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Background: Patients with impaired renal function are at an increased risk of dehydration due to vomiting, diarrhoea or fever (so-called sick days). Temporary medication adjustment during sick days is necessary and current initiatives and information materials for patients are available. However, the knowledge, experiences and information needs of patients and informal caregivers about sick day guidance are unknown., Aim: To gain insight into the understanding of safe medication use during periods of dehydration risk in elderly patients with impaired renal function and their informal caregivers., Design and Setting: Qualitative interview study with patients with impaired renal function and unrelated informal caregivers from three community pharmacies in the Netherlands., Method: The interviews were conducted by telephone or live by two researchers in November 2020-September 2021 and audiotaped and transcribed verbatim. The coding of transcripts was performed deductively and inductively in Nvivo 12, a thematic analysis was applied., Results: In total 12 patients and 11 unrelated informal caregivers were included. Three main themes were derived from the interview guide and subthemes emerged from the transcripts. The included patients and informal caregivers had limited knowledge about medication management during sick days. In contrast to patients, informal caregivers seemed interested in a medication management protocol for sick days., Conclusion: Patients with impaired renal function and informal caregivers have little knowledge about and experience with dehydration and safe use of medication during sick days. General practitioners and pharmacists should involve the care network, including informal caregivers, when implementing sick day guidance.

Background and Purpose: Clinical decision-making (CDM) is crucial in pharmacy practice, necessitating effective teaching in undergraduate and postgraduate pharmacy education. This study aims to explore undergraduates and postgraduates' perceptions of how a new teaching model supports their CDM when addressing patient cases., Educational Activity and Setting: Implemented in a full-day CDM course for pharmacy students and a half-day course for pharmacists in the Netherlands, the model, accompanied by a learning guide, facilitated CDM in patient cases. Eight courses were conducted between September 2022 to June 2023, followed by an online survey measuring participants' agreement on how the model supported their CDM, using a 5-point Likert scale. Additionally, three open-ended questions were included to elicit learning outcomes and self-development opportunities., Findings: Of 175 invited participants, 159 (91%) completed the survey. Most agreed the teaching model supported their CDM, particularly in considering the patient's healthcare needs and context (96%), and exploring all available options (96%). Participants found the model provided a clear structure (97%), and fostered critical thinking (93%). The most frequently mentioned learning outcomes and self-development opportunities included collecting sufficient relevant information, maintaining a broad perspective, and decelerating the process to avoid premature closure., Summary: Participants agreed that the teaching model helped them to make clinical decisions. Both undergraduate and postgraduate pharmacy education could possibly benefit from the teaching model's implementation in supporting pharmacy students and pharmacists conducting CDM in pharmacy practice., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Introduction and Objective: The recent rise in acute kidney injury (AKI) incidence, with approximately 30% attributed to potentially preventable adverse drug events (ADEs), poses challenges in evaluating drug-induced AKI due to polypharmacy and other risk factors. This study seeks to consolidate knowledge on the drugs with AKI potential from four distinct sources: (i) bio(medical) peer-reviewed journals; (ii) spontaneous reporting systems (SRS); (iii) drug information databases (DIDs); and (iv) NephroTox website. By harnessing the potential of these underutilised sources, our objective is to bridge gaps and enhance the understanding of drug-induced AKI., Methods: By searching Medline, studies with lists of drugs with AKI potential established through consensus amongst medical experts were selected. A final list of 63 drugs was generated aggregating the original studies. For these 63 drugs, the AKI reporting odds ratios (RORs) using three SRS databases, the average frequency of ADEs from four different DIDs and the number of published studies identified via NephroTox was reported., Results: Drugs belonging to the antivirals, antibacterials, and non-steroidal anti-inflammatory pharmacological classes exhibit substantial consensus on AKI potential, which was also reflected in strong ROR signals, frequent to very frequent AKI-related ADEs and a high number of published studies reporting adverse kidney events as identified via NephroTox. Renin-angiotensin aldosterone system inhibitors and diuretics also display comparable signal strengths, but this can be attributed to expected haemodynamic changes. More variability is noted for proton-pump inhibitors., Conclusions: By integrating four disjointed sources of knowledge, we have created a novel, comprehensive resource on drugs with AKI potential, contributing to kidney safety improvement efforts., (© 2024. The Author(s).)

Abstract: The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Patients with impaired renal function using medication that affects glomerular filtration rate are at increased risk of developing acute kidney injury (AKI) leading to hospital admissions. The risk increases during periods of dehydration due to diarrhoea, vomiting or fever (so-called "sick days"), or high environmental temperatures (heat wave). This study aims to gain insight into the characteristics and preventability of medication-related admissions for AKI and dehydration in elderly patients., Methods: Retrospective case series study in patients aged ≥ 65 years with admission for acute kidney injury, dehydration or electrolyte imbalance related to dehydration that was defined as medication-related. General practitioner's (GP) patient records including medication history and hospital discharge letters were available. For each admission, patient and admission characteristics were collected to review the patient journey. A case-by-case assessment of preventability of hospital admissions was performed., Results: In total, 75 admissions were included. Most prevalent comorbidities were hypertension, diabetes, and known impaired renal function. Diuretics and RAS-inhibitors were the most prevalent medication combination. Eighty percent of patients experienced non-acute onset of symptoms and 60% had contacted their GP within 2 weeks prior to admission. Around 40% (n = 29) of admissions were considered potentially preventable if pharmacotherapy had been timely and adequately adjusted., Conclusion: A substantial proportion of patients admitted with AKI or dehydration experience non-acute onset of symptoms and had contacted their GP within 2 weeks prior to admission. Timely adjusting of medication in these patients could have potentially prevented a considerable number of admissions., (© 2024. The Author(s).)

The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT). This was a retrospective multicenter observational cohort study based on therapeutic drug monitoring (TDM) data from hospitalized patients treated with cotrimoxazole. We developed two population pharmacokinetic (POPPK) models: a model of trimethoprim and an integrated model with both sulfamethoxazole and N-acetyl sulfamethoxazole concentrations. Monte Carlo simulations were performed to determine the optimal dosing regimen. A total of 348 measurements from 168 patients were available. The estimated glomerular filtration rate (eGFR) and CRRT were included as covariates on the clearance of all three compounds. Cotrimoxazole TID 1,920 mg and b.i.d. 2,400 mg led to sufficient exposure for infections with P. jirovecii in patients without renal insufficiency. To reach equivalent exposure, a dose reduction of 33.3% is needed in patients with an eGFR of 10 mL/minute/1.73 m 2 and of 16.7% for an eGFR of 30 mL/minute/1.73 m 2 . N-acetyl sulfamethoxazole accumulates in patients with a reduced eGFR. CRRT increased the clearance of sulfamethoxazole, but not trimethoprim or N-acetyl sulfamethoxazole, compared with the median clearance in the population. Doubling the sulfamethoxazole dose is needed for patients on CRRT to reach equivalent exposure., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In this paper we investigate the criterion validity of forced-choice comparisons of the quality of written arguments with normative solutions. Across two studies, novices and experts assessing quality of reasoning through a forced-choice design were both able to choose arguments supporting more accurate solutions-62.2% (SE = 1%) of the time for novices and 74.4% (SE = 1%) for experts-and arguments produced by larger teams-up to 82% of the time for novices and 85% for experts-with high inter-rater reliability, namely 70.58% (95% CI = 1.18) agreement for novices and 80.98% (95% CI = 2.26) for experts. We also explored two methods for increasing efficiency. We found that the number of comparative judgments needed could be substantially reduced with little accuracy loss by leveraging transitivity and producing quality-of-reasoning assessments using an AVL tree method. Moreover, a regression model trained to predict scores based on automatically derived linguistic features of participants' judgments achieved a high correlation with the objective accuracy scores of the arguments in our dataset. Despite the inherent subjectivity involved in evaluating differing quality of reasoning, the forced-choice paradigm allows even novice raters to perform beyond chance and can provide a valid, reliable, and efficient method for producing quality-of-reasoning assessments at scale., (© 2023. The Author(s).)

Measurement of pre-dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration-time curve (AUC). However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long-term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed. In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR., Competing Interests: T.V.G., G.A.B., R.B.M., D.K., S.C., P.N., and A.D. are members of the steering committee for the IMAGINE study and receive consulting fees from CSL Behring. M.Be. received consulting fees from CSL Behring and is a shareholder. L.A.L. is employed by CSL Behring and is a shareholder. The other author declares no conflicts of interest, (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The measurement of whole blood (WB) concentrations has been the primary method for therapeutic drug monitoring of tacrolimus since its introduction in the field of organ transplantation. However, >99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes and, therefore, measuring the intralymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P-glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk., (© 2023 British Pharmacological Society.)

Medicine development for rare diseases, including inborn errors of metabolism (IEMs) is challenging. Many academic innovations fail to reach the patient, either by stranding in the translational stage or due to suboptimal patient access related to pricing or uncertain effectiveness. Expanding and solidifying the role of the academic in public-private partnerships (PPPs) may present an innovative solution to help overcome these complexities. This narrative review explores the literature on traditional and novel collaborative approaches to medicine development for rare diseases and analyzes examples of PPPs, with a specific focus on IEMs. Several academic institutions have introduced guidelines for socially responsible licensing of innovations for private development. The PPP model offers a more integrative approach toward academic involvement of medicine development. By sharing risks and rewards, failures in the translational stage can be mutually absorbed. If socially responsible terms are not included, however, high pricing can impede patient access. Therefore, we propose a framework for socially responsible PPPs aimed at medicine development for metabolic disorders. This socially responsible PPP framework could stimulate successful and accessible medicine development for IEMs as well as other rare diseases if the establishment of such collaborations includes terms securing joint data ownership and evidence generation, fast access, and socially responsible pricing., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Nonadherence to antihypertensive drugs (AHDs) is a major contributor to pseudo-resistant hypertension. The primary objective of this study was to determine the prevalence of nonadherence to AHDs among patients visiting the nephrology and vascular outpatient clinics., Methods: Patients were eligible to participate in this prospective observational study if they used at least two AHDs that could be measured with a validated UHPLC-MS/MS method and had an office blood pressure at least 140 and/or at least 90 mmHg. For resistant hypertension, included patients had to use at least three AHDs including a diuretic or four AHDs. Adherence was assessed by measuring drug concentrations in blood. The complete absence of drug in blood was defined as nonadherence. A posthoc analysis was performed to determine the influence of a having a kidney transplant on the adherence rates., Results: One hundred and forty-two patients were included of whom 66 patients fulfilled the definition of resistant hypertension. The overall adherence rate to AHDs was 78.2% ( n  = 111 patients), with the highest adherence rate for irbesartan (100%, n  = 9) and lowest adherence rate for bumetanide ( n  = 69%, n  = 13). In further analysis, only kidney transplantation could be identified as an important factor for adherence (adjusted odds ratio = 3.35; 95% confidence interval 1.23-9.09). A posthoc analysis showed that patients with a kidney transplant were more likely to be adherent to AHDs (non-KT cohort 64.0% vs. KT-cohort 85.7%, χ 2 (2) = 10.34, P  = 0.006)., Conclusion: The adherence rate to AHDs in hypertensive patients was high (78.2%) and even higher after a kidney transplant (85.7%). Furthermore, patients after kidney transplant had a lower risk of being nonadherent to AHDs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C 0 ) and abbreviated area under the curve from zero to 12 hours (AUC 0-12h ) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC 0-12h (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30-0.50, P < 0.001), Tac-C 0 (HR: 0.46, 95% CI: 0.38-0.57, P < 0.001) and MPA-AUC 0-12h at 1 year (HR: 0.80, 95% CI: 0.68-0.94, P = 0.006), as well as repeated measurements of Tac-C 0 (HR: 0.70, 95% credibility interval (CrI): 0.61-0.82, P < 0.001), and of MPA-AUC 0-12h (HR: 0.75, 95% CrI: 0.62-0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC 0-12h at 1 year would be 75-95 ng*hour/mL and a Tac-C 0 5-7 ng/mL. The Tac-AUC 0-12h predicted BPAR better than Tac-C 0 and identified KTRs with over- or underexposure despite supposedly adequate Tac-C 0 . We did not find evidence to recommend another target than the consensus range of 30-60 mg*hour/L for MPA-AUC 0-12h after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure-response relationship between mycophenolic acid 12-hour area under the curve (AUC 0-12h ) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination - long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC 0-12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC 0-12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79-0.97; P = 0.010) and 0.89 (95% CI, 0.85-0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC 0-12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure-response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three-Dimensional (3D) printing of medicines, which enables small-scale manufacturing at the point-of-care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D-printed tablet formulation at the point-of-care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D-printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D-printed tablets a randomized, an open-label, 2-period, crossover, single-dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC 0-t ) and maximum plasma concentration (C max ) ratios were within the limits of 80.00-125.00%. The manufacturing process provided reproducible 3D-printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC 0-t and C max ratios were within bioequivalence limits (AUC 0-t 90% CI: 87.28-104.14; C max 90% CI: 80.23-109.58). For the first time, we demonstrate the development of a 3D-printed tablet formulation at the point-of-care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Memory T cells are important mediators of transplant rejection but are not routinely measured before or after kidney transplantation. The aims of this study were as follows: (1) validate whether pretransplant donor-reactive memory T cells are reliable predictors of acute rejection (AR) (2) determine whether donor-reactive memory T cells can distinguish AR from other causes of transplant dysfunction., Methods: Samples from 103 consecutive kidney transplant recipients (2018-2019) were obtained pretransplantation and at time of for-cause biopsy sampling within 6 mo of transplantation. The number of donor-reactive interferon gamma (IFN-γ) and interleukin (IL)-21-producing memory T cells was analyzed by enzyme-linked immunosorbent spot (ELISPOT) assay., Results: Of the 63 patients who underwent a biopsy, 25 had a biopsy-proven acute rejection (BPAR; 22 aTCMR and 3 aAMR), 19 had a presumed rejection, and 19 had no rejection. Receiver operating characteristic analysis showed that the pretransplant IFN-γ ELISPOT assay distinguished between patients who later developed BPAR and patients who remained rejection-free (area under the curve [AUC] 0.73; sensitivity 96% and specificity 41%). Both the IFN-γ and IL-21 assays were able to discriminate BPAR from other causes of transplant dysfunction (AUC 0.81; sensitivity 87% and specificity 76% and AUC 0.81; sensitivity 93% and specificity 68%, respectively)., Conclusions: This study validates that a high number of donor-reactive memory T cells before transplantation is associated with the development of AR after transplantation. Furthermore, it demonstrates that the IFN-γ and IL-21 ELISPOT assays are able to discriminate between patients with AR and patients without AR at the time of biopsy sampling., Competing Interests: D.A.H. has received lecture and consulting fees from Astellas Pharma and Chiesi Farmaceutici SpA, as well as grant support from Astellas Pharma, Chiesi Farmaceutici SpA, and Bristol Myers-Squibb. M.C.C.v.G. received project funding from Astellas Pharma paid to the Erasmus MC and is a consultant for Sangamo Therapeutics, Inc. T.v.G. reports study grants from Astellas Pharma and Chiesi Farmaceutici SpA and honoraria for lectures or consulting from Astellas Pharma and Novartis. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Abstract: Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted., Competing Interests: F. Lemaitre received research grants from Astellas Pharma, Sandoz ,and Chiesi Pharma (Paid to his institution) and fees to attend meetings from Chiesi Pharma and Sandoz; K. Budde received Honoraria, research grants from Abbvie, Akebia, Alexion, Astellas, Bristol-Myers Squibb, Calliditas, CSL-Behring, Chiesi, Fresenius, Hexal, Hookipa, MSD Sharp & Dohme, Neovii, Novartis, Otsuka, Pfizer, Quark, Sanofi, Shire, UCB Pharma, Veloxis, Vifor, and Vitaeris Pharma; T. Van Gelder received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma (all paid to his institution); D. A. Hesselink received lecture fees and consulting fees from Astellas Pharma, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He also received grant support from Astellas Pharma, Bristol-Myers Squibb, and Chiesi Pharma (paid to his institution). S. Masuda received lecture fees from Astellas Pharma, Novartis Pharma, and Otsuka Pharmaceutical Factory. He also received consulting fees from Meiji-Seika Pharma. The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Appropriately designed clinical trials can provide the evidence needed to broadly implement therapeutic drug monitoring (TDM). In the past 30 years, some stunning successes but also some fascinating failures in demonstrating the benefits of TDM have been observed. Future TDM studies can be designed based on this experience., Methods: The manuscript is based on a combination of personal experience and published articles and discusses several aspects of the design and conduct of TDM studies., Results: Recommendations are provided to reduce the risk of protocol violations and to maximize the potential impact of a TDM study on clinical practice., Conclusions: There are lessons that can be learned from previous experience, and this article gives an overview of potential TDM study designs, endpoints, pitfalls, and perspectives., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR., Methods: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m 2 , or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia., Discussion: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR., Trial Registration: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018., (© 2022. The Author(s).)

Background: Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose., Methods: This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C 0,obs ), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C 0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C 0,pred ) were predicted., Results: Of 190 tacrolimus C 0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C 0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C 0,pred ( P = 0.89). The median absolute difference between the tacrolimus C 0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C 0,obs versus 1.6 ng/mL for C 0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C 0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL)., Conclusions: The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small., Competing Interests: D. A. Hesselink has received grant support, paid to his institution, from Astellas Pharma, Chiesi Farmaceutici SpA, and Bristol Myers-Squibb, as well as lecture and consulting fees from Astellas Pharma, Chiesi Farmaceutici SpA, Novartis Pharma, and Vifor Pharma, over the past 3 years. R. J. Keizer is a stockholder and employee of InsightRX, a precision dosing software company. T. van Gelder received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma. T. van Gelder neither has employment nor stock ownership at any of these companies, he does not have patents or patent applications. All other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical reasoning is considered a core competency for pharmacists, but there is a lack of conceptual clarity that complicates teaching and assessment. This scoping review was conducted to identify, map, and examine evidence on used cognitive processes and their conceptualization of clinical reasoning by pharmacists., Methods: In March 2021, seven databases were searched for relevant primary research studies. Included were studies that examined cognitive processes in pharmacists while addressing a clinical scenario in a pharmacy-related setting. Using descriptive analysis, study characteristics, conceptualizations, operationalizations, and key findings were mapped, summarized, and examined. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews., Results: From 2252 abstracts, 17 studies were included that examined clinical reasoning in the context of forming a diagnosis (n = 9) or determining medication appropriateness (n = 4). Most studies conceptualized clinical reasoning as a context-dependent cognitive process whereby pharmacists apply and integrate knowledge and clinical experience to interpret available clinical data. Different terms labelled pharmacists' reasoning that showed analytical and intuitive approaches to clinical scenarios, either separately or combined. Medication review studies reported a predominance of analytical reasoning. The majority of diagnosis-forming studies in primary care identified no distinct cognitive reasoning pattern when addressing self-care scenarios., Implications: This overview reflects a small but growing body of research on clinical reasoning by pharmacists. It is recommended that this competence be taught by explicating and reflecting on clinical reasoning as separate stage of the clinical decision-making process with transparent cognitive processes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cytochrome P450 3A (CYP3A) subfamily enzymes are involved in the metabolism of 40% of drugs in clinical use. Twin studies have indicated that 66% of the variability in CYP3A4 activity is hereditary. Yet, the complexity of the CYP3A locus and the lack of distinct drug metabolizer phenotypes has limited the identification and clinical application of CYP3A genetic variants compared to other Cytochrome P450 enzymes. In recent years evidence has emerged indicating that a substantial part of the missing heritability is caused by low frequency genetic variation. In this review, we outline the current pharmacogenomics knowledge of CYP3A activity and discuss potential future directions to improve our genetic knowledge and ability to explain CYP3A variability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhai, van der Lee, van Gelder and Swen.)

Background: Kidney transplant recipients with high intrapatient variability (IPV) in tacrolimus (Tac) exposure experience more rejection and reduced graft survival. To understand the underlying pathophysiology of this association, the authors investigated whether patients with high tacrolimus IPV have a more activated immune system than patients with low IPV. In addition, exposure to tacrolimus and mycophenolic acid (MPA) was studied in relation to rejection and graft survival., Methods: At the time of patient inclusion (5-7 years post-transplantation), the frequency of donor-reactive cells was determined by enzyme-linked immunosorbent assay, and the development of donor-specific anti-Human Leukocyte Antigen antibodies (DSA) was measured by Luminex Single Antigen assay. Tacrolimus IPV was retrospectively calculated between 6 and 12 months and the exposure to tacrolimus and MPA was determined between 1 and 5 years post-transplantation., Results: A total of 371 kidney transplant recipients were included in this study, of whom 56 developed a rejection episode after 12 months and 60 experienced graft failure after 5-7 years. No correlations were found between tacrolimus IPV or immunosuppression exposure and the number of donor-reactive cells after 5 years of transplantation. DSA were detected more often in patients with low exposure to both tacrolimus and MMF [4/21 (19%) versus 17/350 (4.9%), P = 0.04]. In this cohort, neither tacrolimus IPV nor low overall immunosuppression exposure was associated with a higher incidence of rejection. However, regression analysis showed that a higher tacrolimus IPV was associated with an increased incidence of graft failure (odds ratio = 1.03, P = 0.02)., Conclusions: This study verifies the relationship between high tacrolimus IPV and impaired kidney allograft survival in long-term follow-up. DSA was also found to be more prevalent in patients with subtherapeutic concentrations of tacrolimus and MPA. An increased prevalence of donor-specific alloreactivity is yet to be demonstrated in patients with high IPV., Competing Interests: D. A. Hesselink has received lecture and consulting fees from Astellas Pharma and Chiesi Farmaceutici SpA, including grant support from Astellas Pharma, Chiesi Farmaceutici SpA, and Bristol Myers-Squibb. T. van Gelder reports study grants from Astellas Pharma and Chiesi Farmaceutici SpA, including honoraria for lectures or consultations from Astellas Pharma and Novartis. The other authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)