OBJECTIVES:Accurate estimation of glomerular filtration rate (eGFR) is necessary for early detection and staging of chronic kidney disease (CKD), risk stratification, and guiding therapies that prevent complications and progression to advanced CKD. This study aimed to evaluate the performance of different eGFR equations in a large national cohort. METHODS:This multicentre study was conducted at six university hospitals in Norway. Retrospective data from patient's medical records from 2005 to 2024 for 5,552 adults and 2,981 children were used to validate several creatinine-based eGFR equations against measured GFR (mGFR) by Iohexol clearance. Performance was assessed using median bias and P30 accuracy (proportion of eGFR within ±30 % of mGFR). RESULTS:The European Kidney Function Consortium (EKFC) creatinine-based eGFR equation outperformed the CKD-EPI 2009 and 2021, the Modification of Diet in Renal Disease (MDRD) in adults, the Schwarts bedside and the CKiD U25 equations in children ≥2 years and was comparable to the Lund-Malmö equation (LM) in adults. Both CKD-EPI equations had the lowest accuracy and were overestimating GFR in young people (<25 years) and elderly patients (≥65 years). Replacing the CKD-EPI equations with the EKFC equation will result in lower eGFR values and a higher prevalence of CKD stages 3-5. Replacing the LM and MDRD with the EKFC equation will result in higher eGFR and a lower prevalence of CKD stages 3-5. CONCLUSIONS:The EKFC equation was overall the best suited creatinine-based eGFR equation for this Norwegian population from 2 years of age. Clinicians should be informed about clinical implications of shifting from other equations to the EKFC equation.

ABSTRACT Variability in low‐density lipoprotein cholesterol (LDL‐C) has emerged as a potential independent cardiovascular risk factor, but the impact of short‐term discontinuation of statins on LDL‐C remains to be defined. Furthermore, the relationship between individual statin metabolites and changes in LDL‐C has not yet been examined. The present study aimed to investigate changes in LDL‐C concentrations during a four‐day discontinuation of atorvastatin therapy and to examine correlations between the half‐lives of atorvastatin metabolites and LDL‐C concentrations. This pharmacokinetic intervention study included 60 adults with confirmed adherence to atorvastatin, using doses of 20 mg (N = 20), 40 mg (N = 20), or 80 mg (N = 20) at study start. Atorvastatin was then discontinued, and blood samples were collected from day zero to day four. We assessed daily concentrations of LDL‐C and of atorvastatin with its metabolites by liquid chromatography–tandem mass spectrometry. The mean (SD) LDL‐C at baseline was 1.84 (0.6) mmol/L. LDL‐C increased on average by 0.50 mmol/L (27%) from day zero to day four. The increase in LDL‐C was significant already 48 h after the last statin intake and was affected by individual variation in baseline concentrations and the slope of the daily increase. A moderate correlation was found between differences in LDL‐C concentrations and the half‐lives of hydroxylated atorvastatin metabolites. In conclusion, 4 days without atorvastatin resulted in an almost 30% increase in LDL‐C concentrations, and the increase was significant already after the first omitted dose. The half‐lives of hydroxylated atorvastatin metabolites showed a moderate correlation with the increase in LDL‐C concentrations.

Everolimus is used in the treatment of patients with advanced neuroendocrine tumors (NET) and is administered at fixed doses despite known interpatient pharmacokinetic variability. This may affect both efficacy and tolerability. We wanted to investigate the relationship between prescribed dose, blood trough concentrations ( C trough ), and toxicity in NET patients receiving everolimus in routine clinical practice. In this prospective observational study NET patients were treated with everolimus, mostly as third‐ or fourth‐line therapy. Dose was adjusted according to adverse effects and tumor response. Concentrations ( C trough ) of everolimus were measured at each routine follow‐up and correlated to dose and cumulative adverse event (cAE) scores. Associations were evaluated using linear and generalized linear mixed models which accounted for repeated measurements within patients and varying dose regimens over time. Thirty‐six patients were included. Everolimus dose was a significant predictor of C trough ( p < .001), but considerable interindividual variability was observed. Median C trough levels increased with dose: 3.9, 5.1, 7.4, and 16.4 ng/mL for 2.5, 5.0, 7.5, and 10.0 mg per day, respectively. Considerable overlap in blood concentration was observed across dose groups; patients receiving 2.5 mg reached levels as high as 8.6 ng/mL, while those on 5 mg exhibited a wide range from 1.1 to 21.2 ng/mL. C trough ≥ 6.0 ng/mL was associated with increased toxicity ( p = .03), whereas nominal dose was not a reliable independent predictor of adverse events. Although median blood concentrations increased with higher doses, there was considerable variation between patients, resulting in overlapping concentration ranges across all dose groups. This indicates that fixed‐dose regimens may not reliably predict systemic drug exposure. Everolimus blood concentrations were superior to dose levels in predicting adverse events. Therapeutic drug monitoring and individualized dose adjustment may improve the balance between efficacy and toxicity in NET patients treated with everolimus.

Patients with familial hypercholesterolemia (FH) have an increased risk of premature cardiovascular disease due to inherited elevated levels of low-density lipoprotein cholesterol (LDL-C). Cholesterol-lowering medications are crucial for optimal LDL-C control in these patients. However, self-perceived side effects remain a potential barrier for medication adherence. Knowledge of factors associated with self-perceived side effects may be useful to improve treatment and follow-up care. To compare clinical and psychosocial characteristics of patients with FH, with and without self-perceived side effects to cholesterol-lowering treatment. A group of 929 adult outpatients with confirmed genetic FH from a regional treatment register in Norway were invited to an observational study. The participants completed a digital questionnaire covering self-perceived side effects (any symptoms), use of cholesterol-lowering medications, musculoskeletal disorders or rheumatic diseases, and muscular symptoms and pain treatment. We collected data on FH diagnosis, comorbidities, and biomarkers in blood from the last consultation listed in the treatment register. Mean age was 52 (SD 15) years, and 57% were women. Thirty-eight (15%) out of 255 participants reported self-perceived side effects to cholesterol-lowering treatment. Patients with self-perceived side effects were more frequently living alone (26% vs. 12%, p=0.025) and had slightly higher LDL-C than those without side effects, whereas no differences in creatine kinase or alanine transaminase were observed. Patients with self-perceived side effects had a higher frequency of musculoskeletal disorders or rheumatic diseases (58% vs. 37%, p<0.001) than those with no side effects (Table 1). They also reported more muscle symptoms the last month in general, and specifically from the hips, thighs, calves, shoulders, and neck. Median pain intensity the last 24-hours was significantly higher (3 vs. 1 on a 0 [no] to 10 [worst imaginable] numeric rating scale, p<0.001) in patients with side effects, and 58% currently used no pain medication (Table 2). Patients with FH and self-perceived side effects frequently have musculoskeletal disorders or rheumatic diseases and clinically significant pain without treatment. Our study suggests that a considerable proportion of patients misattribute muscle symptoms and pain to their cholesterol-lowering medications. Future work should focus on musculoskeletal- and rheumatic conditions as an alternative explanation for self-perceived side effects to cholesterol-lowering medication.

Multiple myeloma is characterized by malignant cells which produce high amounts of monoclonal immunoglobulin. Myeloma cells are, therefore, dependent on effective protein degradation. Proteasomal protein degradation is targeted by proteasome inhibitors in routine care. Autophagic protein degradation is currently not targeted in myeloma treatment. This Phase I trial showed that the combination of the proteasome inhibitor carfilzomib and the autophagy inhibitor hydroxychloroquine was well tolerated in patients with relapsed/refractory multiple myeloma. Adverse events were mostly Grades 1 and 2. An overall response rate of 44% indicates a meaningful clinical efficacy of this combination. Trial Registration: The study was registered at clinicaltrials.gov # NCT04163107.

BACKGROUND:The evidence supporting beta-blocker therapy after myocardial infarction was established before the introduction of modern coronary reperfusion therapy and secondary prevention strategies. METHODS:In an open-label, randomized trial with blinded end-point evaluation, conducted in Denmark and Norway, we assigned patients who had had a myocardial infarction and who had a left ventricular ejection fraction of at least 40%, in a 1:1 ratio, to receive long-term beta-blocker therapy within 14 days after the event or no beta-blocker therapy. The primary end point was a composite of death from any cause or major adverse cardiovascular events (new myocardial infarction, unplanned coronary revascularization, ischemic stroke, heart failure, or malignant ventricular arrhythmias). RESULTS:A total of 5574 patients underwent randomization and were included in the main analyses - 2783 in the beta-blocker group and 2791 in the no-beta-blocker group. After a median follow-up of 3.5 years (interquartile range, 2.2 to 4.6), a primary end-point event had occurred in 394 patients (14.2%) in the beta-blocker group and in 454 patients (16.3%) in the no-beta-blocker group (hazard ratio, 0.85; 95% confidence interval [CI], 0.75 to 0.98; P = 0.03). Death from any cause occurred in 4.2% of the patients in the beta-blocker group and in 4.4% of those in the no-beta-blocker group; myocardial infarction occurred in 5.0% and 6.7%, respectively (hazard ratio, 0.73; 95% CI, 0.59 to 0.92), unplanned coronary revascularization in 3.9% and 3.9%, ischemic stroke in 1.6% and 1.3%, heart failure in 1.5% and 1.9%, and malignant ventricular arrhythmias in 0.5% and 0.6%. No apparent differences in safety outcomes were observed between the groups. CONCLUSIONS:Among patients with a myocardial infarction and a left ventricular ejection fraction of at least 40%, beta-blocker therapy led to a lower risk of death or major adverse cardiovascular events than no beta-blocker therapy. (Funded by the Health South-East research program in Norway and others; BETAMI-DANBLOCK ClinicalTrials.gov numbers, NCT03646357 and NCT03778554.).

Background and aims An accurate and feasible method to assess adherence to statin therapy is needed. We developed a novel blood test to identify reduced statin adherence and compared statin adherence determined by a single blood test to pharmacy registry data. Methods In a retrospective cohort study of patients prescribed atorvastatin or simvastatin during hospitalization for a coronary heart disease event, a single blood sample was collected median 18 months later. Patients were unaware of the forthcoming statin analyses. Statin adherence was determined by drug concentration measurements using liquid chromatography mass spectrometry and the Norwegian Prescription Database by gaps in statin dispenses. Results Out of 451 patients, 9 % (n = 39) had reduced adherence (≥2 doses omitted) determined by the blood test. Among those classified as adherent by the blood test, only 0.7 % (n = 3) had a treatment gap ≥90 days during the preceding three months, whereas 28 % (n = 115) during the entire follow-up period (median 5.9 years). Of 39 patients classified with reduced adherence by the blood test, 28 % (n = 11) had treatment gaps ≥90 days during the preceding three months, and 66 % (n = 26) during the entire study period. Patients classified with reduced adherence by the blood test, but not registry data, had numerically more coronary events prior to the index event compared to adherent patients. Conclusions In coronary outpatients, high adherence to statin treatment measured by a novel blood test aligns with adherence assessed by pharmacy registry. The blood test emerges as a promising tool for enhancing lipid management in clinical practice.

INTRODUCTION:Early and lifelong treatment is essential in patients with familial hypercholesterolaemia (FH) due to genetically elevated low-density lipoprotein cholesterol (LDL-C) from the first years of life. In women with FH, lipid-lowering treatment is interrupted during childbearing years due to contraindication of the medication during conception, pregnancy and breastfeeding. However, little is known about the impact of breastfeeding on lipid profile and other risk markers for atherosclerotic cardiovascular disease (ASCVD) in women with FH compared with women without hypercholesterolaemia, and to what extent statins transfer into breast milk.We aim to investigate (1) the association between breastfeeding and serum lipid profile in women with and without FH; (2) the association between breastfeeding and other ASCVD risk markers in women with and without FH and (3) the concentration of statins in breast milk of women with FH. METHODS AND ANALYSIS:FH-FEMINA is a prospective study aiming to include 50 women with FH in Norway, the Netherlands and the Czech Republic. Additionally, 20 women without hypercholesterolaemia will be enrolled as a control group in Norway. Women will be included at the first study visit in gestational week 36, and follow-up visits will be scheduled at 2-4 weeks, and at 3, 6, 9 and 12 months postpartum. Information on lifestyle factors, treatment history and current and previous pregnancies will be collected. At each visit, a non-fasting blood sample, breast milk sample and information on diet, body mass index and blood pressure will be collected. Additional blood samples will be collected from the women with FH at 2, 4, 5, 7, 8, 10 and 11 months postpartum for as long as they are breastfeeding. At (re-)initiation of statin treatment, breast milk samples from women with FH will be collected for drug concentration measurements. ETHICS AND DISSEMINATION:Ethical approval will be obtained prior to study start in all three countries. Participants will be informed about the study and receive ample time to ask questions before the informed consent form is signed. The findings from this study will be disseminated to healthcare professionals, researchers and patients via peer-reviewed scientific article(s), conferences, patient organisations and social media. TRIAL REGISTRATION NUMBER:NCT05367310.

Vethe, Nils Tore PhD; Andersen, Anders Mikal BSc; Gedde-Dahl, Tobias MD, PhD; Büchner, Jochen MD, PhD; Bergan, Stein PhD Author Information

Background: Home-based hospital services are becoming increasingly popular, and the addition of remote outpatient appointments after kidney transplantation facilitates more practical and closer follow-up. In this context, finger-prick self-sampling is an important aspect of monitoring of immunosuppressants and biomarkers. Nevertheless, several issues must be addressed to ensure the feasibility and quality when implementing microsampling in clinical practice. We summarize our experiences and opinions in this field. Methods: This article is based on the authors' experience regarding the laboratory and clinical implementation of finger-prick self-sampling in kidney transplant recipients. The referenced literature is related to the authors' knowledge in this field. Results: We present considerations for the selection of relevant analytes, key characteristics of selected volumetric sampling tools (Mitra and Capitainer), and the associated sampling pitfalls. In addition, we address the requirements for patients performing finger-prick sampling, appropriate design of methods and workflow, critical points for validation, and aspects related to logistics and digital solutions. Conclusions: Volumetric finger-prick self-sampling is suitable for monitoring immunosuppressants and certain biomarkers that are relevant to outpatient follow-up after kidney transplantation. We believe that a carefully designed system for the entire workflow, including patient training, will be beneficial in enabling a safe experience for transplant recipients, as well as ensuring overall efficiency and adequate quality. In the future, a combination of immunosuppressants with a wide range of biomarkers has significant potential for use in at-home self-sampling after kidney transplantation.

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference -38%, range -77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range -47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho -0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference -8.1 (-22 to 3.5) nmol/L versus -25 (-93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.

AIMS:Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS:The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION:This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.

Abstract Introduction An optimal method to assess adherence to statin therapy is needed. We have developed a novel test analysing atorvastatin, simvastatin and their metabolites in blood, to identify reduced adherence (≥2 consecutively omitted doses). The association between statin adherence measured in blood and long-term adherence is yet to be defined. Purpose To compare statin adherence measured by a single blood test with pharmacy registry data. Methods In a cross-sectional study including 451 patients using either atorvastatin or simvastatin, a spot blood sample was collected 2-35 (median 18) months after a coronary heart disease event. Participants were unaware of the forthcoming statin analyses. Reduced adherence to atorvastatin and simvastatin was determined by drug concentration measurements using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Study data was linked to the pharmacy registry. Indirect adherence was defined by a statin treatment gap exceeding 90 days; i. the three months period prior to the blood test, and ii. from six months before until six months after the blood test. We accounted for overlapping prescriptions of statins. Results Mean age was 61 (SD 9) years, and 19% were women. Thirty-nine (9%) out of 412 patients had reduced adherence to statins, determined by the direct method. The non-adherent patients had higher LDL-cholesterol levels, higher rates of multiple coronary events, lower participation rates at cardiac rehabilitation, and were more often smokers compared with the adherent patients (Table 1). Among patients classified as adherent by the blood test, only one (0.2%) had a treatment gap exceeding 90 days during the preceding three months (Table 2). Correspondingly, of 39 patients with reduced adherence by the blood test, 11 (28%) had treatment gaps exceeding 90 days. The negative agreement between the methods was 97% and the positive agreement 43%. Among patients classified as adherent by the blood test, 21 (5%) had treatment gaps exceeding 90 days from six months before until six months after the blood test. Correspondingly, of 39 patients with reduced adherence by the blood test, 15 (39%) had at least one treatment gap exceeding 90 days. The negative agreement between measurements was 95% and the positive agreement 40%. Conclusions Of 412 coronary outpatients classified adherent by the statin blood test, registry data only identified one patient (0.2%) with a treatment gap exceeding 90 days. The novel blood test emerges as a promising tool to identify patients adherent to statins, and thus may improve lipid management in clinical practice.

Background. Hyperkalemia is common in kidney transplant (KTx) recipients. Patiromer, a potassium-binding polymer used to treat acute and chronic hyperkalemia, has the potential to bind charged particles in the gastrointestinal tract and thereby potentially affect the absorption of coadministered drugs. The immunosuppressive drug tacrolimus (Tac) has a narrow therapeutic window, is susceptible to drug-drug interactions (DDIs), and a potential gastrointestinal interaction with patiromer could elevate the risk of allograft rejection. We aimed to investigate the potential DDI between patiromer and Tac pharmacokinetics in KTx with hyperkalemia by sampling capillary blood using volumetric absorptive microsampling (VAMS). Methods. Thirteen KTx recipients on Tac twice daily (BID) with plasma potassium levels of >4.6 mmol/L were included. Two 12 h Tac pharmacokinetic investigations were performed with and without 8.4 mg patiromer/d for 1 wk. Oral Tac dose remained unchanged and patiromer was administered 3 h after Tac dose. Tac sampling was self-conducted using VAMS after mastering the technique. Results. Ten patients provided 2 evaluable pharmacokinetic profiles. The Tac area under the curve (AUC)0–12 ratio (AUCTac+patiromer/AUCTac) was 0.99 (90% confidence interval [CI], 0.86-1.14), and the Cmax ratio was 1.01 (90% CI, 0.86-1.19). Tac C0 and C12 fulfilled the bioequivalence criteria with a ratio of 0.98 (90% CI, 0.90-1.07) and 0.93 (90% CI, 0.83-1.04), respectively. Conclusions. When administered 3 h after the Tac morning dose, patiromer has no clinically relevant impact on Tac pharmacokinetics. We demonstrate that VAMS is a well-suited sampling method to simplify the execution of DDI studies.

Background and aims: Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables. Methods: Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to >= 3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment. Results: We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma. Conclusion: Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceived SAMS, but the findings have to be confirmed in larger studies.

BACKGROUND:Home-based hospital services are becoming increasingly popular, and the addition of remote outpatient appointments after kidney transplantation facilitates more practical and closer follow-up. In this context, finger-prick self-sampling is an important aspect of monitoring of immunosuppressants and biomarkers. Nevertheless, several issues must be addressed to ensure the feasibility and quality when implementing microsampling in clinical practice. We summarize our experiences and opinions in this field. METHODS:This article is based on the authors' experience regarding the laboratory and clinical implementation of finger-prick self-sampling in kidney transplant recipients. The referenced literature is related to the authors' knowledge in this field. RESULTS:We present considerations for the selection of relevant analytes, key characteristics of selected volumetric sampling tools (Mitra and Capitainer), and the associated sampling pitfalls. In addition, we address the requirements for patients performing finger-prick sampling, appropriate design of methods and workflow, critical points for validation, and aspects related to logistics and digital solutions. CONCLUSIONS:Volumetric finger-prick self-sampling is suitable for monitoring immunosuppressants and certain biomarkers that are relevant to outpatient follow-up after kidney transplantation. We believe that a carefully designed system for the entire workflow, including patient training, will be beneficial in enabling a safe experience for transplant recipients, as well as ensuring overall efficiency and adequate quality. In the future, a combination of immunosuppressants with a wide range of biomarkers has significant potential for use in at-home self-sampling after kidney transplantation.

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.