Intrapatient Variability Research Articles

A pharmacist-led intervention to improve kidney transplant recipient outcomes and identify patients at risk of highly variable trough tacrolimus levels: a cohort study

ObjectivesGiven the positive impact of appropriate medication management on graft outcome and therefore of patient survival and graft function, the pharmacist’s role in the kidney transplantation team has evolved over...

Pharmacokinetic Alterations Associated with Critical Illness.

Haemodynamic, metabolic, and biochemical derangements in critically ill patients affect drug pharmacokinetics and pharmacodynamics making dose optimisation particularly challenging. Appropriate therapeutic dosing depends on the knowledge of the physiologic changes caused by the patient's comorbidities, underlying disease, resuscitation strategies, and polypharmacy. Critical illness will result in altered drug protein binding, ionisation, and volume of distribution; it will also decrease oral drug absorption, intestinal and hepatic metabolism, and renal clearance. In contrast, the resuscitation strategies and the use of vasoactive drugs may oppose these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion. Metabolism is the main mechanism for drug clearance and is one of the main pharmacokinetic processes affected; it is influenced by patient-specific factors, such as comorbidities and genetics; therapeutic-specific factors, including drug characteristics and interactions; and disease-specific factors, like organ dysfunction. Moreover, organ support such as mechanical ventilation, renal replacement therapy, and extracorporeal membrane oxygenation may contribute to both inter- and intra-patient variability of drug pharmacokinetics. The combination of these competing factors makes it difficult to predict drug response in critically ill patients. Pharmacotherapy targeted to therapeutic goals and therapeutic drug monitoring is currently the best option for the safe care of the critically ill. The aim of this paper is to review the alterations in drug pharmacokinetics associated with critical illness and to summarise the available evidence.

Retrospective analysis of intra-patient laboratory variation demonstrates that the BD Vacutainer® Barricor™ blood collection tube reduces troponin variation

ObjectiveThe BD Vacutainer® Barricor™ plasma blood collection tube uses a mechanical separator during centrifugation to separate plasma from the cellular elements of blood. Compared to use of plasma separator tubes (PST™) with gel, Barricor™ produces a cleaner sample with less residual cellular content. We sought to determine if Barricor™ reduces pre-analytical error compared to PST™. Design & MethodsWe used a model previously published that utilizes serial differences between intra-patient measurements transformed into a Taylor series of variation vs time with the y-intercept equal to the sum of short-term analytic variation, preanalytic variation and biologic variation. The intra-patient variation of chloride, sodium, potassium, and troponin-T (hs-TnT) obtained from the Emergency Department of a large tertiary care center sampled with PST™ (May 2015-April 2018, n = 59,762 specimens) or Barricor™ (May 2018-May 2021, n = 61,512 specimens) was evaluated. All specimens were analyzed on either Roche Modular or Cobas® instruments. For each analyte, pairs of intra-patient results were tabulated and separated by 1 h intervals. The average between-pair variations were then regressed against time. We also determined the number of intra-patient outliers using the reference change value for each analyte. ResultsThe Barricor™ hs-TnT y-intercept (-0.0132) was significantly lower than the PST™ intercept (0.9109; p = 0.022). This was also true for chloride (y-intercept = 1.0067 in Barricor™ and 1.3431 in PST™, p = 0.037). The percentage of hs-TnT outliers was significantly lower in Barricor™ (8.32 %) vs PST™ (12.2 %; p < 0.001). ConclusionThe analytical and biological variations are assumed to be steady over the study periods; we ascribe the difference in the y-intercept to the preanalytical effect of the Barricor™ tube reducing platelets and other cellular debris.

Task-aware asynchronous multi-task model with class incremental contrastive learning for surgical scene understanding.

Surgery scene understanding with tool-tissue interaction recognition and automatic report generation can play an important role in intra-operative guidance, decision-making and postoperative analysis in robotic surgery. However, domain shifts between different surgeries with inter and intra-patient variation and novel instruments' appearance degrade the performance of model prediction. Moreover, it requires output from multiple models, which can be computationally expensive and affect real-time performance. A multi-task learning (MTL) model is proposed for surgical report generation and tool-tissue interaction prediction that deals with domain shift problems. The model forms of shared feature extractor, mesh-transformer branch for captioning and graph attention branch for tool-tissue interaction prediction. The shared feature extractor employs class incremental contrastive learning to tackle intensity shift and novel class appearance in the target domain. We design Laplacian of Gaussian-based curriculum learning into both shared and task-specific branches to enhance model learning. We incorporate a task-aware asynchronous MTL optimization technique to fine-tune the shared weights and converge both tasks optimally. The proposed MTL model trained using task-aware optimization and fine-tuning techniques reported a balanced performance (BLEU score of 0.4049 for scene captioning and accuracy of 0.3508 for interaction detection) for both tasks on the target domain and performed on-par with single-task models in domain adaptation. The proposed multi-task model was able to adapt to domain shifts, incorporate novel instruments in the target domain, and perform tool-tissue interaction detection and report generation on par with single-task models.

Unsupervised EEG preictal interval identification in patients with drug-resistant epilepsy

Typical seizure prediction models aim at discriminating interictal brain activity from pre-seizure electrographic patterns. Given the lack of a preictal clinical definition, a fixed interval is widely used to develop these models. Recent studies reporting preictal interval selection among a range of fixed intervals show inter- and intra-patient preictal interval variability, possibly reflecting the heterogeneity of the seizure generation process. Obtaining accurate labels of the preictal interval can be used to train supervised prediction models and, hence, avoid setting a fixed preictal interval for all seizures within the same patient. Unsupervised learning methods hold great promise for exploring preictal alterations on a seizure-specific scale. Multivariate and univariate linear and nonlinear features were extracted from scalp electroencephalography (EEG) signals collected from 41 patients with drug-resistant epilepsy undergoing presurgical monitoring. Nonlinear dimensionality reduction was performed for each group of features and each of the 226 seizures. We applied different clustering methods in searching for preictal clusters located until 2 h before the seizure onset. We identified preictal patterns in 90% of patients and 51% of the visually inspected seizures. The preictal clusters manifested a seizure-specific profile with varying duration (22.9 ± 21.0 min) and starting time before seizure onset (47.6 ± 27.3 min). Searching for preictal patterns on the EEG trace using unsupervised methods showed that it is possible to identify seizure-specific preictal signatures for some patients and some seizures within the same patient.

Adiponectin, Leptin and Resistin in Patients with Psoriasis.

Psoriasis is a common chronic, inflammatory skin disease characterised by keratinocyte hyperproliferation, parakeratosis, and T-cell infiltration. Adipose tissue has an endocrine function, producing an abundance of cytokines and adipokines. It has also been described that the major adipokines, leptin, resistin, and adiponectin, may be involved in the pathogenesis of psoriasis. The aim of the study was to examine the plasma levels of adiponectin, leptin, and resistin in patients with psoriasis and their correlations with disease activity parameters: Psoriasis Activity Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Body Surface Area (BSA) index, as well as selected clinical parameters. The study included 53 patients with the plaque type and 31 healthy controls. The plasma concentrations of adiponectin were significantly lower in patients with psoriasis (p &lt; 0.001) than in the control group. The plasma concentrations of leptin were higher in patients with psoriasis, however, due to high intra-patient variability of leptin plasma concentrations these differences did not reach statistical significance (p = 0.2). The plasma concentrations of resistin were significantly increased in patients with psoriasis compared to healthy controls (p = 0.02). There were no statistically significant correlations between adiponectin and leptin plasma concentrations and values of PASI, DLQI, and BSA. The resistin plasma concentrations correlated significantly with DLQI values. Additionally, we examined the correlations between adiponectin, leptin, and resistin plasma concentrations, and selected clinical parameters. Plasma concentrations of adiponectin correlated significantly with CRP values and ALT values. Leptin plasma concentrations correlated significantly with creatinine values. The results of our study confirm the role of adiponectin, leptin, and resistin in the pathogenesis of psoriasis.

Removal of ethnicity adjustment for creatinine-based estimated glomerular filtration rate equations.

Creatinine-based estimated glomerular filtration rate equations (eGFRcreatinine) are used to measure excretory kidney function in clinical practice. Despite inter and intra-patient variability, eGFRcreatinine has excellent clinical utility and provides the basis for the classification system for chronic kidney disease (CKD), for kidney function monitoring, treatment interventions and referral pathways. The 4-variable modification of diet in renal disease (MDRD) eGFRcreatinine equation was introduced in 2000 and recommended by the National Institute for Health and Care Excellence (NICE) in 2008. Subsequently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcreatinine equation was introduced in 2009 and is more accurate than MDRD in patients with mild and moderate CKD. In 2014, NICE recommended that CKD-EPI eGFRcreatinine replace MDRD eGFRcreatinine in routine clinical practice across England. Both equations originally incorporated adjustments for age, gender and ethnicity. However, the evidence for ethnicity adjustment has been increasingly questioned, and in 2021 NICE recommended that kidney function should be estimated by CKD-EPI eGFRcreatinine without using ethnicity adjustment. Recently, a CKD-EPI equation has been presented without ethnicity adjustment; however, this has not been validated outside of North America and NICE continues to recommend CKD-EPI 2009. We review the status of eGFRcreatinine in clinical practice, including the limitations of eGFRcreatinine and the rationale for removal of ethnicity adjustment and the potential impact of this change on clinical care for patients with kidney disease.

Physical Therapy Combined with Transcranial Magnetic Stimulation Therapy: Treatment Practice Considering the Effect of Reducing Upper Limb Spasticity on Gait.

We perform physical therapy combined with repetitive transcranial magnetic stimulation (rTMS) in stroke patients with hemiplegia in the maintenance phase with the intent of improving the support of paralyzed leg. In gait evaluation in patients with hemiplegia, it is important to assess elements related to coordination carefully. rTMS therapy is effective in alleviating the tension of upper limbs. As rTMS helps upper-limb swing to become evident during gait, it makes trunk rotation necessary for left-right coordination appear more easily. As a result, rTMS has potential for improved upper-limb swing or trunk rotation. Post-rTMS therapy may prepare for the environment suitable for hip extending the stance phase of the paralyzed side. In physical therapy, it is advisable to practice standing up, maintaining standing posture or walking by making good use of these effects. We conduct practices in combination with the following: standing up focusing on load evenly distributed on both sides, standing on slant-board training, which enables forward shift of center of mass, walking by fixating upper limbs to the back of the body with the intent of extending the stance phase of the paralyzed side, and increasing trunk rotation. It is also necessary to discuss the combination with injection with botulinum toxin, which suppresses spasticity of ankle plantar flexors with the physician. Gait is associated with a variety of factors and has significant intrapatient and interpatient variations. In this regard, physiotherapists are required to develop a treatment program based on a quantitative evaluation, especially, in patients with hemiplegia.

Nonlinear Model Predictive Control of Vagal Nerve Stimulation to regulate hemodynamic variables

Various pre-clinical investigations indicate that the electrical stimulation of the cervical branch of the vagus that innervates the heart has therapeutic value in the management of various cardiac diseases. In theory, the design of a closed-loop control mechanism that automatically adjusts vagal nerve stimulation (VNS) parameters based on real-time physiological feedback can eliminate intra-patient variability in VNS outcomes and therefore represents a major step towards patient-specific therapy. This study develops a nonlinear model predictive control (NMPC) approach for VNS of a pulsatile, human cardio-baroreflex system. The manipulated variables are the frequency and amplitude of a charge-balanced biphasic current. The effects of these variables on hemodynamic quantities such as heart rate, blood pressure, heart contractility e.t.c. are estimated under the assumption that the desired activation of efferent vagal nerve fibers within the vagosympathetic complex can not be realistically isolated from the off-target activation of afferent fibers. An approximate, cycle-averaged cardiovascular model is derived to eliminate pulsatility and is used for prediction in the controller. The feasibility of this NMPC scheme is explored with a set-point tracking example.

Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer

Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.

Quantification of belatacept by liquid chromatography-tandem mass spectrometry in human plasma: Application to a pharmacokinetic study in renal transplant recipients

Therapeutic drug monitoring is the cornerstone of immunosuppressive treatment in transplantation. The immunosuppressive drugs used in kidney transplant patients are mostly comprised of biologics, including therapeutic monoclonal antibodies (mAbs) and fusion proteins. Therefore, a specific and sensitive analytical technique that can universally quantify mAbs, as well as fusion proteins, is essential for clinical pharmacokinetics studies.In this short communication, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantification of the fusion protein belatacept in the plasma of kidney-transplant patients. Sample preparation was based on our previously published and implementable electrospray ionization LC-MS/MS method that allows the simultaneous quantification of seven mAbs. Immunocapture was made possible by the Fc domain of belatacept and identification/quantification by the choice of MRM transitions of peptides. The temporal evolution of the belatacept concentration after intravenous infusion and inter-individual variability of trough concentrations were assessed in 17 human plasma samples.The belatacept calibration curves were linear from 1 to 200 mg.L−1 and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Residual belatacept concentrations (n = 8) ranged from 5.1 to 15.0 mg.L−1, with a median of 8.9 mg.L−1 and an inter-individual CV of 33.0%.Our generic LC-MS/MS method allows the quantification of fusion proteins, such as belatacept, and could be used for therapeutic drug monitoring. This method provides a useful tool to study the intra-patient variability of belatacept and the association between belatacept exposure and its therapeutic effects.

Direct blood fluorescence signal intensity of neutrophils (NEU-SFL): A predictive marker of death in hospitalized COVID-19 patients?

Coronavirus disease 2019 (COVID-19) is a respiratory disease triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical role in the innate immunity and are able to produce neutrophil extracellular traps (NETs: NETosis process) to combat infections. Some NETs markers are increased in patients who died from COVID-19. Recently, the neutrophil fluorescence variable (NEU-SFL), available on certain automated complete blood count (CBC) analyzers, has been correlated with NET formation and may reflect NETosis in patients. Here we evaluate whether NEU-SFL measured after admission of COVID-19 patients is associated with in-hospital survival or death. 1,852 patients admitted for severe COVID-19 at Nîmes University Hospital in 2021 were retrospectively included in the study: 1,564 who survived the hospital stay and 288 who did not. The NEU-SFL was obtained on the Sysmex™ XN-10® analyzer and values for survivors and non-survivors were compared. The intra-patient NEU-SFL variations between the hospital entry and the last day of hospitalization were also analyzed (IRB 22.06.01, NCT05413824). Non-survivors presented higher NEU-SFL values. NEU-SFL values above the 4th quartile were independently associated with a 2.88-fold risk of death. Furthermore, the difference of NEU-SFL values between the first and the last available data during hospitalization revealed that a decrease in NEU-SFL was associated to survivors and vice versa. Our study reinforces the role of neutrophils and NETosis in the pathophysiology and prognosis of COVID-19. Further studies combining NEU-SFL with other NETosis markers could improve the management of COVID-19 patients.

A Comprehensive Review: Transdermal Drug Delivery System: A Tool For Novel Drug Delivery System

In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery and interest in life cycle management strategies among pharmaceutical companies. Transdermal drug delivery system was presented to overcome the difficulties of drug delivery especially oral route. Transdermal drug delivery refers to a means of delivering drugs through the surface of the skin for local or systemic treatment. The drug functions after absorption through the skin into the systemic circulation via capillary action at a certain rate. Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of delivery system such as oral, topical, intravenous (i.v.), intramuscular (i.m.), etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin composition offers very effective barrier that allow only small molecule based drugs to penetrate the skin and pass through the barrier. Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and more recently, it has been used for the treatment of pulmonary arterial hypertension and the enhancement of uteroplacental perfusion in case of fetal growth retardation. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. The main objective of transdermal drug delivery system is to deliver drugs into systemic circulation through skin at predetermined rate with minimal inter and intrapatient variations. Keyword: Skin delivery, Transdermal drug delivery, Oral rout, Sildenafil citrate, Pulmonary arterial hypertension

Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide.

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.

Techniques et intérêt clinique de la débitmétrie à domicile : une revue de la littérature

Urine flowmetry (UF) is a key non-invasive urodynamic test for the evaluation of the voiding phase in patients with lower urinary tract symptoms (LUTS). Traditional free urodynamic testing (FUT) performed on a one-time basis in the office is limited by difficulty in capturing normal voiding and high intrapatient variability in urine flow parameters. Home measurement of urine flow by the patient could be a way to obtain multiple data in real-life conditions, addressing its limitations. The objective of this article was to review the literature on the different techniques of home uroflowmetry (HUF) and their clinical interest in comparison with FUT. A search on the PubMed database using the key words "Urodynamics, Uroflowmetry, non-invasive urodynamics, Ambulatory urodynamics, bladder outlet obstruction, male LUTS" was performed to find articles in English or French that had been published with no time limit and March 2022. The sorting by reading the abstract allowed the selection of all articles describing and/or evaluating a HUF technique that were read entirely according to the same collection grid to propose a narrative synthesis. Thirty-one articles were identified, selected, and analyzed. Simple and inexpensive techniques by timing or use of funnels reliably and reproducibly estimate the average and maximum urine flow in relation to the FUT, without providing a complete flow curve. More sophisticated electronic or sonometric methods, some using connected mobile applications, present results that are more consistent with ICS recommendations for flow measurement. With the possibility of studying the average of several values of the maximum urinary flow (Qmax) captured during micturition in physiological conditions, some studies suggest a gain in diagnostic value in the evaluation of the emptying phase and lower urinary tract symptoms in men. However, the literature is sparse, old and the clinical benefits are not yet proven. There is a wide range of techniques for measuring urine flow in the patient's home, all of which aim to fill the gaps in conventional urine flow measurement. Further studies are needed to demonstrate the acceptability of this type of measurement by patients, the existence of a real clinical benefit, to assess the cost/benefit balance and finally to define a possible place for home uroflowmetry in daily practice, compared with traditional free flowmetry and invasive urodynamics (pressure-flow test).

Event-based MPC for propofol administration in anesthesia

Background and Objective: The automatic control of anesthesia is a demanding task mostly due to the presence of nonlinearities, intra- and inter-patient variability and specific clinical requirements to be meet. The traditional approach to achieve the desired depth of hypnosis level is based on knowledge and experience of the anesthesiologist. In contrast to a typical automatic control system, their actions are based on events that are related to the effect of the administrated drug. Thus, it is interesting to build a control system that will be able to mimic the behavior of the human way of actuation, simultaneously keeping the advantages of an automatic system.Methods: In this work, an event-based model predictive control system is proposed and analyzed. The nonlinear patient model is used to form the predictor structure and its linear part is exploited to design the predictive controller, resulting in an individualized approach. In such a scenario, the BIS is the controlled variable and the propofol infusion rate is the control variable. The event generator governs the computation of control action applying a dead-band sampling technique. The proposed control architecture has been tested in simulation considering process noise and unmeasurable disturbances. The evaluation has been made for a set of patients using nonlinear pharmacokinetic/pharmacodynamic models allowing realistic tests scenarios, including inter- and intra-patient variability.Results For the considered patients dataset the number of control signal changes has been reduced of about 55% when compared to the classical control system approach and the drug usage has been reduced of about 2%. At the same time the control performance expressed by the integrated absolute error has been degraded of about 11%.Conclusions: The event-based MPC control system meets all the clinical requirements. The robustness analysis also demonstrates that the event-based architecture is able to satisfy the specifications in the presence of significant process noise and modelling errors related to inter- and intra-patient variability, providing a balanced solution between complexity and performance.

Intrapatient variability of tacrolimus in a recurrently ill kidney transplant recipient

Intrapatient variability of tacrolimus in a recurrently ill kidney transplant recipient

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

High intrapatient variability and low nadir of tacrolimus level with high class II eplets mismatch are associated with inferior graft survival

High intrapatient variability and low nadir of tacrolimus level with high class II eplets mismatch are associated with inferior graft survival

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.