PMID- 30414331
OWN - NLM
STAT- MEDLINE
DCOM- 20200207
LR  - 20210209
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 85
IP  - 3
DP  - 2019 Mar
TI  - The impact of tacrolimus exposure on extrarenal adverse effects in adult renal 
      transplant recipients.
PG  - 516-529
LID - 10.1111/bcp.13811 [doi]
AB  - AIMS: Tacrolimus has been associated with notable extrarenal adverse effects 
      (AEs), which are unpredictable and impact patient morbidity. The association 
      between model-predicted tacrolimus exposure metrics and standardized extrarenal 
      AEs in stable renal transplant recipients was investigated and a limited sampling 
      strategy (LSS) was developed to predict steady-state tacrolimus area under the 
      curve over a 12-h dosing period (AUC(ss,0-12h) ). METHODS: All recipients 
      receiving tacrolimus and mycophenolic acid >/=6 months completed a 12-h 
      cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients 
      were evaluated for the presence of individual and composite gastrointestinal, 
      neurological, and aesthetic AEs during the study visit. The associations between 
      AEs and tacrolimus exposure metrics generated from a published population 
      pharmacokinetic model were investigated using a logistic regression analysis in 
      NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the 
      same patients. RESULTS: Dose-normalized tacrolimus AUC(ss,0-12h) and apparent 
      clearance were independently associated with diarrhoea, dyspepsia, insomnia and 
      neurological AE ratio. Dose-normalized tacrolimus maximum concentration was 
      significantly correlated with skin changes and acne. No AE associations were 
      found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 
      0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root 
      mean squared prediction error < 10%), which was not well characterized using 
      trough concentrations only (root mean squared prediction error >15%). 
      CONCLUSIONS: Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE 
      ratio) were associated with tacrolimus dose normalized AUC(ss,0-12h) and 
      clearance. Skin changes and acne were associated with dose-normalized maximum 
      concentrations. To facilitate clinical implementation, a LSS was developed to 
      predict AUC(ss,0-12h) values using sparse patient data to efficiently assess 
      projected immunosuppressive exposure and potentially minimize AE manifestations.
CI  - (c) 2018 The British Pharmacological Society.
FAU - Campagne, Olivia
AU  - Campagne O
AD  - Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, 
      USA.
AD  - Faculty of Pharmacy, Universites Paris Descartes-Paris Diderot, Paris, France.
FAU - Mager, Donald E
AU  - Mager DE
AD  - Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, 
      USA.
FAU - Brazeau, Daniel
AU  - Brazeau D
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of New 
      England, Portland, ME, USA.
FAU - Venuto, Rocco C
AU  - Venuto RC
AD  - Erie County Medical Center, Division of Nephrology; Department of Medicine: 
      Nephrology Division; School of Medicine and Biomedical Sciences, University at 
      Buffalo, Buffalo, NY, USA.
FAU - Tornatore, Kathleen M
AU  - Tornatore KM
AUID- ORCID: 0000-0003-2028-4998
AD  - Erie County Medical Center, Division of Nephrology; Department of Medicine: 
      Nephrology Division; School of Medicine and Biomedical Sciences, University at 
      Buffalo, Buffalo, NY, USA.
AD  - Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, 
      Immunosuppressive Pharmacology Research Program, University at Buffalo, Buffalo, 
      NY, USA.
LA  - eng
GR  - R01 AG056392/AG/NIA NIH HHS/United States
GR  - R21 DK077325/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190104
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Immunosuppressive Agents)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
CIN - Br J Clin Pharmacol. 2020 Dec;86(12):2535. PMID: 31144343
CIN - Br J Clin Pharmacol. 2020 Dec;86(12):2536-2537. PMID: 31849089
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Area Under Curve
MH  - Cross-Sectional Studies
MH  - Dose-Response Relationship, Drug
MH  - Drug Therapy, Combination/adverse effects/methods
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology/etiology/prevention 
      & control
MH  - Female
MH  - Graft Rejection/immunology/prevention & control
MH  - Humans
MH  - Immunosuppressive Agents/administration & dosage/*adverse 
      effects/pharmacokinetics
MH  - Incidence
MH  - Kidney Transplantation/*adverse effects
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Mycophenolic Acid/administration & dosage/adverse effects/pharmacokinetics
MH  - Tacrolimus/administration & dosage/*adverse effects/pharmacokinetics
MH  - Transplant Recipients/statistics & numerical data
MH  - Young Adult
PMC - PMC6379234
OTO - NOTNLM
OT  - AUC
OT  - adverse effects
OT  - area under the curve
OT  - limited sampling
OT  - tacrolimus; pharmacokinetics
EDAT- 2018/11/11 06:00
MHDA- 2020/02/08 06:00
PMCR- 2020/03/01
CRDT- 2018/11/11 06:00
PHST- 2018/03/10 00:00 [received]
PHST- 2018/10/12 00:00 [revised]
PHST- 2018/10/24 00:00 [accepted]
PHST- 2018/11/11 06:00 [pubmed]
PHST- 2020/02/08 06:00 [medline]
PHST- 2018/11/11 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - BCP13811 [pii]
AID - 10.1111/bcp.13811 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2019 Mar;85(3):516-529. doi: 10.1111/bcp.13811. Epub 2019 
      Jan 4.