Population Pharmacokinetic Analysis Research Articles

Quantification of maternal and fetal valaciclovir exposure in a pharmacokinetic study of cytomegalovirus-infected pregnant women treated to prevent vertical transmission.

In cases of maternal primary infection with cytomegalovirus (CMV-MPI) maternal treatment with oral valaciclovir 8 g/day has been shown to reduce the risk of fetal infection. The pharmacological profile of this high dosage during pregnancy is not yet known. To quantify maternal-fetal exposure to valaciclovir 8 g/day in a population pharmacokinetic (popPK) study. Between October 2019 and April 2023, pregnant women referred for CMV-MPI were offered to participate following: (i) CMV-MPI <14 weeks of gestation; (ii) acceptance of valaciclovir 8 g/day; and (iii) consent for amniocentesis. Amniotic fluid was tested for (i) CMV PCR for prenatal diagnosis; and (ii) dosage of aciclovir concentration (the active form of valaciclovir). Maternal serum levels of aciclovir were also measured. Aciclovir assays in both compartments were used for popPK analysis. Pharmacokinetics were described using non-linear mixed-effect modelling. We prospectively included 119 women with their 122 fetuses. CMV-MPI occurred at a median of 3.0 (range: -12; + 14) weeks of gestation. CMV-infected pregnant women were treated at a median of 12.3 (range: 4.6-21.4) weeks of gestation for a median duration of 35 days (range: 7-90 days). Median pharmacokinetic parameters (Cmin, Cmax and AUC0-24) were all successfully defined in both maternal blood and amniotic fluid compartments. No differences in aciclovir exposure were observed between infected (n = 12, 9.8%) and non-infected fetuses. Simulations showed that after a last maternal dose, aciclovir concentration would be undetectable in the amniotic fluid after 43-47 h. In this popPK study, maternal and fetal pharmacokinetics were established using in vivo data. The results provide a better understanding of how this fetal therapy works.

PK/PD-Guided Strategies for Appropriate Antibiotic Use in the Era of Antimicrobial Resistance

Antimicrobial resistance (AMR) poses a critical global health threat, necessitating the optimal use of existing antibiotics. Pharmacokinetic/pharmacodynamic (PK/PD) principles provide a scientific framework for optimizing antimicrobial therapy, particularly to respond to evolving resistance patterns. This review examines PK/PD strategies for antimicrobial dosing optimization, focusing on three key aspects. First, we discuss the importance of drug concentration management for enhancing efficacy while preventing toxicity, considering various patient populations, including pediatric and elderly patients with their unique physiological characteristics. Second, we analyze different PK modeling approaches: the classic top-down approach exemplified by population PK analysis, the bottom-up approach represented by physiologically based PK modeling, and hybrid models combining both approaches for enhanced predictive performance. Third, we explore clinical applications, including nomogram-based dosing strategies, Bayesian estimation, and emerging artificial intelligence applications, for real-time dose optimization. Critical challenges in implementing PK/PD simulation are addressed, particularly the selection of appropriate PK models, the optimization of PK/PD indices, and considerations concerning antimicrobial concentrations at infection sites. Understanding these principles and challenges is crucial for optimizing antimicrobial therapy and combating AMR through improved dosing strategies.

Population Pharmacokinetics of Telmisartan in Healthy Subjects and Hypertensive Patients.

Telmisartan exhibits significant pharmacokinetic (PK) variability, but it remains unclear whether its PK profile is altered in hypertensive patients. This study aimed to characterize telmisartan PKs by conducting a meta-analysis and developing a pooled population PK model based on data from healthy subjects and hypertensive patients. Relevant literature was identified by a systematic approach. Eighteen studies were selected for analysis, which included 394 healthy subjects receiving single doses of telmisartan, 190 healthy subjects receiving repeated doses, along with 295 hypertensive patients receiving repeated doses. Pooled population PK analysis incorporated 20 mean concentration-time profiles from 14 studies. Meta-analyses were performed using OpenMeta-Analyst, and population PK modeling was performed using NONMEM®. Repeated telmisartan doses increased peak plasma concentrations. However, other noncompartmental PK parameters remained consistent across healthy and hypertensive populations. Telmisartan PKs were best described using a two-compartment model with first-order absorption and elimination in pooled analysis. Typical PK parameter values for apparent clearance (CL/F), apparent central and peripheral volumes of distribution (V1/F and V2/F), absorption rate constant (ka), and absorption lag time were 18.3 L/h, 20.7 L, 360 L, 0.183 h-1 and 0.228 h, respectively. Interindividual variabilities in CL/F, V1/F, and ka were 84%, 122%, and 106%, respectively. Covariate analysis revealed significantly lower CL/F (63.7%) and V1/F (90.3%) values in hypertensive patients than healthy subjects. These findings quantified the variability of telmisartan PK profile and highlighted the differences between healthy individuals and hypertensive patients, suggesting the need for optimized dosage strategies to improve therapeutic outcomes.

Population Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma.

Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100kg) on certepetide exposure (steady-state maximum concentration [Cmax,ss] and area under the concentration-time curve [AUCss]), as well as low and high CrCL (50 and 150mL/min) on AUCss. Exposure predictions illustrated a relationship between certepetide exposure (AUCss) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide's PKs and will inform dose optimization in ongoing drug development activities.

Population pharmacokinetic analysis in children with different diseases treated with mycophenolate mofetil-Integrated analysis of clinical trials and real-world clinical data.

This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases. To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model. A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95 % confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h-1. Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka. An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population.

Vedolizumab Clearance as a Surrogate Marker for Remission in Inflammatory Bowel Disease Patients: Insights from Real-World Pharmacokinetics.

Background/Objectives: Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to investigate the variability in VDZ trough levels and PK parameters, to assess the relationship between VDZ PK and biochemical response, as well as clinical and endoscopic outcomes. Methods: We included 61 UC and 45 CD patients. Patients' data and trough VDZ concentrations were retrospectively obtained. Population PK analysis was performed using non-linear mixed-effects modelling with NONMEM (version 7.5). Graphs and statistical analyses were performed using R (version 4.1.3). Results: In total, 116 trough VDZ concentrations from 106 patients were described by a two-compartment model. For a typical patient, clearance (CL) was estimated at 0.159 L/day, while in patients previously treated with anti-TNFα agents, VDZ CL increased by 26.4% on average. In univariate binary logistic regression, VDZ trough concentration was not statistically significant predictor of remission, whereas CL was. Moreover, combined CL and faecal calprotectin (FCP) were a statistically significant predictors of remission. The hazard ratio (HR) for CL above 0.1886 L/day was 0.35 (p = 0.05) and for FCP below 250 µg/g was 2.66 (p = 0.02) in a time-to-event analysis. Conclusions: Our population PK model incorporates the effect of prior anti-TNFα agents on CL, suggesting its association with more severe forms of IBD. VDZ CL emerged as a more robust and clinically relevant predictor of remission in IBD patients than trough concentration.

Drug-drug interaction of phenytoin sodium and methylprednisolone on voriconazole: a population pharmacokinetic model in children with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.

Voriconazole (VRC) is recommended for the prevention and treatment of invasive fungal infections in children undergoing hematopoietic stem cell transplantation (HSCT). It demonstrates nonlinear pharmacokinetics (PK) and exhibits substantial inter- and intraindividual variability. Phenytoin sodium (PHT) and methylprednisolone (MP) are commonly used in the early stages of HSCT to prevent epilepsy and graft-versus-host disease. Drug-drug interactions between VRC and these medications represent a significant concern in HSCT recipients. This study aims to investigate the effects of coadministration with PHT, MP, and other covariates on VRC metabolism in children with thalassemia (TM) undergoing allogeneic HSCT (Allo-HSCT) using population pharmacokinetics (PPK) and to recommend the optimal dosage regimen for this unique group. A total of 237 samples from 57 children with TM undergoing Allo-HSCT were collected. Non-linear mixed effects modeling and Monte Carlo simulation (MCS) were applied for PPK analysis and for optimizing VRC dosing, respectively. The VRC data were characterized by a two-compartment model with linear elimination and first-order absorption. All parameters were incorporated in allometric scaling form, with PHT and MP significantly influencing VRC clearance. The MCS revealed a negative correlation between the children's body weight (ranging from 10 to 40kg) and the required dose. When PHT was co-administered, approximately three times the regular dose of VRC was required. In contrast, when MP was administered together, the dose needed to be increased by 12.5-50%. The proposed regimen improved the probability of target attainment for VRC and may serve as a reference for the individualized administration of VRC in clinical practice.

Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL. Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling. Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (tmax) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics. Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.

Implementing a Bayesian approach using Stan with Torsten: Population pharmacokinetics analysis of somatrogon.

Fully Bayesian approaches are not commonly implemented for population pharmacokinetic (PK) modeling. In this paper, we evaluate the use of Stan with R and Torsten for population PK modeling of somatrogon, a recombinant long-acting growth hormone approved for the treatment of growth hormone deficiency. As a software for Bayesian inference, Stan provides an easy way to conduct MCMC sampling for a wide range of models with efficient sampling algorithms, and there are several diagnostic tools to evaluate the MCMC convergence and other potential issues. Three different sets of priors were evaluated for estimation and prediction: a weakly informative uniform set, a moderately informative set, and a very informative set of priors. All three prior sets showed good performance and all chains mixed well. There were some minor differences in the final parameter posterior distributions while implementing different prior sets, but the posterior predictions covered the observations nicely, not only for the individuals included in posterior sampling but also for new individuals. The impact of a centered versus non-centered parameterization were evaluated, with the non-centered approach improving the estimation time, but it was still computationally intensive. Computational resources had the biggest impact on sampling time. Stan took approximately 2.5 h total for the MCMC sampling on a high-performance computing platform (6 cores) and may be reduced further with additional computational resources. The model and comparisons presented show that with adequate computational resources, the Bayesian approaches using Stan and Torsten are useful for population PK analysis, especially for the analysis of special populations, small sample datasets, and when complex model structures are needed.

Continuous infusion of piperacillin/tazobactam optimizes intraoperative antibiotic exposure in patients undergoing elective pelvic exenteration surgery.

Patients undergoing elective pelvic exenteration surgery who receive piperacillin/tazobactam as surgical prophylaxis are at risk of suboptimal intraoperative antibiotic exposure. With this work, we aimed to study the plasma pharmacokinetics of piperacillin and tazobactam in this population to provide dosing recommendations that optimize antibiotic exposure. We developed a prospective, observational, pharmacokinetic study of piperacillin/tazobactam in patients undergoing pelvic exenteration. Population pharmacokinetic analysis and Monte Carlo simulations were performed with Monolix and Simulx software. Probabilities of target attainment of different dosing regimens against the minimum inhibitory concentration (MIC) breakpoints (8 and 16 mg/L) were calculated. Twelve patients were included in the study, with a median age of 50.0 years [interquartile interval (45.3-57.5)] and a median weight of 79.0 kg (61.3-88.3). Median surgical time was 10.5 h (9.8-11.7). A two-compartment linear model best fitted piperacillin and tazobactam data (190 plasma samples). Monte Carlo simulations showed that a lower dose of 2 g/0.25 g loading dose followed by 4 g/0.5 g q8h by continuous infusion provided ≥90% probability of target attainment for MIC = 16 mg/L for most of the patients. For non-continuous infusion regimens, only the 2-hourly bolus re-dosing achieved intraoperative concentrations of piperacillin ≥16 mg/L. Patients with weights ≥ 100 kg and glomerular filtration rates ≥ 120 mL/min required 4 g/0.5 g q6h by continuous infusion after a loading dose. In conclusion, continuous infusion of lower doses of piperacillin/tazobactam is as adequate as the 2-hourly re-dosing recommended by the current guidelines for surgical prophylaxis in pelvic exenteration. Patients with higher weights and glomerular filtration rates are at greater risk of inadequate exposure.

Population pharmacokinetics and dosing simulations of temocillin in liver transplanted paediatric patients: a prospective, open-label, non-randomized study.

Temocillin is a β-lactam antibiotic used for preventing or treating bacterial infections in liver-transplanted children. We characterized its pharmacokinetics in plasma and ascitic fluid and proposed dosing regimens that maximize achievement of effective drug exposures in this patient group. Patients aged 6-36months received 25 mg/kg/12h (n=14) or 25 mg/kg/8h (n=23). Total and unbound temocillin concentrations were measured in plasma and ascitic fluid. Drug safety was monitored. Non-compartmental and population pharmacokinetic analyses were performed, together with Monte-Carlo simulations. No safety concerns were reported. For 25 mg/kg/12h, the unbound mean (±SD) Cmax and Cmin were 38±16 and 2±1 mg/L, respectively. For the 25 mg/kg/8h dose, the unbound Cmax remained similar although the mean Cmin increased to 5±3 mg/L. Protein binding was saturable. Median penetration in ascitic fluid from plasma was 82% (min-max: 63-95%). A three-compartment model with first order elimination best described unbound pharmacokinetic profiles in plasma and ascitic fluid, with body weight and eGFR as significant covariates. Monte-Carlo simulations suggested that 90% Probability of Target Attainment (PTA) was achieved in both fluids with 25 mg/kg/12h for MICs ≤4 mg/L, eGFR ≤180 mL/min/1.73m2 or weight ≥6 kg, and with 25 mg/kg/8h, for MICs ≤8 mg/L, GFR ≤120mL/min/1.73m2 or weight ≥11 kg. Although adequate in many instances, the current dosing regimen is likely inadequate for patients with low body weight, high renal function, or bacteria with high MIC, emphasizing the need for patient-specific factors to be considered in dose selection. These data support the importance of paediatric pharmacokinetic studies to optimize drug dosing regimens.

Population pharmacokinetic analysis identifies an absorption process model for mycophenolic acid in patients with renal transplant.

The pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty-two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed-effects modeling program NONMEM. The MPA area under the concentration-time curve at 0-12 h (AUC0-12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two-compartment model incorporating sequential zero- and first-order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half-life, lag time, and duration of zero-order absorption, respectively. Simulation results showed that a dose regimen of 500-1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF.

Building vancomycin population pharmacokinetic model for Japanese low birth weight infants in comparing it with previously reported pediatric population pharmacokinetic models.

Vancomycin (VAN) is one of therapeutic agents for severe infections, and its efficacy and safety are subject to therapeutic drug monitoring. However, there is a lack of data regarding the administration of VAN to low birth weight (LBW) infants. This presents a challenge to ensure optimal dosing and maximize the benefits of VAN therapy in this specialized patients. VAN serum samples were collected through opportunistic sampling for clinical use. Population Pharmacokinetics (PopPK) analysis was conducted with a one-compartment model in a nonlinear mixed-effects model using Phoenix NLME (Certara ver.8.4). We compared the final model with the 12 previously reported PopPK models. A total of 106 samples from 25 patients were obtained to establish the PopPK model for LBW infants. We successfully developed one-compartment PopPK model using Phoenix NLME based on Japanese LBW infants receiving VAN with body weights of less than 2,500 g. The covariates in our PopPK model are postmenstrual age, body weight, and serum creatinine for clearance and postnatal age for volume of distribution. A comparison of the goodness-of-fit metrics indicated that our PopPK model achieved better prediction accuracy for VAN blood concentrations, as indicated by the lower values of these metrics. We successfully established a PopPK model incorporating PNA and PMA as new covariates. By addressing the issue of data scarcity in LBW infants, our study provides insights and strategies to manage VAN therapy in LBW infants, thus optimizing its effectiveness and safety.

An Extensive Therapeutical Drug Monitoring Repository for Localized Population Pharmacokinetics Research

Aim: The study's long-term goals, such as determining supratherapeutic ranges according to age distributions specific to the country, adjusting dosages for additional drugs used by patients in different disease groups, and providing the opportunity for etiological studies in the light of diagnosis and drug metabolism perspective, are of great importance in defining the study. Method: Population pharmacokinetics is a method expressed to evaluate processes such as absorption, distribution, metabolism, and elimination of a drug from an individual's blood-plasma concentration. In drug pharmacokinetic experiments, generating data without considering any pharmacokinetic differences among patients prevents the measurement or observation of variability among individuals in the population as a simple approach. The dose-concentration relationship is crucial for individualized dose adjustment. Additionally, the impact of other drugs used by the individual on metabolite levels and the metabolic interactions between drugs play a critical role in the development of personalized treatments. Population approaches provide a foundation that benefits the observation of these effects. The variability in drug metabolism among individuals forms one of the fundamental building blocks of personalized treatment approaches, specifically through Therapeutic Drug Monitoring (TDM), which plays an important role in determining the therapeutic range of drugs. Materials: In this study, drug metabolism findings of patients served at NP Istanbul Brain Hospital between 2010 and 2022 were examined within the repository created along with other patient-specific parameters. Results and Conclusion: The analysis results have been followed up longitudinally, partially demographically, and retrospectively. Thanks to the repository of NP Istanbul Brain Hospital, population pharmacokinetic analyses aimed in this study are being conducted for the first time globally and nationally in terms of scope. The repository has been studied with TDM for individualized treatment methods, and within this project, it is anticipated to perform phenotyping with the population pharmacokinetic approach.

The use of population pharmacokinetics to extrapolate food effects from human adults and beagle dogs to the pediatric population illustrated with ibuprofen as a case

Oral drug administration is the most convenient route of administration in the pediatric population. However, children are often not fasted when drugs are orally administered, hence potential food-drug interactions might occur. Most of these interactions are extrapolated from studies performed in human adults where a recommended high-fat, high-calorie meal is administered prior to drug dosing. As the recommended protocols are based on studies in support of adult drug development, these studies do not mimic the meal composition administered to the pediatric population, especially the very young ones, which renders food-drug interactions in this population understudied. Therefore, it was evaluated to what extent population pharmacokinetics could reliably extrapolate food effects from human adults and beagle dogs to mimic the real-life situation in the pediatric population. Eight human adults and six beagle dogs received ibuprofen under different dosing conditions (fasted, reference meal fed condition, infant formula fed condition). Population pharmacokinetic analysis was performed to derive the pharmacokinetic parameters to be scaled to pediatric ages. For both species, a one-compartment model best described the data, where in human adults a dual-input function to capture the double absorption peak significantly improved the model fit. Simulations for a virtual pediatric population demonstrated that the predictive ability of human adults and beagle dogs to inform absorption effects under different dosing conditions using population pharmacokinetic modeling appeared to be reasonable. However, to be able to fully validate the predictability of both species for ibuprofen, additional studies in the pediatric population are required to generate more informative data.

Population pharmacokinetic analysis of quizartinib in patients with newly diagnosed FLT3-internal-tandem-duplication-positive acute myeloid leukemia.

The population pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 have been previously described in healthy volunteers (HV) and relapsed/refractory (R/R) FLT3-internal-tandem-duplication-positive (FLT3-IDT-positive) acute myeloid leukemia (AML) patients receiving quizartinib monotherapy. In this analysis, we characterized the population PK of quizartinib and AC886 in newly diagnosed FLT3-ITD-positive AML patients receiving standard induction and consolidation chemotherapy as background treatment, using data from the Phase 3 QuANTUM-First trial and 12 earlier studies. Quizartinib PK were best described by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. A two-compartment model with first-order metabolite formation and first-order elimination best fitted AC886 data. The PK of both moieties showed large interindividual variability (approximately 70% coefficient of variation for systemic clearances). The use of strong cytochrome P450 3A (CYP3A) inhibitors had the largest impact on exposure, increasing the steady-state area under the curve during the dosing interval (AUCss) by 1.8-fold. This is consistent with observations in HV and R/R AML patients and confirms the need for dose adjustments during coadministration. A novel finding in newly diagnosed AML patients was the phase-dependent change in steady-state quizartinib exposure: dose-normalized AUCss values were 0.6-fold during induction, similar during consolidation, and 1.4-fold during continuation compared to R/R AML patients receiving quizartinib monotherapy. The present analysis highlighted the comparison of quizartinib and AC886 PK between newly diagnosed AML patients and previously studied populations, informed dose modifications needed with strong CYP3A inhibitors, and supported the use of derived individual exposure metrics in separate exposure-response analyses.

Pharmacokinetic Modeling and Model-Based Hypothesis Generation for Dose Optimization of Clonidine in Neonates With Neonatal Opioid Withdrawal Syndrome.

The No-POPPY study (NCT03396588), a double-blind, randomized trial compared morphine with clonidine therapy for neonatal opioid withdrawal syndrome (NOWS) and found that the duration of treatment was similar across groups. This is significant because perinatal use of morphine has the potential for neurodevelopmental consequences. Still, the clonidine group reached symptom stabilization (Finnegan score (FS) < 8) later than the morphine group and had a more significant number of patients who required adjunct therapy. However, the mean FS was consistently lower in the clonidine group after day 6. This prompted us to use pharmacokinetic (PK) and parametric time-to-event (TTE) modeling to simulate dosage schedules that may decrease the time to stabilization and reduce the need for adjunct therapy. Population PK (popPK) analysis was conducted, and the final model was a one-compartment model with first-order absorption and elimination, incorporating allometric scaling and age effect on apparent clearance (CL/F) and apparent volume (V/F). The population estimates for CL/F and V/F were 13.6 L/h/70 kg and 416 L/70 kg, respectively, similar to the reported values. A Weibull model described the TTE data best, followed by incorporating predicted average concentrations to yield the final Weibull accelerated failure time model. Simulations of dosing strategies showed that increasing both the starting and maximum doses could potentially shorten the time to stabilization, and thus, length of treatment and hospital stay. Given the hypothesis-generating nature of this analysis, the recommended dosing regimens should be tested prospectively to evaluate their benefits.

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.

Abstract 4135497: Model-informed dosing recommendations for digoxin in interstage single ventricle heart disease

Digoxin is commonly used in infants with single ventricle heart disease (SVD) and may decrease mortality in the interstage period. While labeled for the treatment of heart failure in infants, dosing recommendations do not account for alterations in drug disposition in SVD. We aimed to characterize digoxin pharmacokinetics (PK) in interstage infants with SVD. Infants &lt;3 months with SVD who received enteral digoxin per standard of care after stage 1 and prior to stage 2 palliation were included in this prospective, multicenter, open-label PK study. Preterm infants and those with creatinine &gt;2mg/dL or on extracorporeal support at enrollment were excluded. PK samples were prospectively collected and digoxin plasma concentrations quantitated by HPLC/MS/MS assay validated per FDA guidance. Population PK analysis was performed in NONMEM. Effects of covariates on PK parameters were evaluated. Dosing simulations were conducted in a virtual cohort of infants with SVD that optimized dosing to achieve trough concentrations of 0.5-2 ng/mL, the label-endorsed reference range for heart failure. Across 10 sites, 50 infants contributed 207 PK samples. Table 1 shows cohort characteristics. A 2-compartment model with transit compartment absorption and linear elimination best described the data. Renal function and weight were significant covariates. Infants with SVD had lower apparent clearance than previously reported in infants without SVD. Current labeled dosing resulted in simulated exposures above the reference range ( Figure 1 ). A new dosing regimen for infants with SVD is proposed. Digoxin PK is altered in infants with SVD. Dosing should account for renal function, age, and weight.