Pharmacokinetics of Edoxaban 15 mg in Very Elderly Patients with Nonvalvular Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Study.

BACKGROUND: We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk. METHODS: This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies. RESULTS: The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 (n = 427) and 93.3 ± 57.8 ng/mL (n = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 (n = 79; 12.4 ± 12.1 and n = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group (n = 83; 25.1 ± 36.6 and n = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study (n = 39; 18.4 ± 11.2 and n = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not. CONCLUSION: PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Trastuzumab Deruxtecan Dosing in Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer: Population Pharmacokinetic Modeling and Exposure-Response Analysis.

This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials, primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates, ORRs) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, and 79 with other cancers). In gastric cancer, the T-DXd 6.4 mg/kg steady-state exposure metrics were lower compared with 6.4 mg/kg in breast cancer, but were similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, the T-DXd steady-state minimum concentration was associated with a confirmed ORR in univariate logistic regression analysis (P = .023). The model-predicted confirmed ORRs in gastric cancer were 36.0% (90%CI 29.3% to 43.7%) with 5.4 mg/kg and 40.0% (90%CI 33.1% to 47.6%) with 6.4 mg/kg. Among 808 patients in the exposure-safety analyses, the model-predicted estimates for the rates of any-grade interstitial lung disease (ILD) over a period of 180 days were 10.2% (90%CI 8.7% to 12.8%) with 6.4 mg/kg in gastric cancer and 9.7% (90%CI 8.2% to 11.8%) with 5.4 mg/kg in breast cancer. In gastric cancer, the efficacy of T-DXd was higher at 6.4 mg/kg than at 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer.

SuPreme Study: a protocol to study the neuroprotective potential of sulfate among very/extremely preterm infants.

INTRODUCTION: Antenatal maternal magnesium sulfate (MgSO4) administration is a proven efficacious neuroprotective treatment reducing the risk of cerebral palsy (CP) among infants born preterm. Identification of the neuroprotective component with target plasma concentrations could lead to neonatal treatment with greater efficacy and accessibility. METHODS AND ANALYSIS: This is a prospective observational cohort study, in three tertiary Australian centres. Participants are preterm infants, irrespective of antenatal MgSO4 exposure, born in 2013-2020 at 24+0 to 31+6 weeks gestation, and followed up to 2 years corrected age (CA) (to September 2023). 1595 participants are required (allowing for 17% deaths/loss to follow-up) to detect a clinically significant reduction (30% relative risk reduction) in CP when sulfate concentration at 7 days of age is 1 SD above the mean.A blood sample is collected on day 7 of age for plasma sulfate and magnesium measurement. In a subset of participants multiple blood and urine samples are collected for pharmacokinetic studies, between days 1-28, and in a further subset mother/infant blood is screened for genetic variants of sulfate transporter genes.The primary outcome is CP. Surviving infants are assessed for high risk of CP at 12-14 weeks CA according to Prechtl's Method to assess General Movements. Follow-up at 2 years CA includes assessments for CP, cognitive, language and motor development, and social/behavioural difficulties.Multivariate analyses will examine the association between day 7 plasma sulfate/magnesium concentrations with adverse neurodevelopmental outcomes. A population pharmacokinetic model for sulfate in the preterm infant will be created using non-linear mixed-effects modelling. ETHICS AND DISSEMINATION: The study has been approved by Mater Misericordiae Ltd Human Research Ethics Committee (HREC/14/MHS/188). Results will be disseminated in peer-reviewed journal publications, and provided to the funding bodies. Using consumer input, a summary will be prepared for participants and consumer groups.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. CONCLUSION: A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

Evaluation of a Meropenem and Piperacillin Monitoring Program in Intensive Care Unit Patients Calls for the Regular Assessment of Empirical Targets and Easy-to-Use Dosing Decision Tools.

The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1-5 × MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8-40 mg/L and 16-80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing.

Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance.

This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once-daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration-time data were analyzed using a nonlinear mixed-effects approach. The developed PK model was used to assess achievement of target exposure under six dose-adjustment scenarios based on simulations performed in RStudio (RxODE package)®. A total of 2491 busulfan plasma concentration-time measurements were collected from 95 patients characterizing 379 dosing days. A two-compartment model with time-associated CL best described the data with a typical CL of 14.5 L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6 L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model-based exposure estimates with each dose, and either a proportional dose-adjustment calculation or model-based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time-associated reduction in CL during once-daily busulfan treatment was described.

Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications.

AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Evaluation of published population pharmacokinetic models to inform tacrolimus dosing in adult heart transplant recipients.

BACKGROUND AND AIM: Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. METHODS: Population pharmacokinetic models of tacrolimus were selected (n = 17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. RESULTS: Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n = 152). The prediction-corrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. CONCLUSION: All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.

Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing-A Translational Example for Intensive Care Units.

The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA > 90% or LPIFR > 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions.

Population pharmacokinetic and exploratory exposure-response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study.

PURPOSE: To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure-response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure-efficacy and -safety relationships and support the approved SC dosing regimen. METHODS: Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression. RESULTS: SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest. CONCLUSION: The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit-risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation.

AIM: To assess the ability of model-based personalised dosing tools to estimate busulfan exposure (i) in comparison to clinically used intensive sampling exposure estimation procedure, (ii) using limited sampling strategies and (iii) to predict changes in busulfan clearance during busulfan treatment. METHODS: Data on intravenous busulfan dosing for patients with 4 consecutive days were entered into Bayesian forecasting software, InsightRX and NextDose. Prediction of busulfan cumulative exposure was compared to current clinical practice estimation, aiming for pre-defined individualised target of cumulative exposure. Estimation performance was tested given several limited sampling strategies. RESULTS: Thirty-two paediatric patients (0.2-16.5 years) provided a total of 103 daily exposure measurements estimated using 7 samples taken per day (full sampling), with 19 patients having sampling following all doses administered. Both software tools utilising Bayesian methods provided acceptable relative bias and precision of cumulative exposure estimations under the tested sampling scenarios. Relative bias ranged from median RE of 0.1-14.6% using InsightRX and from 3.4-7.8% using NextDose. Precision ranged from median RMSE of 0.19-0.32 mg·h·L-1 for InsightRX and 0.08-0.1 mg·h·L-1 for NextDose. A median reduction in busulfan clearance from day 1 to day 4 was observed in the clinical data (-10.9%), when using InsightRX (-18.6%) and with NextDose (-14.7%). CONCLUSION: Bayesian methods were shown to have relatively low bias and precisely estimate busulfan exposure using intensive sampling and several limited sampling strategies, which provides evidence for prospective studies to evaluate these tools in clinical practice. A trend to overestimation of exposure using Bayesian methods was observed compared to clinical practice. Reduction of busulfan clearance from day 1 to 4 of once daily dosing was confirmed and should be considered when adjusting doses.

Review of the Pharmacokinetics and Pharmacodynamics of Intravenous Busulfan in Paediatric Patients.

We aimed to review the pharmacokinetics (PK) of intravenous busulfan in paediatric patients, identify covariate factors influencing exposure, investigate evidence of changes in PK behaviour over time, and correlate exposure with efficacy and toxicity outcomes. A literature review was undertaken of original research published between 2007 and 2019, investigating the PK and pharmacodynamics (PD) of intravenous busulfan in patients ≤ 18 years of age. The review identified 41 publications characterising the PK, and 45 publications describing the PD, of busulfan. Median typical clearance (CL) was 0.22 L/h/kg and median typical volume of distribution was 0.69 L/kg. Patient weight, age, glutathione-S-transferase A1 (GSTA1) genotype and busulfan dosing day/time were the most commonly identified factors affecting CL. Of nine studies investigating changes in CL, seven reported reduced CL over the 4-day course of treatment. Exposure monitoring methods and therapeutic targets were heterogeneous across studies. Relationships between busulfan exposure and patient outcomes were observed in five studies. One study observed a cumulative area under the concentration-time curve over all days of treatment of between 78 and 101 mg/L·h, and two studies observed an average concentration at first dose of < 600 ng/mL improved overall survival, transplant-related mortality, or relapse. One study observed increased sinusoidal obstructive syndrome with maximum busulfan concentration > 1.88 ng/mL. Patient weight, age and GSTA1 genotype are important covariates to consider when individualising busulfan therapy. Reduced busulfan CL over time may need to be accounted for, particularly in patients not receiving phenytoin co-therapy. Standardised monitoring of busulfan exposure over the entire course of treatment and further investigation of the role of busulfan metabolites and pharmacogenomics is warranted.

Population Pharmacokinetic Models of Tacrolimus in Adult Transplant Recipients: A Systematic Review.

BACKGROUND AND OBJECTIVES: Numerous population pharmacokinetic (PK) models of tacrolimus in adult transplant recipients have been published to characterize tacrolimus PK and facilitate dose individualization. This study aimed to (1) investigate clinical determinants influencing tacrolimus PK, and (2) identify areas requiring additional research to facilitate the use of population PK models to guide tacrolimus dosing decisions. METHODS: The MEDLINE and EMBASE databases, as well as the reference lists of all articles, were searched to identify population PK models of tacrolimus developed from adult transplant recipients published from the inception of the databases to 29 February 2020. RESULTS: Of the 69 studies identified, 55% were developed from kidney transplant recipients and 30% from liver transplant recipients. Most studies (91%) investigated the oral immediate-release formulation of tacrolimus. Few studies (17%) explained the effect of drug-drug interactions on tacrolimus PK. Only 35% of the studies performed an external evaluation to assess the generalizability of the models. Studies related variability in tacrolimus whole blood clearance among transplant recipients to either cytochrome P450 (CYP) 3A5 genotype (41%), days post-transplant (30%), or hematocrit (29%). Variability in the central volume of distribution was mainly explained by body weight (20% of studies). CONCLUSION: The effect of clinically significant drug-drug interactions and different formulations and brands of tacrolimus should be considered for any future tacrolimus population PK model development. Further work is required to assess the generalizability of existing models and identify key factors that influence both initial and maintenance doses of tacrolimus, particularly in heart and lung transplant recipients.

What "Impact" Do NLME Publications Have Outside Our Community?

The number of publications applying nonlinear mixed-effect (NLME) modeling has increased yearly since its first appearance in 1979. Here, we evaluated articles that have used NLME modeling, were published in journals that attract a broader audience, and we discussed the standard of presentation of these to stimulate target audience-specific improvements for increased impact in the future.