scholarly journals An Evaluation of Using Population Pharmacokinetic Models to Estimate Pharmacodynamic Parameters for Propofol and Bispectral Index in Children

2011 ◽  
Vol 115 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Marc J. Coppens ◽  
Douglas J. Eleveld ◽  
Johannes H. Proost ◽  
Luc A. M. Marks ◽  
Jan F. P. Van Bocxlaer ◽  
...  
Keyword(s):  
Objective Function ◽  
Bispectral Index ◽  
Pharmacokinetic Model ◽  
Dental Treatment ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Accurate Estimation ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Objective Function Values

Background To study propofol pharmacodynamics in a clinical setting a pharmacokinetic model must be used to predict drug plasma concentrations. Some investigators use a population pharmacokinetic model from existing literature and minimize the pharmacodynamic objective function. The purpose of the study was to determine whether this method selects the best-performing pharmacokinetic model in a set and provides accurate estimates of pharmacodynamic parameters in models for bispectral index in children after propofol administration. Methods Twenty-eight children classified as American Society of Anesthesiologists physical status 1 who were given general anesthesia for dental treatment were studied. Anesthesia was given using target-controlled infusion of propofol based on the Kataria model. Propofol target plasma concentration was 7 μg/ml for 15 min, followed by 1 μg/ml for 15 min or until signs of awakening, followed by 5 μg/ml for 15 min. Venous blood samples were taken 1, 2, 5, 10, and 15 min after each change in target. A classic pharmacokinetic-pharmacodynamic model was estimated, and the methodology of other studies was duplicated using pharmacokinetic models from the literature and (re-)estimating the pharmacodynamic models. Results There is no clear relationship between pharmacokinetic precision and the pharmacodynamic objective function. Low pharmacodynamic objective function values are not associated with accurate estimation of the pharmacodynamic parameters when the pharmacokinetic model is taken from other sources. Conclusion Minimization of the pharmacodynamic objective function does not select the most accurate pharmacokinetic model. Using population pharmacokinetic models from the literature instead of the 'true' pharmacokinetic model can lead to better predictions of bispectral index while incorrectly estimating the pharmacodynamic parameters.

scholarly journals External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1191
Author(s):  
Celine Konecki ◽  
Catherine Feliu ◽  
Yoann Cazaubon ◽  
Delphine Giusti ◽  
Marcelle Tonye-Libyh ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Inflammatory Diseases ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
External Evaluation ◽  
Immunomodulatory Treatment ◽  
Weighted Residuals ◽  
Prediction Distribution ◽  
Target Plasma

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

scholarly journals Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4907-4913 ◽  
Author(s):  
Marieke G. G. Sturkenboom ◽  
Leonie W. Mulder ◽  
Arthur de Jager ◽  
Richard van Altena ◽  
Rob E. Aarnoutse ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Mean Squared Error ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Optimal Sampling ◽  
Sampling Strategies ◽  
Wide Range

ABSTRACTRifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n= 1,000). The geometric mean AUC0–24value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with anr2value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

Modeling Population Pharmacokinetics of Lidocaine

2001 ◽  
Vol 94 (4) ◽  
pp. 566-573 ◽  
Author(s):  
Jette A. Kuipers ◽  
Fred Boer ◽  
Annemiek de Roode ◽  
Erik Olofsen ◽  
James G. Bovill ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Pharmacokinetic Models ◽  
Population Pharmacokinetic Modeling ◽  
Population Pharmacokinetic Study ◽  
Electrical Bioimpedance ◽  
Demographic Covariates ◽  
The Individual

Background Inclusion of cardiac output and other physiologic parameters, in addition to or instead of, demographic variables might improve the population pharmacokinetic modeling of lidocaine. Methods Thirty-one patients were included in a population pharmacokinetic study of lidocaine. After bolus injection of lidocaine (1 mg/kg), 22 or 10 blood samples per patient were taken from a radial artery. During the experiment, cardiac output was measured using a thoracic electrical bioimpedance method. The following four population pharmacokinetic models were constructed and their performances investigated: a model with no covariates, a model with cardiac output as covariate, a model with demographic covariates, and a model with both cardiac output and demographic characteristics as covariates. Model discrimination was performed with the likelihood ratio test. Results Inclusion of cardiac output resulted in a significant improvement of the pharmacokinetic model, but inclusion of demographic covariates was even better. However, the best model was obtained by inclusion of both demographic covariates and cardiac output in the pharmacokinetic model. Conclusions When population pharmacokinetic models are used for individualization of dosing schedules, physiologic covariates, e.g., cardiac output, can improve their ability to predict the individual kinetics.

scholarly journals Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients

2019 ◽  
Vol 20 (7) ◽  
pp. 592-600 ◽  
Author(s):  
Zhiqi Wang ◽  
Nan Zhang ◽  
Chaoyang Chen ◽  
Shuqing Chen ◽  
Junyu Xu ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Genetic Factors ◽  
Plasma Concentrations ◽  
Chinese Patients ◽  
Estimation Methods ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
The Impact

Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. Method: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. Conclusion: : In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

scholarly journals Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

2013 ◽  
Vol 58 (1) ◽  
pp. 432-439 ◽  
Author(s):  
Brioni R. Moore ◽  
Sam Salman ◽  
John Benjamin ◽  
Madhu Page-Sharp ◽  
Leanne J. Robinson ◽  
...  
Keyword(s):  
Single Dose ◽  
Vivax Malaria ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Pharmacokinetic Data ◽  
Radical Cure ◽  
Papua New Guinean

ABSTRACTSince conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higherCmaxfor PMQ and CPMQ, respectively. All predicted medianCmaxconcentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group.

scholarly journals A population pharmacokinetic model is beneficial in quantifying hair concentrations of ritonavir-boosted atazanavir: A study of HIV-infected Zimbabwean adolescents.

2020 ◽  
Author(s):  
Bernard NGARA ◽  
Simbarashe Zvada ◽  
Tariro Dianah Chawana ◽  
Babill Stray-Pedersen ◽  
Charles Fungai Brian Nhachi ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Model Development ◽  
Normal Weight ◽  
Hiv Treatment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Modelling ◽  
Hair Samples

Abstract Background Adolescents experience higher levels of non-adherence to HIV treatment. Drug concentration in hair promises to be reliable for assessing exposure to antiretroviral (ARV) drugs. Pharmacokinetic modelling can explore utility of drug in hair. We aimed at developing and validating a pharmacokinetic model based on atazanavir/ritonavir (ATV/r) in hair and identify factors associated with variabilities in hair accumulation. Methods We based the study on secondary data analysis whereby data from a previous study on Zimbabwean adolescents which collected hair samples at enrolment and three months follow-up was used in model development. We performed model development in NONMEM (version 7.3) ADVAN 13. Results There is 16% / 18% of the respective ATV/r in hair as a ratio of steady-state trough plasma concentrations. At follow-up, we estimated an increase of 30% /42% of respective ATV/r in hair. We associated a unit increase in adherence score with 2% increase in hair concentration both ATV/r. Thinner participants had 54% higher while overweight had 21% lower atazanavir in hair compared to normal weight participants. Adolescents receiving care from fellow siblings had atazanavir in hair at least 54% less compared to other forms of care. Conclusion The determinants of increased ATV/r concentrations in hair found in our analysis are monitoring at follow up event, body mass index, and caregiver status. Measuring drug concentration in hair is feasibly accomplished and could be more accurate for monitoring ARV drugs exposure. Keywords Pharmacokinetic modelling, HIV/AIDS, Adolescents, Adherence, Hair, NONMEM

Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

2000 ◽  
Vol 18 (12) ◽  
pp. 2459-2467 ◽  
Author(s):  
James M. Gallo ◽  
Paul B. Laub ◽  
Eric K. Rowinsky ◽  
Louise B. Grochow ◽  
Sharyn D. Baker
Keyword(s):  
Phase I ◽  
Population Model ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Total Clearance ◽  
Phase I Clinical Trials

PURPOSE: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. PATIENTS AND METHODS: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m2. Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling. RESULTS: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 + [0.356(WT − 71) + 0.308(HT − 168.5) − 8.42(SCR − 1.1)] × [1 + 0.671 sex]) was dependent on the patients’ weight (WT), height (HT), serum creatinine (SCR), and sex and had a moderate ability to predict (r2 = 0.64) each patient’s individual clearance value. The addition of covariates to the population model improved the prediction errors, particularly for clearance. Removal of 10 outlying patients from the analysis improved the ability of the model to predict individual clearance values (r2 = 0.77). CONCLUSION: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to predict total clearance. The model can be used prospectively to obtain a revised and validated model that can then be used to design individualized dosing regimens.

scholarly journals Moxifloxacin Pharmacokinetic Profile and Efficacy Evaluation in Empiric Treatment of Community-Acquired Pneumonia

2015 ◽  
Vol 59 (4) ◽  
pp. 2398-2404 ◽  
Author(s):  
Kristina Öbrink-Hansen ◽  
Tore Forsingdal Hardlei ◽  
Birgitte Brock ◽  
Søren Jensen-Fangel ◽  
Marianne Kragh Thomsen ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Community Acquired Pneumonia ◽  
Population Pharmacokinetic ◽  
Efficacy Evaluation ◽  
Therapeutic Success ◽  
Content Type ◽  
Drug Concentrations

ABSTRACTWhen antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0–24) values predicted for each patient were evaluated against epidemiological cutoff MIC values forStreptococcus pneumoniae,Haemophilus influenzae, andLegionella pneumophila. PK-PD targets adopted were aCmax/MIC of ≥12.2 for all pathogens, anfAUC0–24/MIC of >34 forS. pneumoniae, and anfAUC0–24/MIC of >75 forH. influenzaeandL. pneumophila. Individual predicted estimates forCmax/MIC andfAUC0–24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable forS. pneumoniaeandH. influenzaebut not forL. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused byL. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.)

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