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Vancomycin has a narrow therapeutic window and a high inter-individual pharmacokinetic variability, especially in neonates with fast maturational and pathophysiological changes, that needs individualized dosing. Physiologically based pharmacokinetic (PBPK) model and population pharmacokinetic (PopPK) model are both useful tools in model-informed precision dosing, while the former is under research in application of vancomycin in neonates. This study aimed to develop a PBPK model of vancomycin in adult and pediatric population, and compared it with published PopPK model (priori or Bayesian method) in predicting vancomycin concentration in 230 neonatal patients (postmenstrual age, PMA, 25-45 weeks). The developed PBPK model showed a good fit between predictions and observations. PBPK model and PopPK model are complementary in different clinical scenarios of vancomycin application. The physiological-change description of PBPK model showed a superior advantage in initial dosing optimization. As for subsequent dose optimization, PopPK Bayesian forecasting performed better than the PBPK estimation in neonates. However, initial precision dosing tools for early neonates (with PMA < 36 weeks) still need further exploitation.
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Aims: A strategy based on therapeutic drug monitoring and population pharmacokinetic (popPK) models would likely increase the rate of clinical remission (CR) after infliximab (IFX) induction in patients with Crohn's disease (CD). This study aimed to evaluate the relationship between early IFX levels and antibodies to infliximab (ATI) and CR at week 14 and simulate the probability of attaining the identified exposure target. Methods: Patients with CD (n = 140) treated with IFX were enrolled to develop the popPK model. Of these, 43 moderate-to-severe patients with CD were followed up at week 14. Simulations were performed on patients with different dosage regimens and covariates. Results: IFX levels >20.08 µg/mL at week 2, >18.44 µg/mL at week 6, and >3.08 µg/mL at week 14 were linked to CR. A one-compartment model fit the data best. The covariates influencing clearance were fat free mass, albumin and ATI levels. To achieve IFX levels >20.08 µg/mL at week 2, ≥400 mg IFX was predicted to be required in over 50% patients with 45-70 kg and 35-45 g/L albumin, except for patients with 70 kg and 30 g/L albumin. Conclusion: IFX levels >20.08 µg/mL at week 2 and absence of ATI at week 14 are associated with CR. Optimising IFX induction dosing will be critical to achieve the target of early IFX levels associated with CR.
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BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations. OBJECTIVES: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens. METHOD: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model. RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained. CONCLUSION: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population. CLINICAL TRIAL REGISTRATION: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.
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PURPOSE: This study aims to assess the predictive performance of published valproic acid (VPA) population pharmacokinetic (PPK) models using an external data set in Chinese adults with epilepsy or after neurosurgery. METHODS: A total of 384 concentrations from 290 Chinese adults with epilepsy or after neurosurgery were used for external validation. Data on published VPA PPK models were extracted from the literature. Prediction-based diagnostics (such as F20 and F30), simulation-based diagnostics, and Bayesian forecasting were used to evaluate the predictability of models. RESULTS: The results of prediction-based diagnostics of all models were unsatisfactory. Models B, F, and H showed the best prediction performance in simulation-based diagnostics and Bayesian forecasting, demonstrating superior precision and accuracy. Bayesian forecasting demonstrated significant improvements in the model predictability. CONCLUSION: The published PPK models showed extensive variation in predictive performance for extrapolation among Chinese adults with epilepsy or after neurosurgery patients. Fixed parameters of Vd and Ka in the PPK modeling of VPA might be the reason for the unsatisfied predictive performance. Bayesian forecasting significantly improved model predictability and may help to individualize VPA dosing.
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INTRODUCTION: Administration of vancomycin dose by continuous infusion (CI) according to population pharmacokinetic (Pop Pk) models is highly recommended in critically ill patients who exhibit pathophysiological changes. OBJECTIVE: The objective of this study was to develop and validate a Pop Pk model of vancomycin administered by CI in critically ill patients with normal and impaired renal functions. METHODS: The Pop Pk study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (gender, age, weight, height, and creatinine clearance [Cr-Cl]) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. RESULTS: A one-compartment model (volume of distribution [Vd], elimination from compartment [Ke]) was found to show a good prediction performance. The influence of covariates has shown that age and Cr-Cl affected significantly Vd and Ke, respectively. The distribution of simulated vancomycin clearance (CLv) according to different renal function levels showed a negative correlation between CLv and the severity of the renal impairment. The internal validation of the final model showed that the plot of individual-predicted concentration versus observed concentration resulted in r2 = 0.86 in the final model. The external validation of the final model showed an acceptable predictive performance. CONCLUSION: We developed a Pop Pk model for vancomycin administered by CI in critically ill patients. A significant impact of Cr-Cl and different stages of renal failure on CLv has been demonstrated. The establishment of an individualized proposal dose based on this model may be helpful to achieve the target range which is critical in optimizing the efficacy and safety of this antibiotic.
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Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.
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AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.
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Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.
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Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5-15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0-18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.
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Anomalías Linfáticas , Modelos Biológicos , Sirolimus , Humanos , Sirolimus/farmacocinética , Sirolimus/administración & dosificación , Sirolimus/sangre , Niño , Preescolar , Femenino , Masculino , Lactante , Adolescente , Anomalías Linfáticas/tratamiento farmacológico , Estudios Retrospectivos , Método de Montecarlo , Recién Nacido , Medicina de Precisión/métodos , Inmunosupresores/farmacocinética , Inmunosupresores/administración & dosificación , Inmunosupresores/sangreRESUMEN
Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.
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Factor VIII , Hemofilia A , Factor de von Willebrand , Humanos , Factor VIII/farmacocinética , Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Factor de von Willebrand/farmacocinética , Factor de von Willebrand/administración & dosificación , Modelos Biológicos , Adulto , Masculino , Adulto Joven , Cinética , Polietilenglicoles/farmacocinética , Polietilenglicoles/administración & dosificación , AdolescenteRESUMEN
This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure-response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2-compartment model with time-dependent nonlinear elimination. The prediction-corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure-response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation-based methods.
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Anticuerpos Monoclonales Humanizados , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Modelos Biológicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Esquema de Medicación , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Adulto Joven , China , Pueblos del Este de AsiaRESUMEN
Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS "Burlo Garofolo" in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12-15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient's general well-being and providing the necessary treatment.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores , Tacrolimus , Humanos , Tacrolimus/uso terapéutico , Tacrolimus/farmacocinética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Femenino , Masculino , Inmunosupresores/uso terapéutico , Inmunosupresores/farmacocinética , Estudios Retrospectivos , Preescolar , Adolescente , Lactante , Resultado del Tratamiento , Trasplante Homólogo , ItaliaRESUMEN
AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.
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The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.
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AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. METHODS: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. RESULTS: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. CONCLUSIONS: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.
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Antipsicóticos , Preparaciones de Acción Retardada , Modelos Biológicos , Risperidona , Esquizofrenia , Humanos , Risperidona/farmacocinética , Risperidona/administración & dosificación , Antipsicóticos/farmacocinética , Antipsicóticos/administración & dosificación , Masculino , Femenino , Esquizofrenia/tratamiento farmacológico , Adulto , Preparaciones de Acción Retardada/farmacocinética , Persona de Mediana Edad , Adulto Joven , Teorema de Bayes , Disponibilidad Biológica , Adolescente , Voluntarios SanosRESUMEN
OBJECTIVE: Several population pharmacokinetic models of tacrolimus in liver transplant patients were built, and their predictability was evaluated in their settings. However, the extrapolation in the prediction was unclear. This study aimed to evaluate the predictive performance of published tacrolimus models in adult liver transplant recipients using data from the Thai population as an external dataset. METHODS: The selected published models were systematically searched and evaluated for their quality. The external dataset of patients who underwent the first liver transplant and received immediate-release tacrolimus was used to assess the predictive performance of each selected model. Trough concentrations between 3 and 6 months were retrospectively collected to evaluate the predictability of each model using prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. RESULTS: Sixty-seven patients with 360 trough concentrations and eight selected published models were included in this study. None of the models met the predictive precision criteria in prediction-based diagnostics. Meanwhile, four published population pharmacokinetic models showed a normal distribution in NPDE testing. Regarding Bayesian forecasting, all models improved their forecasts with at least one prior information data point. CONCLUSION: Bayesian forecasting is more accurate and precise than other testing methods for predicting drug concentrations. However, none of the evaluated models provides satisfactory predictive performance for generalization to Thai liver transplant patients. This underscores the need for future research to develop population PK models tailored to the Thai population. Such efforts should consider the inclusion of nonlinear pharmacokinetics and region-specific factors, including genetic variability, to improve model accuracy and applicability.
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Teorema de Bayes , Inmunosupresores , Trasplante de Hígado , Modelos Biológicos , Tacrolimus , Humanos , Tacrolimus/farmacocinética , Tacrolimus/sangre , Inmunosupresores/farmacocinética , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Masculino , Femenino , Tailandia , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Anciano , Pueblos del Sudeste AsiáticoRESUMEN
Aims: The population pharmacokinetic (PPK) model-based machine learning (ML) approach offers a novel perspective on individual concentration prediction. This study aimed to establish a PPK-based ML model for predicting tacrolimus (TAC) concentrations in Chinese renal transplant recipients. Methods: Conventional TAC monitoring data from 127 Chinese renal transplant patients were divided into training (80%) and testing (20%) datasets. A PPK model was developed using the training group data. ML models were then established based on individual pharmacokinetic data derived from the PPK basic model. The prediction performances of the PPK-based ML model and Bayesian forecasting approach were compared using data from the test group. Results: The final PPK model, incorporating hematocrit and CYP3A5 genotypes as covariates, was successfully established. Individual predictions of TAC using the PPK basic model, postoperative date, CYP3A5 genotype, and hematocrit showed improved rankings in ML model construction. XGBoost, based on the TAC PPK, exhibited the best prediction performance. Conclusion: The PPK-based machine learning approach emerges as a superior option for predicting TAC concentrations in Chinese renal transplant recipients.
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A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Piridonas , Humanos , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Lamivudine/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Masculino , Femenino , VIH-1/efectos de los fármacos , Persona de Mediana Edad , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Combinación de MedicamentosRESUMEN
OBJECTIVES: Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration. METHODS: Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen. RESULTS: In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively. CONCLUSION: The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.