Performance Of Population Pharmacokinetic Models Research Articles

Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients

Background and aimChronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram.MethodsA systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions.ResultsEight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models.ConclusionMenon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Predictive Performance of Population Pharmacokinetic Models for Amikacin in Term Neonates.

Amikacin is preferred in treating Gram-negative infections in neonates and it has a narrow therapeutic window. The population pharmacokinetic modeling approach can aid in designing optimal dosage regimens for amikacin in neonates. In this study, we attempted to identify the suitable population pharmacokinetic model from the published reports for the study population from an Indian setting. Published population pharmacokinetic studies for amikacin in neonates were identified. Data on structural models and typical pharmacokinetic parameters were extracted from the studies. For the clinical study, neonates who met the inclusion criteria were enrolled in the study from the NICU, Kasturba Medical College, Manipal, during Jan 2020 to March 2022. Drug concentrations were estimated, and demographic and clinical data were collected. Identified population pharmacokinetic models were used to predict the amikacin concentrations in neonates. Predicted concentrations were compared against the observed concentrations. Differences between predicted and observed concentrations were quantified using statistical measures. The population pharmacokinetic model, which was able to predict the data well, is considered a suitable model for the study population. Dosing regimens were suggested for neonates using the pharmacometric simulation approach generated by the selected model. A total of 43 plasma samples were collected from 31 neonates. Twelve population pharmacokinetic models were found for amikacin in neonates. The predictive performance of the 12 studies was performed using clinical data. A two-compartment model reported by Illamola et al. predicted the amikacin concentrations better than other models. Illamola et al. reported creatinine clearance and body weight as the significant covariates impacting the pharmacokinetic parameters of amikacin. This model was able to predict the clinical data with 29.97% and 0.686 of relative median absolute prediction error and relative root mean square error, respectively, which is the best among the published models. The Illamola et al. model was selected as the final model to perform pharmacometric simulations for the subjects with different combinations of creatinine clearance and body weight. Dosage regimens were designed to attain target therapeutic concentrations for the virtual subjects and a nomogram was developed. The population pharmacokinetic model reported by the Illamola et al. model was selected as the final model to explain the clinical data with the lowest relative median absolute prediction error and relative root mean square error when compared with other models. An amikacin nomogram was developed for the neonates whose creatinine clearance and body weight ranged between 10 and 90 mL/min and between 2 and 4 kg, respectively. A developed nomogram can assist clinicians to design an optimal dosage regimen of amikacin for term neonates.

A comparison of pharmacokinetics software for therapeutic drug monitoring of piperacillin in patients with severe infections

ObjectiveTo evaluate the predictive performance of population pharmacokinetic models for piperacillin (PIP) available in the software MwPharm, TDMx and ID-ODs for initial dosing selection and therapeutic drug monitoring (TDM) purposes.MethodsThis...

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients.

Polymyxin B (PMB) has reemerged as a last‐line therapy for infections caused by multidrug‐resistant gram‐negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction‐based and simulation‐based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two‐compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model‐informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease.

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

Predictive Performance of Population Pharmacokinetic Models of Levetiracetam in Children and Evaluation of Dosing Regimen

Levetiracetam is a broad-spectrum antiepileptic drug that exhibits high interindividual variability in serum concentrations in children. A population pharmacokinetic approach can be used to explain this variability and optimize dosing schemes. The objectives are to identify the best predictive population pharmacokinetic model for children and to evaluate recommended doses using simulations and Bayesian forecasting. A validation cohort included children treated with levetiracetam who had a serum drug concentration assayed during therapeutic drug monitoring. We assessed the predictive performance of all the population pharmacokinetic models published in the literature using mean prediction errors, root mean squared errors, and visual predictive checks. A population model was finally constructed on the data, and dose simulations were performed to evaluate doses. We included 267 levetiracetam concentrations ranging from 2 to 69 mg/L from 194 children in the validation cohort. Six published models were externally evaluated. Most of the models underestimated the variability of our population. A 1-compartment model with first-order absorption and elimination with allometric scaling was finally fitted on our data. In our cohort, 57% of patients had a trough concentration <12 mg/L and 12% <5 mg/L. To reach a trough concentration >5 mg/L, doses ≥30 mg/kg/d for patients ≤50 kg and ≥2000 mg/d for patients >50 kg are required. In our population, a high percentage of children had low trough concentrations. Our population pharmacokinetic model could be used for therapeutic drug monitoring of levetiracetam in children.

Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures.

Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in individual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood samples were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 < 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to individualized dosing.

Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model

PurposeA variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external validation, which requires a new dataset, is considered a more rigorous approach, especially if the model is to be used for predictive purposes. Our first objective was to validate a previously published population pharmacokinetic model of darunavir, an HIV protease inhibitor boosted with ritonavir or cobicistat. Our second objective was to use this model to derive optimal sampling strategies that maximize the amount of information collected with as few pharmacokinetic samples as possible.MethodsA validation dataset comprising 164 sparsely sampled individuals using ritonavir-boosted darunavir was used for validation. Standard plots of predictions and residuals, NPDE, visual predictive check, and bootstrapping were applied to both the validation set and the combined learning/validation set in NONMEM to assess model performance. D-optimal designs for darunavir were then calculated in PopED and further evaluated in NONMEM through simulations.ResultsExternal validation confirmed model robustness and accuracy in most scenarios but also highlighted several limitations. The best one-, two-, and three-point sampling strategies were determined to be pre-dose (0 h); 0 and 4 h; and 1, 4, and 19 h, respectively. A combination of samples at 0, 1, and 4 h was comparable to the optimal three-point strategy. These could be used to reliably estimate individual pharmacokinetic parameters, although with fewer samples, precision decreased and the number of outliers increased significantly.ConclusionsOptimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies.

Incorporating nonlinear kinetics to improve predictive performance of population pharmacokinetic models for ciclosporin in adult renal transplant recipients: A comparison of modelling strategies

BackgroundCiclosporin has been shown to follow nonlinear pharmacokinetics (PK) in renal transplant recipients who received ciclosporin (NeoralⓇ, Novartis)-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population PK (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability as well as to analyse multiple nonlinear factors in the in vivo process. MethodsA total of 2969 ciclosporin whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. ResultsModel predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance compared to the other three compartmental models. The saturated binding of ciclosporin to erythrocytes, auto-inhibition induced by the inhibitory effects of ciclosporin on cytochrome P450 3A4/P-glycoprotein may have contributed to the nonlinearity. Ciclosporin-prednisolone drug interaction should be given serious consideration in clinical settings. ConclusionsIncorporation of nonlinear properties is likely to be a promising approach for improving ciclosporin model predictability. Theory-based modelling is helpful to improve model predictability. However, ciclosporin nonlinear kinetics resources need further investigation.

Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h−1. During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.