Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration–time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells–regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

ABSTRACT:Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil is primarily metabolized by glucuronidation. The nature of UDP-glucuronosyltransferases (UGTs) involved in this pathway is still debated. The present study aimed at identifying unambiguously the UGT isoforms involved in the production of MPA-phenyl-glucuronide (MPAG) and MPA-acylglucuronide (AcMPAG). A liquid chromatography-tandem mass spectrometry method allowing the identification and determination of the metabolites of mycophenolic acid was developed. The metabolites were characterized in urine and plasma samples from renal transplant patients under mycophenolate mofetil therapy and in vitro after incubation of mycophenolic acid with human liver (HLM), kidney (HKM), or intestinal microsomes (HIM). The UGT isoforms involved in MPAG or AcMPAG production were investigated using induced rat liver microsomes, heterologously expressed UGT (Supersomes), and chemical-selective inhibition of HLM, HKM, and HIM. The three microsomal preparations produced MPAG, AcMPAG, and two mycophenolate glucosides. Among the 10 UGT isoforms tested, UGT 1A9 was the most efficient for MPAG synthesis with a K m of 0.16 mM, close to that observed for HLM (0.18 mM). According to the chemical inhibition experiments, UGT 1A9 is apparently responsible for 55%, 75%, and 50% of MPAG production by the liver, kidney, and intestinal mucosa, respectively. Although UGT 2B7 was the only isoform producing AcMPAG in a significant amount, the selective inhibitor azidothymidine only moderately reduced this production (approximately ؊25%). In conclusion, UGT 1A9 and 2B7 were clearly identified as the main UGT isoforms involved in mycophenolic acid glucuronidation, presumably due to their high hepatic and renal expression.

What is already known about this subject • Several studies have shown that inappropriate medications induce adverse health outcomes in the elderly. • The hypothesis of Beers et al. that these inappropriate medications increase the likelihood of adverse drug reactions is debated and checked in patients admitted to hospital. What this study adds • Inappropriate medications do not seem to be the major cause of adverse drug reactions in the elderly. • More than the inappropriateness of the drugs themselves, it is the inappropriate use of drugs that is to be tackled when treating the elderly. • The main preventable factor is the reduction in the number of drugs given. Aim To study the occurrence of adverse drug reactions (ADRs) linked to inappropriate medication (IM) use in elderly people admitted to an acute medical geriatric unit. Methods All the elderly people aged ≥ 70 years admitted to the acute medical geriatric unit of Limoges University hospital (France) over a 49‐month period were included, whatever their medical condition. For all the patients, clinical pharmacologists listed the medications given before admission and identified the possible ADRs. The appropriateness of these medications and the causal relationship between drugs (either appropriate or not) and ADRs were evaluated. Results Two thousand and eighteen patients were included. The number of drugs taken was 7.3 ± 3.0 in the patients with ADRs and 6.0 ± 3.0 in those without ADRs (P < 0.0001). Sixty‐six percent of the patients were given at least one IM prior to admission. ADR prevalence was 20.4% among the 1331 patients using IMs and 16.4% among those using only appropriate drugs (P < 0.03). In only 79 of the 1331 IM users (5.9%) were ADRs directly attributable to IMs. The IMs most often involved in patients with ADRs were: anticholinergic antidepressants, cerebral vasodilators, long‐acting benzodiazepines and concomitant use of two or more psychotropic drugs from the same therapeutic class. Using multivariate analysis, after adjusting for confounding factors, IM use was not associated with a significant increased risk of ADRs (odds ratio 1.0, 95% confidence interval 0.8, 1.3). Conclusion Besides a reduction in the number of drugs given to the elderly, a good prescription should involve a reduction in the proportion of IMs and should take into consideration the frailty of these patients.

The goal of this study was to determine the roles of the organic anion-transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the immunosuppressive drug mycophenolate mofetil (MMF). Using OATP-transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not MPA, significantly accumulated in cells expressing OATP1B3 or OATP1B1 (P< 0.05). The pharmacokinetics of both MPA and MPAG were significantly influenced by the OATP1B3 polymorphism 334T>G/699G>A in 70 renal transplant patients receiving combination treatment of MMF with either tacrolimus or sirolimus, but not in 115 patients receiving MMF and cyclosporine. The decrease in dose-normalized (dn) MPA exposure and the concomitant increase in the MPAG/MPA metabolic ratio are consistent with reduced enterohepatic cycling in patients carrying the OATP1B3 334G-699A haplotype. Further studies demonstrated that this variant of OATP1B3 exhibited a reduced maximal velocity (V(max)) in transfected HEK cells, thereby providing functional evidence to support our clinical findings.