Population Pharmacokinetic Model Research Articles

Population Pharmacokinetics and Dose Optimization of Piperacillin in Infants and Children with Pneumonia.

We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia. An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM. The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09-1.72 years for infants and 2.12-11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L. A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia.

Vancomycin population pharmacokinetic models: Uncovering pharmacodynamic divergence amid clinicobiological resemblance.

Vancomycin is an antibiotic used for severe infections. To ensure microbiological efficacy, a ratio of AUC/MIC ≥400 is recommended. However, there is significant interindividual variability in its pharmacokinetic parameters, necessitating therapeutic drug monitoring to adjust dosing regimens and ensure efficacy while avoiding toxicity. Population pharmacokinetic (PopPK) models enable dose personalization, but the challenge lies in the choice of the model to use among the multitude of models in the literature. We compared 18 PopPK models created from populations with the same sociodemographic and clinicobiological characteristics. Simulations were performed for a 47 years old man, weighing 70 kg, with an albumin level of 35.5 g/L, a creatinine clearance of 100 mL/min, an eGFR of 106 mL/min/1.73 m2, and receiving an intravenous infusion of 1 g × 2/day of VCM over 1 h for 48 h. Simulations of time-concentration profiles revealed differences, leading us to determine the probability of achieving microbiological efficacy (AUC/MIC ≥ 400) with each model. Depending on some models, a dose of 1 g × 2/day is required to ensure microbiological efficacy in over 90% of the population, while with the same dose other models do not exceed 10% of the population. To ensure that 90% of the patients are correctly exposed, a dose of vancomycin ranging from 0.9 g × 2/day to 2.2 g × 2/day is necessary a priori depending on the chosen model. These differences raise an issue in choosing a model for performing therapeutic drug monitoring using a PopPK model with or without Bayesian approach. Thus, it is fundamental to evaluate the impact of these differences on both efficacy/toxicity.

Limited sampling approach for model-informed precision dosing of daptomycin to rapidly achieving the target area under the concentration-time curve: A simulation study.

Daptomycin, an anti-methicillin-resistant Staphylococcus aureus drug, causes exposure-dependent muscle toxicity and eosinophilic pneumonia. Although the area under the concentration-time curve (AUC)-guided dosing is crucial, an optimal blood sampling strategy is lacking. This study aimed to identify an optimal limited sampling strategy using Bayesian forecasting to rapidly achieve the target AUC. Two validated population pharmacokinetic models generated a virtual population of 1000 individuals (models 1 and 2 represent diverse patients and kidney transplant recipients, respectively). The AUC for each blood sample was assessed using the probability of achieving the estimated/reference AUC ratio on the second day (AUC24-48) and at the steady state (AUCss). In Model 1, Bayesian posterior probabilities for AUC24-48 increased from 50.7% (a priori) to 59.4% and for AUCss from 48.9% (a priori) to 61.9%, with one-point Ctrough sampling at 24 h. With two-point sampling at 7 and 24 h, the probabilities increased to 73.8% for AUC24-48 and 69.7% for AUCss. In Model 2, the probabilities for both AUC24-48 and AUCss with one-point Ctrough or two-point sampling incorporating Ctrough sampling increased compared to a priori probabilities. These results suggest that two-point sampling incorporating Ctrough during initial dosing enhanced achieving the target AUC24-48 and AUCss rapidly.

SGLT2 Inhibitors in Patients with Heart Failure: A Model-Based Meta-Analysis.

This study aimed to quantify the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a therapeutic approach for heart failure. A systematic literature review was conducted to collect pharmacokinetics (PK) and pharmacodynamics (PD) data on empagliflozin, dapagliflozin, and canagliflozin. Population pharmacokinetic models were developed separately for each drug, along with PK/PD turnover models for SGLT2 inhibitors, to describe the time course of NT-proBNP and simulate its changes over 52 weeks. A total of 42 publications were included in this study. The results showed that baseline NT-proBNP levels, estimated glomerular filtration rate levels, and body weight significantly influenced the therapeutic effects of SGLT2 inhibitors. Among the studied drugs, canagliflozin demonstrated a greater reduction in NT-proBNP at comparable baseline levels. Baseline NT-proBNP concentration, renal function, and body weight were covariates affecting the efficacy of SGLT2 inhibitors in reducing NT-proBNP. Canagliflozin showed the most favorable treatment outcomes at similar baseline levels. This model-based meta-analysis approach may support further drug development for SGLT2 inhibitors.

Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies.

Time-dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure-response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false-positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false-positive ER findings. Two previously published population PK models representative of slow- (pembrolizumab) and fast-onset (rituximab) TDPK were used to simulate virtual patient cohorts with time-dependent clearance and the frequency of false-positive ER findings. The impact of varying the number of dose groups, dose range, and sample size was evaluated over time. Study designs with a single tested dose level showed a high probability of showing a false-positive ER finding. When TDPK has a slow onset, use of exposure measures from early timepoints in ER analysis significantly reduces the risk of a false-positive, while with fast onset it did not. Randomization of patients to two dose levels greatly reduced the risk, with a threefold or greater dose range offering the greatest benefit. The likelihood of false-positive increases with a larger sample size, where greater care should be taken to identify confounding factors. Clinical trial simulation supports that appropriate clinical study design and analysis with adequate dose exploration can reduce but cannot entirely eliminate the risk of misleading ER findings.

Recommended approaches for integration of population pharmacokinetic modelling with precision dosing in clinical practice.

Current methods of dose determination have contributed to suboptimal and inequitable health outcomes in underrepresented patient populations. The persistent demand to individualise patient treatment, alongside increasing technological feasibility, is leading to a growing adoption of model-informed precision dosing (MIPD) at point of care. Population pharmacokinetic (popPK) modelling is a technique that supports treatment personalisation by characterising drug exposure in diverse patient groups. This publication addresses this important shift in clinical approach, by collating and summarising recommendations from literature. It seeks to provide standardised guidelines on best practices for the development of popPK models and their use in MIPD software tools, ensuring the safeguarding and optimisation of patient outcomes. Moreover, it consolidates guidance from key regulatory and advisory bodies on MIPD software deployment, as well as technical requirements for electronic health record integration. It also considers the future application and clinical impact of machine learning algorithms in popPK and MIPD. Ultimately, this publication aims to facilitate the incorporation of high-quality precision-dosing solutions into standard clinical workflows, thereby enhancing the effectiveness of individualised dose selection at point of care.

Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension.

Selexipag is an oral selective prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH) in adults. To date, no treatment targeting the prostacyclin pathway is approved for pediatric patients. Our goal is to identify a pediatric dose regimen that results in comparable exposures to selexipag and its active metabolite JNJ-68006861 as those shown to be efficacious in adult PAH patients. Extrapolation from the population pharmacokinetic (PK) model developed in adults (GRIPHON study; NCT01106014) resulted in the definition of three different pediatric body weight groups (≥9 to <25 kg, ≥25 to <50 kg, and ≥50 kg) with corresponding starting doses (100, 150, and 200 μg twice daily) and maximum allowed doses (800, 1200, and 1600 μg twice daily). The proposed pediatric dose regimen was subsequently tested in a clinical study (NCT03492177), including 63 pediatric PAH patients ≥2 to <18 years of age and a body weight range of 9.9-93.5 kg. The body weight-adjusted dose regimen for selexipag resulted in comparable systemic exposures to selexipag and its active metabolite in pediatric patients as previously observed in adult PAH patients. Updating the adult selexipag population PK model provided overall consistent parameters and confirmed that the PK characteristics of selexipag and its active metabolite were comparable between pediatric and adult patients. The presented selexipag dose regimen for pediatric PAH patients is considered appropriate for continuing the clinical evaluation of the safety and efficacy of selexipag in pediatric patients ≥2 years of age.

Population pharmacokinetic analyses for sulbactam-durlobactam using Phase 1, 2, and 3 data.

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination approved in the United States for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus in adults. A population pharmacokinetic (PK) model of sulbactam-durlobactam in plasma was developed using data from eight Phase 1-3 studies. A total of 432 subjects and 8,100 plasma concentrations were available for the population PK data set. The combined model was a four-compartment (two compartments per drug) model with linear kinetics. Both renal clearance and nonrenal clearance were estimated, and total clearance was calculated as the sum of renal and nonrenal clearance. Individual renal clearances were scaled by baseline creatinine clearance. The sampling-importance-resampling analysis indicated that the parameters were estimated reliably with adequate precision. Hemodialysis (HD) and epithelial lining fluid (ELF) sub-models were developed for each analyte separately. Intermittent HD resulted in an approximately 30% decrease in the daily area under the concentration-time curve (AUC0-24) when HD was started 1 hour after the end of the infusion. Assuming protein binding estimates of 10% and 38% for durlobactam and sulbactam, respectively, ELF penetration ratios were found to be 41.3% for durlobactam and 86.0% for sulbactam. Of the statistically significant covariates of PK identified, which included body weight, body mass index, infection type, and region of origin, renal function was the only clinically relevant covariate. Overall, a robust description of the plasma PK of sulbactam and durlobactam was achieved. The resultant population PK model was expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships.

Exposure-response modeling of liver fat imaging endpoints in non-alcoholic fatty liver disease populations administered ervogastat alone and co-administered with clesacostat.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non-invasive measures such as magnetic resonance imaging proton density fat fraction (MRI-PDFF) and FibroScan® controlled attenuation parameter (CAP™) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure-response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic/pharmacodynamic (PK/PD) modeling of both liver fat measurements simultaneously. Population pharmacokinetic and exposure-response models using individual predictions of average concentrations were used to describe ervogastat/clesacostat PKPD. Due to both liver fat endpoints being continuous-bounded outcomes on different scales, a dynamic transform-both-sides approach was used to link a common latent factor representing liver fat to each endpoint. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described by the model. The clinical trial simulation was able to adequately predict the results of a recent Phase 2 study, where subjects given ervogastat/clesacostat 300/10 mg BID for 6 weeks had a LS means and model-predicted median (95% confidence intervals) percent change from baseline MRI-PDFF of -45.8% and -45.6% (-61.6% to -31.8%), respectively. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies.

Population Pharmacokinetics of Ensitrelvir in Healthy Participants and Participants with SARS-CoV-2 Infection in the SCORPIO-SR Study.

Ensitrelvir, a novel oral inhibitor of the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shown efficacy and safety in participants with mild to moderate coronavirus disease 2019 (COVID-19) with once-daily multiple doses of 375mg on day 1 followed by 125mg on days 2-5. The aims of this study were to characterize the pharmacokinetics of ensitrelvir and to explore its exposure-response relationships on the dose regimen. Pharmacokinetic data, including 8034 plasma concentration datasets from 2060 participants, from two phase I and one phase II/III study in healthy participants and participants infected with SARS-CoV-2 were used to develop a population pharmacokinetic model. The correlation between exposure and drug response was evaluated using observed plasma concentrations and estimated pharmacokinetic parameters as pharmacokinetic indexes and viral RNA as drug response. A two-compartment model with a first-order absorption model effectively described plasma ensitrelvir concentrations. The effects of body weight on clearance and volume of distribution and of food conditions and formulation on the absorption rate constant were selected as significant covariates. The efficacy indexes changed in the active group, but the responses were similar across the exposure range in the phase II/III study (SCORPIO-SR) regardless of the effects of the pharmacokinetic covariates. Population pharmacokinetics revealed that body weight is the most important covariate in the pharmacokinetics of ensitrelvir. The antiviral effect, independent of ensitrelvir exposure, was demonstrated on the current dose regimen for treatment of SARS-CoV-2 infection.

Challenges in Validating Population Pharmacokinetic Models for Clozapine Dosage Prediction and Therapeutic Drug Monitoring

Challenges in Validating Population Pharmacokinetic Models for Clozapine Dosage Prediction and Therapeutic Drug Monitoring

A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups.

The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin. A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages. First, the effect of age in young patients was investigated, by adding a maturation function on clearance (CL), the central compartment (V1) and peripheral compartments (V2 and V3). Second, the impact of ageing was investigated by adding a maximal effect (Emax) function on CL, V1, V2, and V3. To investigate the overall impact of age on doxorubicin exposure, various simulations were conducted. A total of 168 patients (age: 0.11-90 years) with 555 doxorubicin samples were included. The maturation function was relevant for V1 and V2 (13.1 and 23.7L, respectively), leading to an increase in V1 and V2 with increasing age. In contrast, adding an Emax function only impacted V3 (1063L), resulting in a decrease of V3 with age. Simulations showed no clinically relevant difference in the exposure of doxorubicin between age groups. A population pharmacokinetic model with data across the age range showed that age predominantly affected volumes of distribution of the central and peripheral compartments. These effects were not considered to be clinically relevant based on performed simulations. This supports the use of currently used doxorubicin dosages of 1 mg/kg for infants and toddlers <10 kg and body surface area-based dosing for other patients.

External evaluation of neonatal vancomycin population pharmacokinetic models: Moving from first-order equations to Bayesian-guided therapeutic monitoring.

Guidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration-time curve over first-order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models. Models were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction-based diagnostics, then by simulation-based diagnostics and a posteriori analyses only if deemed satisfactory; model-informed vancomycin exposure was also compared with reference first-order pharmacokinetic equations. The best-performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target. A total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli etal. and Mehrotra etal. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment. We externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations.

Establishment of a population pharmacokinetic model for linezolid in neonates with sepsis

To establish the pharmacokinetic model of linezolid in neonates, and to optimize the administration regimen. A prospective study was conducted among 64 neonates with sepsis who received linezolid as anti-infective therapy, and liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of the drug. Clinical data were collected, and nonlinear mixed effects modeling was used to establish a population pharmacokinetic (PPK) model. Monte Carlo simulation and evaluation was performed for the optimal administration regimen of children with different features. The pharmacokinetic properties of linezolid in neonates could be described by a single-compartment model with primary elimination, and the population typical values for apparent volume of distribution and clearance rate were 0.79 L and 0.34 L/h, respectively. The results of goodness of fit, visualization verification, and the Bootstrap method showed that the model was robust with reliable results of parameter estimation and prediction. Monte Carlo simulation results showed that the optimal administration regimen for linezolid in neonates was as follows: 6 mg/kg, q8h, at 28 weeks of gestational age (GA); 8 mg/kg, q8h, at 32 weeks of GA; 9 mg/kg, q8h, at 34-37 weeks of GA; 11 mg/kg, q8h, at 40 weeks of GA. The PPK model established in this study can provide a reference for individual administration of linezolid in neonates. GA and body weight at the time of administration are significant influencing factors for the clearance rate of linezolid in neonates.

Population Pharmacokinetic Model of Vitamin D3 and Metabolites in Chronic Kidney Disease Patients with Vitamin D Insufficiency and Deficiency.

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD3) and its three major metabolites, 25-hydroxyvitamin D3 (25D3), 1,25-dihydroxyvitamin D3 (1,25D3), and 24,25-dihydroxyvitamin D3 (24,25D3), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD3 (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD3 and its metabolites. The simultaneous fit of a two-compartment model for VitD3 and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD3 and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD3 and metabolites. This is the first reported population pharmacokinetic modeling of VitD3 and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D3 concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD.

Population Pharmacokinetics of Vancomycin in Intensive Care Patients with the Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy.

This study characterized the population pharmacokinetics (PK) of vancomycin in patients treated with and without continuous renal replacement therapy (CRRT) or temporary mechanical circulatory support (tMCS), including extracorporeal membrane oxygenation or extracorporeal ventricular assist device. Critically ill adults with and without tMCS or CRRT prescribed vancomycin were enrolled for population PK modeling. MonteCarlo simulation provided dosing recommendations based on the probability of target attainment (PTA), achieving a 24-h area under curve (AUC24h) of 400-600mg*h/L. Twenty-five patients with 184 plasma samples were analyzed. The median age was 61.0years. The final model was a two-compartment PK model. CRRT, serum creatinine, and body weight were significant predictors of clearance. CRRT was a covariate on the central volume of distribution. tMCS significantly decreased the intercompartmental clearance. The simulated mean trough levels at the 48th hour were lower in the tMCS group (13.4 versus 14.2mg/dL in non-tMCS, p < 0.001) in a 70-kg subject with a creatinine of 1mg/dL and a daily dose of 20mg/kg, but the PTA was similar (61.8% versus 62.2%). A reduction of maintenance dose from 30 to 10mg/kg/day with loading dose from 25 to 15mg/kg is recommended while serum creatinine progresses from 0.5 to 4.0mg/dL. For CRRT, the optimal regimen consists of 20-25mg/kg loading and maintenance of 15mg/kg/day. The dosing strategy of vancomycin can be based on body weight or renal function, regardless of tMCS. Intercompartmental clearance decreases under tMCS, which can mislead a dosing adjustment based on trough level.

Population Pharmacokinetics of Tamibarotene in Pediatric and Young Adult Patients with Recurrent or Refractory Solid Tumors.

Tamibarotene is a synthetic retinoid that inhibits tumor cell proliferation and promotes differentiation. We previously reported on the safety and tolerability of tamibarotene in patients with recurrent or refractory solid tumors. Therefore, in this study, we aimed to evaluate the pharmacokinetic properties of tamibarotene and construct a precise pharmacokinetic model. We also conducted a non-compartmental analysis and population pharmacokinetic (popPK) analysis based on the results of a phase I study. Targeted pediatric and young adult patients with recurrent or refractory solid tumors were administered tamibarotene at doses of 4, 6, 8, 10, and 12 g/m2/day. Serum tamibarotene concentrations were evaluated after administration, and a popPK model was constructed for tamibarotene using Phoenix NLME. During model construction, we considered the influence of various parameters (weight, height, body surface area, and age) as covariates. Notably, 22 participants were included in this study, and 109 samples were analyzed. A two-compartment model incorporating lag time was selected as the base model. In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory.

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.

An integrated population pharmacokinetic model of febuxostat in pediatric patients with hyperuricemia including gout and adult population of healthy subjects and patients with renal dysfunction.

The study objective was to validate febuxostat dosage and administration in pediatric patients with hyperuricemia including gout, using an integrated population pharmacokinetic (PopPK) analysis in the Japanese population. Integrated PopPK analysis of febuxostat used a nonlinear mixed-effects modeling (NONMEM) program on plasma febuxostat concentration data for 2611 samples from Japanese pediatric patients with hyperuricemia including gout (n = 29) and from adult subjects who are healthy or have renal dysfunction (n = 113). We described febuxostat pharmacokinetics using an integrated PopPK model applicable both to pediatric patients and to the adult population. The covariates of body weight and eGFR were identified for CL/F and the covariate of fasted/fed status for bioavailability. The range of steady-state exposures (Cmax,ss and AUCτ,ss) for 5, 10, 20, and 30 mg of febuxostat in fed pediatric patients weighing 20 to 40 kg was within that for 10, 20, 40, and 60 mg of febuxostat in fed pediatric patients and adults weighing 40 to 120 kg. Post hoc estimates of CL/F, adjusted by body weight, differed little between pediatric patients and the adult population in the renal function categories of normal, mild dysfunction, and moderate dysfunction. We successfully validated the febuxostat dose that provided the same level of exposure in pediatric patients as in the adult population: half the adult dose for pediatric patients weighing <40 kg and the full adult dose for pediatric patients weighing ≥40 kg. As in adults, the results support the use of febuxostat without dose adjustment in pediatric patients who have mild to moderate renal dysfunction.

External evaluation of intravenous vancomycin population pharmacokinetic models in adults receiving high-flux intermittent haemodialysis.

Patients undergoing haemodialysis (HD) are at greater risk of methicillin-resistant Staphylococcus aureus infections requiring intravenous vancomycin. Close vancomycin therapeutic drug monitoring is warranted in HD patients as renal clearance is the primary elimination pathway. Clinically, population pharmacokinetics (popPK) model-informed dosing is commonly used. This study aimed to perform an external evaluation of published vancomycin popPK models developed for adults undergoing high-flux intermittent HD, and to create a dosing nomogram derived from the model that performed best. A literature review was conducted through PubMed and EMBASE to identify relevant popPK models. an external dataset was collected retrospectively from patients of 2 healthcare centres in Quebec, Canada. Selected models were implemented in NONMEM (v7.5; ICON Development Solutions). Predictive performance was assessed through prediction and simulation-based diagnostics. In total, 2386 vancomycin concentrations were collected from 274 patients and 476 antibiotic courses. Four vancomycin popPK models were selected for evaluation. None of the models demonstrated overall satisfactory or clinically acceptable predictive performance. Nonetheless, Bae et al.'s model performed best with a median prediction error of 16.25% and median absolute prediction error of 34.66%. Different predictive performance was also observed for vancomycin concentrations from samples collected during and between HD sessions. All evaluated models presented poor overall predictive performance. Further studies are required, through existing popPK model parameter re-estimation or new model development, to adequately describe vancomycin pharmacokinetics for our high-flux intermittent HD patient cohort.