Search Results (56)

Background: Amikacin is still an essential antimicrobial to treat life-threatening infections, including multidrug-resistant microorganisms. The effectiveness of treatment has been correlated with the Cmax/MIC ratio, with a ratio of 8 being recommended, which is difficult to reach in some patients. Appropriate antibiotic exposure is important for knowing the disposition of the drug in the population. Objectives: We aimed to integrate therapeutic drug monitoring and a populational pharmacokinetic model to assess an optimal dose regimen and respective plasma exposure. Methods: Plasma levels of amikacin in peaks and troughs were determined by LC-MS/MS. The pharmacokinetic parameter was estimated to use nonlinear mixed effect modeling in Monolix^® software. The probability of target attainment was also determined using the Simulx™ software. Results: A total of 39 patients were enrolled. A one-compartment model with proportional error model best described amikacin pharmacokinetic parameters, providing a Cl of 1.49 L/h and Vc of 23.18 L. The model developed could characterize the pharmacokinetic profile in Brazilian patients who underwent therapeutic drug monitoring. Conclusions: Amikacin therapeutic drug monitoring should be associated with population pharmacokinetic analysis in dose optimization and individualization, helping maintain appropriate drug exposure in special populations such as critically ill patients. This strategy may contribute to enhancing clinical outcomes. 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

The objective of this work was to develop a population physiologically based pharmacokinetic (popPBPK) model to characterize the variability in the clinical PK of monoclonal antibodies (mAbs) following intravenous (IV) and subcutaneous (SC) administration. An extensive literature search was conducted and clinical PK data for FDA-approved as well as non-approved mAbs were collected. Training and validation datasets of 44 and 9 mAbs exhibiting linear pharmacokinetics were used for model development. The variability in antibody PK was captured by accounting for different rate constants of pinocytosis (CL_up) and intracellular degradation (k_deg) for different mAbs. Typical values for CL_up and k_deg and their respective inter-antibody variabilities (${\omega }_{Clup}$, ${\omega }_{Kdeg})$ were estimated to be 0.32 L/h/L and 26.1 ${\mathrm{h}}^{-1}$ (73% and 46%). Varied absorption profiles following SC dosing were characterized by incorporating inter-antibody variability in local degradation (k_SC) and rate of lymphatic uptake (S_Lu) of mAbs. Estimates for typical k_SC and S_Lu values, and ${\omega }_{Ksc},{\omega }_{S\_Lu},$ were found to be 0.0015 ${\mathrm{h}}^{-1}$ and 0.54 (193%, and 49%). FDA-approved mAbs showed less local degradation (0.0014 ${\mathrm{h}}^{-1}$ vs. 0.0038 ${\mathrm{h}}^{-1}$) compared with other clinically tested mAbs, whereas no substantial differences in physiological processes involved in disposition were observed. To evaluate the generalizability of estimated PK parameters and model validation, the final popPBPK model was used to simulate the range of expected PK for mAbs following SC administration of nine different mAbs that were not used for model-building purposes. The predicted PK of all nine mAbs was within the expected range specified a priori. Thus, the popPBPK model presented here may serve as a tool to predict the clinical PK of mAbs with linear disposition before administering them to humans. The model may also support preclinical-to-clinical translation and ‘first-in-human’ dose determination for mAbs. Full article

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting β₂-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol’s PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes. Full article

Background: Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. Objective: This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. Methods: We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. Results: A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. Conclusion: At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients. Full article

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy. Full article