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Tacrolimus pharmacokinetics

Xiao Zhang, Guigao Lin, Liming Tan, Jinming Li
Tacrolimus is effective for the prevention of acute rejection, but is also highly toxic and has great intra- and inter-individual variability in transplant patients. Genetic variation and other factors influence the response of an individual to tacrolimus treatment. Therefore, even if therapeutic drug monitoring is universally applied, rejection and toxicity still occur. Although the appropriate action on pharmacogenomic variability provides a cornerstone for the precise tacrolimus prescription, at present there are many obstacles to translating it into clinical practice...
March 15, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Keiji Kurata, Kimikazu Yakushijin, Atsuo Okamura, Motohiro Yamamori, Hiroya Ichikawa, Rina Sakai, Yu Mizutani, Seiji Kakiuchi, Yoshiharu Miyata, Akihito Kitao, Shinichiro Kawamoto, Hiroshi Matsuoka, Tohru Murayama, Hironobu Minami
PURPOSE: Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation. METHODS: Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients...
March 6, 2018: Cancer Chemotherapy and Pharmacology
Pierre Marquet, Anne Bedu, Caroline Monchaud, Franck Saint-Marcoux, Jean-Philippe Rérolle, Isabelle Etienne, Nassim Kamar, Bruno Moulin, Elisabeth Cassuto, Marie Essig, Jean-Baptiste Woillard
BACKGROUND: ISBA is an online expert system, routinely used by approximately 140 transplantation centers in the world for the dose adjustment of immunosuppressive drugs in transplant patients. This system determines the drug area-under-the-curve (AUC) by PK modeling and Bayesian estimation. The purpose of this study was to analyze tacrolimus exposure after administration of its modified-release formulation (Advagraf) in kidney allograft recipients, in order to optimize its therapeutic drug monitoring...
March 2, 2018: Therapeutic Drug Monitoring
Agnieszka Prytuła, Teun van Gelder
The calcineurin inhibitor tacrolimus, cornerstone of most immunosuppressive regimens, is a drug with a narrow therapeutic window: underexposure can lead to allograft rejection and overexposure can result in an increased incidence of infections, toxicity and malignancies. Tacrolimus is metabolised in the liver and intestine by the cytochrome P450 3A (CYP3A) isoforms CYP3A4 and CYP3A5. This review focusses on the clinical aspects of tacrolimus pharmacodynamics, such as efficacy and toxicity. Factors affecting tacrolimus pharmacokinetics, including pharmacogenetics and the rationale for routine CYP3A5*1/*3 genotyping in prospective paediatric renal transplant recipients, are also reviewed...
February 26, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Benjamin Philosophe, Nicolae Leca, Patricia M West-Thielke, Timothy Horwedel, Christine Culkin-Gemmell, Kristin Kistler, Daniel R Stevens
The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers...
February 20, 2018: Journal of Clinical Pharmacology
Jean-Baptiste Woillard, Franck Saint-Marcoux, Jean Debord, Anders Åsberg
Due to a high inter-individual variability in its pharmacokinetics, tacrolimus dose individualization is mandatory. Even though the expert opinion has defined the area under the curve (AUC) as the best marker to use when performing dose adjustment of tacrolimus, most centres only use trough levels. Multiple targets have been proposed for this parameter and physicians rely largely on their personal experience when making a decision about dose adjustment. Several population pharmacokinetics models (POPPK) allowing AUC determination have been developed, but only a few are actually used in routine practice for dose individualization...
February 13, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Michael H Woodworth, Colleen S Kraft, Erika J Meredith, Aneesh K Mehta, Tiffany Wang, Yafet T Mamo, Tanvi Dhere, Kaitlin L Sitchenko, Rachel E Patzer, Rachel J Friedman-Moraco
Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 solid organ transplant patients from September 2012 - December 2016 who were taking tacrolimus at time of FMT for recurrent Clostridium difficile infection. We compared the differences in tacrolimus concentration / dose ratio (C/D ratio) three months prior to FMT vs three months after FMT...
February 15, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Fenglei Huang, Claudia Voelk, Matthias Trampisch, Lois Rowland, Armin Schultz, John P Sabo
Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, cross-over study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N=16) or tacrolimus (TAC) 0.5 mg (N=16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0...
February 10, 2018: Basic & Clinical Pharmacology & Toxicology
Motoyuki Onodera, Katsuya Endo, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Yoichi Kakuta, Kenichi Negoro, Yoshitaka Kinouchi, Tooru Shimosegawa
BACKGROUND: In the tacrolimus treatment for refractory ulcerative colitis (UC), dose adjustment is necessary because the required doses to keep appropriate drug concentrations are significantly different among individuals. Cytochrome P450 (CYP) 3A5 polymorphism affects tacrolimus blood concentrations. However, it is difficult to obtain genetic information in real clinical practice. In the present study, we investigated possible factors that may predict CYP3A5 polymorphism and proposed a dose optimization strategy based on the obtained predicting factors...
February 1, 2018: Digestion
Meng Yu, Mouze Liu, Wei Zhang, Yingzi Ming
Tacrolimus(Tac) is a first-line immunosuppressive drug used mainly after allogeneic organ transplant to reduce rejection. Tac is proved to be effective in preventing acute rejection, yet it has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics(PK) and pharmacodynamics(PD). Established pharmacogenetics(PG) discoveries are being investigated on drug absorption, metabolism, disposition, excretion and response for better clinical application. The purpose of the present review is to picture the current status of Tac PG, and discuss the relationship between its PK and PD in kidney transplantation...
January 29, 2018: Current Drug Metabolism
Yuichi Muraki, Shugo Mizuno, Kaname Nakatani, Hiroki Wakabayashi, Eiji Ishikawa, Toshimitsu Araki, Akira Taniguchi, Shuji Isaji, Masahiro Okuda
A total of 25 patients with autoimmune diseases receiving tacrolimus were screened using a peripheral blood cluster of differentiation 4+ adenosine triphosphate (ATP) activity assay (IMK assay) between October 2013 and July 2014. The autoimmune diseases of patients were as follows: Rheumatoid arthritis (n=15), lupus nephritis (n=6), ulcerative colitis (n=2) and myasthenia gravis (n=2). Patients were divided into two groups based on CYP3A5 genotype [expression of *1 allele: Expressor (EX; n=6) and non-expressor (NEX; n=19)]...
January 2018: Experimental and Therapeutic Medicine
Jae Hyun Kim, Nayoung Han, Myeong Gyu Kim, Hwi-Yeol Yun, Sunhwa Lee, Eunjin Bae, Yon Su Kim, In-Wha Kim, Jung Mi Oh
The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped...
January 26, 2018: Scientific Reports
Mario Fernández-Ruiz, Natalia Polanco, Ana García-Santiago, Raquel Muñoz, Ana M Hernández, Esther González, Verónica R Mercado, Inmaculada Fernández, José María Aguado, Manuel Praga, Amado Andrés
The medium-term impact on graft function and immunosuppressive drug pharmacokinetics of direct antiviral agents (DAAs) among hepatitis C virus (HCV)-infected kidney transplant (KT) recipients remains unclear. We compared pre- and post-treatment 12-month trajectories of estimated glomerular filtration rate (ΔeGFR) and 24-hour proteinuria (Δ24-hour proteinuria) in 49 recipients treated with DAAs (mostly sofosbuvir plus ledipasvir). Among evaluable patients, 66.7% and 100.0% had undetectable viral load by week 4 and end of therapy (EoT)...
January 22, 2018: Transplant International: Official Journal of the European Society for Organ Transplantation
Hwa-Ping Feng, Luzelena Caro, Christine M Fandozzi, Zifang Guo, Jennifer Talaty, Dennis Wolford, Deborah Panebianco, Marian Iwamoto, Joan R Butterton, Wendy W Yeh
Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4-part, open-label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once-daily EBR 50 mg/GZR 200 mg...
January 12, 2018: Journal of Clinical Pharmacology
Malek Okour, Pamala A Jacobson, Mariam A Ahmed, Ajay K Israni, Richard C Brundage
Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions...
January 12, 2018: Journal of Clinical Pharmacology
Michel Rayar, Camille Tron, Caroline Jézéquel, Jean Marie Beaurepaire, Antoine Petitcollin, Pauline Houssel-Debry, Christophe Camus, Marie Clémence Verdier, Ammar Dehlawi, Mohamed Lakéhal, Véronique Desfourneaux, Bernard Meunier, Laurent Sulpice, Eric Bellissant, Karim Boudjema, Florian Lemaitre
BACKGROUND: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high inter- and intrapatient variability leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC intrapatient variability (IPV) on graft and patient outcomes after liver transplantation. METHODS: We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations...
January 8, 2018: Transplantation
Katharina Schutte-Nutgen, Gerold Tholking, Barbara Suwelack, Stefan Reuter
The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose)...
December 31, 2017: Current Drug Metabolism
Hitesh S Purohit, Niraj S Trasi, Dajun D Sun, Edwin C Y Chow, Hong Wen, Xinyuan Zhang, Yi Gao, Lynne S Taylor
Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or upon storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both USP and non-compendial dissolution tests with different dissolution media and volumes...
December 28, 2017: Journal of Pharmaceutical Sciences
Divya Dheer, Jyoti, Prem N Gupta, Ravi Shankar
From the current trends, tacrolimus (TAC) has become an important therapeutic option for the optimal individualization of immunosuppressive therapy especially in case of transplant recipients. TAC is used most frequently in comparison to other immunosuppressants because it offers better safety profile with increased long-term survival in patients especially in children and adolescents. This drug has developed an immense interest in the research field owing to its potential pharmacological scope but due to its poor water solubility, need of concomitant steroids and higher incidences of nephrotoxicity, there comes a need for future research to minimize such limitations and decipher maximum use of the drug...
December 22, 2017: European Journal of Pharmaceutical Sciences
Taek Hwan Shin, Myoung Jin Ho, Sung Rae Kim, Sung Hyun Im, Chang Hyun Kim, Sangkil Lee, Myung Joo Kang, Young Wook Choi
A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media...
December 22, 2017: International Journal of Biological Macromolecules
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