according to the POD because of the regeneration of grafted liver [8,9]. According to the previously estimated population pharmacokinetic parameters [8], a typical adult LDLT recipient in this study (grafted liver weight of 611 g, normal hepatic and renal function, and body weight of 67.1 kg during week 1 and 63.5 kg during week 3)…”

Section: Discussionmentioning

confidence: 63%

“…Levy et al [7] reported that a new monitoring strategy based on C 2 levels was superior to traditional C 0 monitoring for liver transplant recipients in reduction of the incidence and severity of acute rejections. Therefore, the relationship between C 0 and AUC of tacrolimus should be clarified in adult LDLT patients, because the pharmacokinetics of tacrolimus during the early post-transplantation period may fluctuate widely, according to the regeneration of grafted liver [8,9].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

Yano

Masuda

Egawa

et al. 2011

Eur J Clin Pharmacol

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

Yano

Masuda

Egawa

et al. 2011

Eur J Clin Pharmacol

View full text Add to dashboard Cite

show abstract

“…It has previously been hypothesised that high serum creatinine may be a surrogate indicator of a subclinical hepatic injury that causes altered renal blood flow 15 or some other alteration in drug metabolism related to the hepatorenal syndrome. 16 It is also possible that the impact of creatinine clearance in our model could be driven by changes in bioavailability caused by renal dysfunction. Notably, a study in rats found increased tacrolimus bioavailability in those animals with cisplatin-induced renal failure versus animals with normal renal function.…”

Section: Discussionmentioning

confidence: 99%

Predicting tacrolimus concentrations in children receiving a heart transplant using a population pharmacokinetic model

Rower

Linakis

Kumar

et al. 2017

bmjpo

View full text Add to dashboard Cite

ObjectiveImmunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual’s future concentrations.Design, setting and patientsRetrospective data from 48 children who received tacrolimus as inpatients at Primary Children’s Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant.Outcome measuresData analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset.ResultsConcentrations ranged between 1.5 and 37.7 μg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 μg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (−2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)).ConclusionsThe use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.

show abstract

“…Day posttransplant was a significant covariate towards tacrolimus where TVCl/F is 33% higher in the first nine days posttransplant compared to after day 9 which is consistent with other studies. ( 14 , 23 , 70 , 71 , 82 , 83 ) The higher TVCl/F may be due to early physiological changes such as fluid status, hepatic and kidney function and/or decreased bioavailability from dietary changes or concomitant medications. Concomitant steroid use was associated with a 23% higher tacrolimus TVCl/F most likely because steroids induce CYP3A enzymes.…”

Section: Discussionmentioning

confidence: 99%

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

et al. 2015

View full text Add to dashboard Cite

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AA) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AA have primarily evaluated the CYP3A5*3 variant; however, there are common nonfunctional variants in AA (CYP3A5*6 and CYP3A5*7) which do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AA are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AA using a development and validation cohort. Time posttransplant, steroid and antiviral use, age, CYP3A5*1, *3, *6 and *7 alleles were significant towards clearance. This study is the first to develop an AA specific genotype-guided tacrolimus dosing model to personalize therapy.

show abstract

Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation

Cited by 80 publications

References 11 publications

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

Significance of trough monitoring for tacrolimus blood concentration and calcineurin activity in adult patients undergoing primary living-donor liver transplantation

Predicting tacrolimus concentrations in children receiving a heart transplant using a population pharmacokinetic model

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

Contact Info

Product

Resources

About