Olga Millán

Bio: Olga Millán is an academic researcher from University of Barcelona. The author has contributed to research in topics: Transplantation & Liver transplantation. The author has an hindex of 19, co-authored 48 publications receiving 1047 citations. Previous affiliations of Olga Millán include Carlos III Health Institute.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report

Abstract: 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.

Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study.

Abstract: The main goal of this study was to assess the role of mycophenolate mofetil (MMF) during interruption of highly active antiretroviral therapy (HAART). Seventeen patients with early-stage chronic HIV type 1 infection were treated with HAART for 12 months. They were then randomized (day 0) to receive MMF (HAART-MMF group, n = 9) or to continue the regimen (HAART group, n = 6) for 120 additional days. At day 120 in the HAART-MMF group, HAART was discontinued, and MMF administration was continued. The primary end point of the study was the number of individuals maintaining a plasma viral load (VL) set point of <200 copies/mL after at least 6 months off HAART. At day 120, all patients in both groups had undetectable plasma VLs. After 6 months off HAART, 5 of 9 patients in the HAART-MMF group versus 1 of 6 patients in the HAART group maintained a plasma VL of <200 copies/mL (P = 0.28). According to the ability of their plasma to inhibit cellular proliferation, patients were reclassified and divided into an inhibition group (n = 6) and a no inhibition group (n = 9). The doubling time of VL rebound was significantly higher in the inhibition group (mean +/- SE, 10.22 +/- 1.3) than in the no inhibition group (mean +/- SE, 4.6 +/- 1.6; P = 0.03). Moreover, 5 of 6 patients in the inhibition group maintained a plasma VL of <200 copies/mL versus 1 of 9 patients in the no inhibition group (P = 0.005) after 6 months off HAART. We found that combining MMF and HAART delayed VL rebound and improved control of viral replication without HAART but only when inhibition of lymphocyte proliferation was achieved.

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

Abstract: 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 comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil.

Abstract: Background In liver transplantation, mycophenolate mofetil (MMF) is habitually administered using fixed doses. We assessed whether mycophenolic acid (MPA) monitoring could be advisable in liver transplant patients. Methods In 15 liver transplant patients receiving tacrolimus, daclizumab and MMF (1 g bid, orally), we determined the 12-hour plasma MPA pharmacokinetic profile after one dose of MMF at days 6, 10, and 16, and months 3 and 6. The inhibitory capacity of serum MPA on proliferation of CEM cells, a cell line insensitive to other immunosuppressants, was also determined. Results A large interindividual variability in MPA profiles was observed at any time. Regardless of a gradual increase in individual MPA AUC and C(0) over time following transplantation, a substantial proportion of patients had these parameters below the ranges recommended in other organ transplantations throughout the study. When MPA AUC and C(0) were within the recommended ranges, CEM proliferation was inhibited by almost all serum samples, but when these pharmacokinetic parameters were below the recommended ranges, CEM proliferation was very variable and, therefore, unpredictable. No relationship between MPA pharmacokinetics and the efficacy of MMF could be established (only one patient developed rejection), probably due to the concomitant administration of tacrolimus and daclizumab. Gastrointestinal symptoms were the only adverse events with a significant relationship with MPA levels. Conclusions During the first postoperative months, exposure to MPA is low in a considerable proportion of liver transplant patients receiving MMF at a fixed dose of 1 g bid. MPA monitoring appears necessary in these patients.

Clinical Pharmacokinetics and Pharmacodynamics of Mycophenolate in Solid Organ Transplant Recipients

Abstract: This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety. Currently, two mycophenolate compounds are available, mycophenolate mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to 94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of approximately 72%. MPA binds 97–99% to serum albumin in patients with normal renal and liver function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is the major metabolite of MPA. MPAG is usually present in the plasma at 20- to 100-fold higher concentrations than MPA, but it is not pharmacologically active. At least three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is excreted into the urine via active tubular secretion and into the bile by multi-drug resistance protein 2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-mycophenolate sodium display linear pharmacokinetics. Following mycophenolate mofetil administration, MPA maximum concentration usually occurs in 1–2 hours. EC-mycophenolate sodium exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A secondary peak in the concentration-time profile of MPA, due to enterohepatic recirculation, often appears 6–12 hours after dosing. This contributes approximately 40% to the area under the plasma concentration-time curve (AUC). The mean elimination half-life of MPA ranges from 9 to 17 hours. MPA displays large between- and within-subject pharmacokinetic variability. Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentrations should be interpreted with caution in patients with severe renal impairment, liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG plasma protein binding may be altered, changing the fraction of free MPA available. Apparent oral clearance (CL/F) of total MPA appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. However, there may be little change in the MPA free concentration. Ciclosporin inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recirculation of MPA. Exposure to MPA when mycophenolate mofetil is given in combination with ciclosporin is approximately 30–40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have involved mycophenolate mofetil rather than EC-mycophenolate sodium therapy. In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1 to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus co-therapy). Patient bodyweight, serum albumin concentration and immunosuppressant co-therapy have a significant influence on CL/F. The majority of pharmacodynamic data on MPA have been obtained in patients receiving mycophenolate mofetil therapy in the first year after kidney transplantation. Low MPA AUC is associated with increased incidence of biopsy-proven acute rejection. Gastrointestinal adverse events may be dose related. Leukopenia and anaemia have been associated with high MPA AUC, trough concentration and metabolite concentrations in some, but not all, studies. High free MPA exposure has been identified as a risk factor for leukopenia in some investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30–60 mg ∙ hr/L is likely to minimise the risk of acute rejection and may reduce toxicity. IMPDH monitoring is in the early experimental stage. Individualisation of mycophenolate therapy should lead to improved patient outcomes. MPA AUC12 appears to be the most useful exposure measure for such individualisation. Limited sampling strategies and Bayesian forecasting are practical means of estimating MPA AUC12 without full concentration-time profiling. Target concentration intervention may be particularly useful in the first few months post-transplant and prior to major changes in anti-rejection therapy. In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure.

Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference.

Abstract: In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

HIV-associated chronic immune activation

Abstract: Systemic chronic immune activation is considered today as the driving force of CD4(+) T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by anti-retroviral therapy, with the extent of this residual immune activation being associated with CD4(+) T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4(+) T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation characteristic of human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to 'show AIDS the door', and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report

Abstract: 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.

Therapeutic drug monitoring of mycophenolate mofetil in transplantation.

Abstract: A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.