Search Results (58)

Background/Objective: Voriconazole exhibits nonlinear pharmacokinetics and wide interindividual variability driven by CYP2C19 phenotype and clinical covariates, necessitating early therapeutic drug monitoring (TDM). This study aimed to assess how the choice of population pharmacokinetic (PopPK) models influences genotype-stratified voriconazole exposure under a standardized adult regimen, and to delineate model-specific implications for clinical prescribing. Methods: Five CYP2C19-informed PopPK models (Yun, Ling, Wang, Dolton, Friberg) were evaluated under one oral dosing scenario with an identical extensive metabolizers (EM)/intermediate metabolizer (IM)/poor metabolizers (PM) cohort; steady-state exposure metrics were compared across models, with sensitivity checks using model-specific cohorts. Results: Yun predicted the highest exposures with the steepest EM–IM–PM gradient, suggesting a need for caution against upper-tail exceedance when genotype effects are pronounced. Ling yielded intermediate exposures with a modest gradient, consistent with adult central tendencies, thus supporting its use for standard adult initial dosing. Wang primarily distinguished between EM and PM, proving useful for lower-bound checks where underexposure risk or limited genotype information is a concern. Friberg (and Dolton) demonstrated lower exposures with limited genotype separation, offering insights when persistent underexposure is suspected. Conclusions: These model-specific patterns indicate that PopPK model choice can influence initial dose-band selection and the timing of early TDM in routine adult care. Ling can serve as a baseline for standard adult initiation, whereas Yun is appropriate for safety-first scenarios when upper-tail risk from strong genotype effects is anticipated; Wang assists when IM data are lacking or when lower-bound checks are needed. Generalizability beyond standardized adult dosing (e.g., special populations) remains limited. Full article

Background/Objectives: Mycophenolic acid (MPA) is used as part of first-line combination immunosuppressive therapy for renal transplant recipients. Personalized dosing approaches are needed to balance efficacy and minimize toxicity due to the pharmacokinetic variability of the drug. In this study, population pharmacokinetic (PopPK) modeling and machine learning (ML) techniques are coupled to provide valuable insights into optimizing MPA therapy. Methods: Using data from 76 renal transplant patients, two PopPK models were developed to describe and predict MPA levels for two different formulations (enteric-coated mycophenolate sodium and mycophenolate mofetil). Covariate effects on drug clearance were assessed, and Monte Carlo simulations were used to evaluate exposure under normal and reduced clearance conditions. ML techniques, including principal component analysis (PCA) and ensemble tree models (bagging and boosting), were applied to identify predictive factors and explore associations between MPA plasma/saliva concentrations and the examined covariates. Results: Total daily dose and post-transplant time (PTP) were identified as key covariates affecting clearance. PCA highlighted MPA dose as the primary determinant of plasma levels, with urea and PTP also playing significant roles. Boosted tree analysis confirmed these findings, demonstrating strong predictive accuracy (R² > 0.91). Incorporating saliva MPA levels improved predictive performance, suggesting that saliva may be a complementary monitoring tool, although plasma monitoring remained superior. Simulations allowed exploring potential dosing adjustments for patients with reduced clearance. Conclusions: This study demonstrates the potential of integrating machine learning with population pharmacokinetic modeling to improve the understanding of MPA variability and support individualized dosing strategies in renal transplant recipients. The developed PopPK/ML models provide a methodological foundation for future research toward more personalized immunosuppressive therapy. Full article

Background/Objectives: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. Methods: A PopPK model was developed in NONMEM using full PK profiles (10–18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. Results: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. CYP3A5*1 expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for CYP3A5*1 expressers and 1:0.7 for non-expressers. Conclusions: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac’s enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. These genotype-specific recommendations provide clinically actionable guidance to complement therapeutic drug monitoring and support more individualized conversion protocols in renal transplantation. Full article

Introduction: Vatiquinone is a first-in-class, small molecule designed to maintain mitochondrial function in the disorders like Friedreich’s ataxia (FA). Vatiquinone inhibits 15-lipoxygenase, consequently decreasing oxidative stress and neuroinflammatory response pathways. Methods: Population pharmacokinetic modeling analysis was conducted to characterize vatiquinone pharmacokinetic profiles in healthy volunteers and patients and explore the effects of covariates on vatiquinone exposures. Results: A two-compartment model with parallel zero- and first-order absorption was developed and verified. The values of essential parameters were: absorption fraction through the first-order process, 74.4%; absorption rate constant, 0.20 h⁻¹; delay time, 2.79 h; zero-order absorption duration, 6.03 h; apparent volume of distribution, 180.75 L for the central and 4852.69 L for the peripheral compartment; and apparent clearance, 162.72 L/h. Strong CYP3A4 inducers could reduce exposure by 50%; strong CYP3A4 inhibitors could increase it by 252%. Vatiquinone exposure was 19% lower in patients with Friedreich’s ataxia versus healthy volunteers. A medium-fat meal increased exposure up to 25-fold versus a fasted status. Body weight and body mass index had significant clinical relevance to exposures. Conclusions: A two-compartment model effectively described the pharmacokinetic profiles of vatiquinone after oral administration. Covariates significantly impacted exposures, including body weight, meals, disease status, comedications and body mass index. Full article

Background/Objectives: MB09 is a denosumab biosimilar to the reference products (RPs) Xgeva and Prolia. A population pharmacokinetic (popPK) meta-analysis was conducted to characterize the denosumab PK profile and to support MB09 biosimilarity. Methods: Pooled denosumab PK data from one phase I study [255 healthy adult men receiving a single 35 mg subcutaneous (SC) dose] and one phase III study (555 postmenopausal women with osteoporosis receiving two 60 mg SC doses, one every six months) were used. A one-compartment model with first-order absorption and elimination and parallel non-linear saturable clearance was used. Body weight was included on clearance as a structural covariate and treatment was tested as a covariate on all PK parameters. PK biosimilarity was assessed at 35 mg dose. Results: For a 70 kg subject, the apparent clearance and central volume of distribution for denosumab were 0.123 L/day [95% confidence interval (CI): 0.114, 0.132] and 9.33 L (95% CI: 9.11, 9.55), respectively. The Michaelis constant was 0.124 ng/mL and the maximum rate for the non-linear clearance was 0.139 ng/day. Model-based bioequivalence criteria were met for RP Xgeva, European and US-sourced, versus MB09 for a dose of 60 mg SC. The mean area under the plasma concentration curve (AUC) resultant from the simulation of MB09 120 mg SC was similar to the published mean AUC observed for Xgeva 120 mg SC every four weeks. Conclusions: This analysis provides a valuable assessment of denosumab PK characteristics and elucidates in more detail how the MB09 PK profile compares to the denosumab RPs, supporting the totality of evidence on MB09 biosimilarity. Full article

Background: The primary treatment of schizophrenia is pharmacotherapy with antipsychotic agents, such as risperidone and paliperidone. Population pharmacokinetic (PopPK) modelling plays a crucial role in optimising therapy by predicting of plasma concentrations, therapeutic efficacy, and the risk of adverse effects using model informed precision dosing. Objectives: This systematic review examined the PopPK models of risperidone and paliperidone in patients diagnosed with schizophrenia based on the available scientific evidence. Methods: A systematic review of the health science databases was conducted. The inclusion criteria were original articles published in peer-reviewed journals, studies focusing on the development of original PopPK models of risperidone and paliperidone, and clinical studies. The exclusion criteria were full-text articles that could not be retrieved; studies not including subjects diagnosed with schizophrenia or schizoaffective disorders; and studies that did not investigate risperidone or paliperidone. Results: A total of 19 studies developing PopPK models were analysed, including one- or two-compartment PopPK model structures. Interindividual variability in the pharmacokinetic parameters was shown to be influenced by factors such as CYP2D6 activity, renal function, body mass index, and sex. Parameter estimation revealed high variability in clearance and volume of distribution. Conclusion: Numerous PopPK models for risperidone and paliperidone have been published with a detailed characterisation of absorption, metabolism, and elimination. Therefore, future research should focus on the external validation of these models to facilitate their integration into clinical practice and optimise individualised dosing, ultimately improving treatment efficacy and safety across diverse patient populations. Full article

Objectives: A population pharmacokinetic (popPK) model was used to evaluate fluconazole dosing regimens for Candida spp. prophylaxis in hemato-oncologic pediatric patients. Methods: Data were collected from patients receiving 3–12 mg/kg of fluconazole once daily as a 0.5 or 1 h infusion. Fluconazole concentrations were determined using a validated HPLC-UV method. The popPK model employed non-linear mixed effects modeling using the FOCEI algorithm implemented in nlmixr2. Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in the rxode2 package to investigate dosing recommendations. Results: Concentration time data from nine patients, aged 7 months to 18 years, with 35 samples, were described by a one-compartment model with first-order elimination and allometric scaling of body weight. Assuming a Candida spp. MIC = 2 mg/L and the ratio of the area under the unbound concentration–time curve at a steady state to the MIC (fAUC/MIC) ≥ 100 as the pharmacokinetic/pharmacodynamic (PK/PD) target, the standard dosing regimens reported in the Summary of Product Characteristics (SmPC) did not achieve the target for patients treated with doses < 6 mg/kg. Conclusions: Hemato-oncologic pediatric patients require increased fluconazole doses to attain therapeutic efficacy. These results warrant clinical validation and should be confirmed by assessing a larger number of patients. Full article

Objectives: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. Methods: Data were collected from four studies in intensive care unit (ICU) adult patients receiving 400–600 mg of ceftaroline every 8–12 h in a one-hour infusion. The PopPK model was developed according to non-linear mixed effects modeling implemented in Monolix 2024R1. To investigate dosing recommendations, Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in Simulx 2024R1. Results: We collected 296 plasma concentrations from 29 non-CRRT patients and 24 pre-filter (systemic), 23 post-filter, and 23 effluent concentrations from four CRRT patients using WebPlotDigitizer (Version 4.7). A five-compartment model, with the first-order elimination from the central compartment and additional elimination with the effluent during CRRT, best described the ceftaroline concentrations. Creatinine clearance (Cl_Cr) was identified as a covariate on the clearance of elimination (Cl) and CRRT modality on the central and peripheral compartments’ volumes and intercompartmental clearance. The results of dosage simulations for different CRRT modalities and Cl_Cr, S. pneumoniae (MIC = 0.25 mg/L) and methicillin-resistant S. aureus (MRSA) (MIC = 1 mg/L) infections, and assumed 100%ƒT_>MIC target, revealed that registered ceftaroline dosages are sufficient to achieve assumed PTA, except MRSA infection in patients with augmented renal clearance (ARC). Conclusions: Our successfully developed model allows flexible PK simulations of ceftaroline, including real-time changes in settings and even temporary or permanent cessation of CRRT. However, the results of our study warrant clinical validation and should be used with caution primarily due to the limited CRRT patient number included in the analysis. Full article

Background: Salbutamol, a short-acting β₂-agonist used in asthma treatment, is available in multiple formulations, including inhalers, nebulizers, oral tablets, and intravenous, intramuscular, and subcutaneous routes. Each formulation exhibits distinct pharmacokinetic (PK) and pharmacodynamic (PD) profiles, influencing therapeutic outcomes and adverse effects. Although asthma management predominantly relies on inhaled salbutamol, understanding how these formulations interact with patient-specific characteristics could improve personalized medicine approaches, potentially uncovering the therapeutic benefits of alternative formulations for an individual patient. Herein, this study aims to analyze how covariates—such as age, weight, gender, body surface area (BSA), cytochrome P450 (CYP) expression, race, and health status—affect the therapeutic regime of orally administered salbutamol using population PK (popPK) modeling. The final model is intended as a tool to support the selection of optimal formulation and dosage regimen based on individual patient profiles. Methods: A dataset of 40 virtual patients derived from a physiologically based PK (PBPK) model of oral salbutamol was included in the popPK model. Results: A two-compartment model with first-order elimination and absorption, with a transit compartment, best described the plasma concentration–time profile following a 4 mg dose. Relationships were identified between gender and mean transit time (M_tt) and clearance (Cl), as well as the effects of weight and BSA on the volume of distribution of the central compartment (V1) and Cl, and a significant impact of health status on Cl. Conclusions: Despite current contraindications for oral salbutamol, our findings suggest that certain individuals, particularly children, may benefit from oral treatment over inhalation. We also identified individual characteristics associated with increased salbutamol toxicity risk, indicating the need for dose adjustment or alternative administration. This study further highlights the potential of popPK modeling in personalized therapy through a fully in silico approach. Full article

Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant covariates that impact gabapentin PK. Methods: Data were retrospectively collected from 82 hospitalized adult patients with TDM gabapentin concentrations. Renal function indicators (i.e., estimated glomerular filtration rate, creatinine clearance, acute kidney injury), body weight parameters (i.e., actual body weight, ideal body weight, adjusted body weight, lean body weight, body mass index, obesity status), fasting plasma glucose levels, and diagnosis of type 2 diabetes were tested as potential covariates. A popPK model was developed in MONOLIX (2020R1, Lixoft, France). Results: A one-compartment model best described gabapentin PK with first-order absorption, dose-dependent bioavailability, first-order elimination, and no lag time. Population parameter estimates for the volume of distribution (V_d), and clearance (Cl) were 44.61 L, and 5.73 L/h, respectively. Serum creatinine was a significant covariate on Cl. Conclusions: The popPK model highlights the importance of renal function in the interindividual variability of gabapentin PK and suggests that diabetes and body weight parameters have no impact on gabapentin PK. Moreover, our study supports the utility of leveraging data obtained from clinical TDM for popPK model development. Full article

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. Full article

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions in the extract matrix that improved the absorption of rutin metabolites compared to the pure compound, among other PK effects. This research aimed to study the PK of rutin alone and in the extract and assess potential PK interactions in the extract matrix on the flavonoid and its metabolites in rabbits, a nonrodent species; Methods: Animals received pure rutin or extract orally and intravenously. The PK analysis used noncompartmental and population pharmacokinetics (popPK) methods, and simple allometry was applied to predict human PK parameters; Results: The rutin concentration–time profile fit a two-compartment model with first-order elimination, while its metabolites fit a double first-order absorption model. The extract matrix led to increased absorption, distribution, and elimination of rutin as well as increased bioavailability of its metabolites in rabbits; Conclusions: The popPK model defined the equations for PK parameters describing these findings, and the increased volume of distribution and clearance of rutin was maintained in human predictions. These results will support the development of a new herbal medicine. Full article

Methotrexate (MTX), which presents high inter-individual variability, is part of the Brazilian Osteosarcoma Treatment Group (BOTG) protocol. This work aimed to develop a MTX population pharmacokinetic model (POPPK) for Brazilian children with osteosarcoma (OS) following the BOTG protocol to guide rescue therapy and avoid toxicity. The model was developed in NONMEM 7.4 (Icon^®) using retrospective sparse data from MTX therapeutic drug monitoring of children attending a southern Brazilian public reference hospital. Data were described by a two-compartment model using 216 MTX cycles from 32 patients (5–18 y.o.) with OS who received 12 g/m² dose/cycle. To explain inter-individual and inter-occasion variability in clearance and peripheral volume, covariates from demographic and biochemical data were evaluated. Serum creatinine was a significant covariate of MTX clearance (14.8 L/h), and the body surface area (BSA) was significant for central compartment volume (82.5 L). Inter-compartmental clearance and volume of peripheral compartment were 0.178 L/h and 5.72 L, respectively. The model adequately describes MTX exposure in Brazilian children with OS. Successful simulations were performed to predict MTX concentrations in pediatric patients above five years old with acute kidney injury and anticipate rescue therapy adjustments. Full article

The aim of the present study was to develop and evaluate the performance of a methodology to estimate the population pharmacokinetic (PK) parameters along with the inter-individual variabilities (IIVs) from patients’ reported aggregate concentration–time data, in particular, mean plasma concentrations and their standard deviations (SDs) versus time, such as those often found in published graphs. This method was applied to the published data of gevokizumab, a novel monoclonal anti-interleukin-1β antibody, in order to estimate the drug’s population pharmacokinetic (PopPK) parameters of a second-generation minimal physiologically based pharmacokinetic (mPBPK) model. Assuming this mPBPK model, a mixed effects approach was utilized to allow accounting for the random inter-group variability (IGV) that was assumed among different dosage groups. The entire analysis was performed using R software (Rstudio) and the Bayesian software tool RStan was used for the application of Bayesian priors on the parameters. Conclusively, the proposed method could be applied to monoclonal antibodies for which the second-generation mPBPK model has been proposed as well as to other drugs with different PK models when only a published graph with aggregate concentration–time data is available. In addition, the method could be used when multiple aggregate datasets from different sources need to be combined in a meta-analysis approach in order to estimate the PopPK parameters of a drug. Full article

Tafenoquine (TQ) is a new 8-aminoquinoline antimalarial drug developed by the US Army for Plasmodium vivax malaria treatment. Modeling and simulation are essential tools for drug development and improving rationality in pharmacotherapy, and different modeling approaches are used. This study aims to summarize and explore the pharmacokinetic (PK) models available for tafenoquine in the literature. An integrative methodology was used to collect and review published data. Fifteen articles were identified using three modeling approaches: non-compartmental analysis (NCA), population pharmacokinetic analysis (popPK), and pharmacokinetic/pharmacodynamic analysis (PK/PD). An NCA was mainly used to describe the PK profile of TQ and to compare its PK profile alone to those obtained in association with other drugs. PopPK was used to assess TQ population PK parameters, covariates’ impact, and dose selection. PK/PD helped understand the relationship between TQ concentrations, some adverse events common for 8-aminoquilones, and the efficacy assessment for Plasmodium falciparum. In summary, pharmacokinetic models were widely used during TQ development. However, there is still a need for different modeling approaches to support further therapeutic questions, such as treatment for special populations and potential drug–drug interactions. Full article