scholarly journals THE ESTIMATION OF PHARMACOKINETIC PARAMETERS AND ACCURACY OF THE PREDICTED EQUATION FOR LITHIUM DOSE IN CHILDREN: A PILOT STUDY AT THE YUWAPRASART WAITHAYOPATHUM CHILD PSYCHIATRIC HOSPITAL

2019 ◽  
Vol 11 (1) ◽  
pp. 72
Author(s):  
Karunrat Tewthanom ◽  
Rinsook Ongarjsakulman ◽  
Theerarat Tankhum
Keyword(s):  
Psychiatric Hospital ◽  
Lithium Concentration ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mathematical Principle ◽  
Accuracy And Precision ◽  
Child Psychiatric ◽  
Daily Dose ◽  
Modified Equation ◽  
Lithium Dose

Objective: The purpose of the study was to estimate the pharmacokinetic parameters and calculate the precision (%RMSE) of the predicted lithium concentration equation.Methods: This research was studied from blood Lithium levels of Children who had visited Yuwaprasart Waithayopathum Child Psychiatric Hospital from 31 December 2009-1 January 2011 The accuracy and precision of the equation were evaluated by the mathematical principle. The assist package software (WIN-NONLIN) was used to create pharmacokinetic parameters.Results: Twenty-nine patients were recruited. The characteristics (mean+SD) presented as the following; age = 15.79+2.64 y, weight = 69.75+22.28 kg and the daily dose = 858.62+274.53 mg. The trough Lithium concentrations (mean+SD) = 0.56+19 mg/l. The kinetic parameter (Mean+SD) presented as the following; t1/2 =7.23+3.38 hr., ke =0.12+0.07 hr-1, Vd = 48.83+15.60 L, AUC0-12 =11.01+5.61 mg x hr/l. The population pharmacokinetic parameters; ke, and AUC (0-∞) = 0.151 hr-1 and 169.81, mg x hr./l respectively. The modified equation from Yukawa for lithium clearance calculation and prediction lithium concentrations were CL (mL/min) = [36.5+(0.242x BW (kg)-7.79]/Scr (mg/dL) and lithium concentration (mg/l) = 4 x Dose (mg)/CL (mL/min)x73.89, respectively with 6.39 %RMSE (test for 20 patients data).Conclusion: In conclusion, the modified Yukawa equation may be used for the prediction of lithium concentration with 6.39% RMSE.

Influence of cyp2d6 polymorphisms on pharmacokinetics, efficacy and safety of antipsychotics

2018 ◽  
pp. 26-39
Author(s):  
А.А. Курылев ◽  
Б.В. Андреев
Keyword(s):  
Genetic Polymorphisms ◽  
Atypical Antipsychotics ◽  
Retrospective Studies ◽  
Pharmacokinetic Parameters ◽  
Clinical Routine ◽  
Elimination Half ◽  
Daily Dose ◽  
Comparison Groups ◽  
Cyp2d6 Polymorphisms ◽  
Positive Significant Correlation

Несмотря на доступность в клинической практике широкого круга классических и атипичных антипсихотиков (АП), по-прежнему наблюдается широкая вариабельность ответа на психофармакотерапию. Эта вариабельность обусловлена генетической гетерогенностью как самой шизофрении, так и метаболизма АП. Стандартные назначаемые дозы АП далеко не всегда являются оптимальными. Генетическая вариабельность систем биотрансформации и биодоступности АП могут играть значимую роль в формировании ответа на терапию и развитии нежелательных реакций. Целью исследования стало проведение обзора литературы по проблеме клинической эффективности применения генотипирования полиморфизмов CYP2D6 при терапии антипсихотиками. Большинство фармакокинетических исследований обнаруживают сильную достоверную положительную корреляцию метаболического статуса CYP2D6, определенного путем генотипирования полиморфизмов CYP2D6 и фармакокинетических параметров АП (AUC, период полувыведения, клиренс). Однако статистически достоверных связей между полиморфизмами CYP2D6 и эффективностью терапии АП в большинстве исследований обнаружено не было, прежде всего из-за недостаточного количества участников, гетерогенности сравниваемых когорт, применении различных АП и использовании разных критериев эффективности. Перспективные исследования с хорошо сбалансированными группами сравнения, а также масштабные ретроспективные исследования демонстрируют достоверную корреляцию метаболического статуса CYP2D6 и частоты развития нежелательных реакций АП (лекарственный паркинсонизм и поздняя дискинезия). Для более точной оценки величины вклада генетических полиморфизмов CYP2D6 в эффективность и безопасность психофармакотерапии необходимы масштабные перспективные клинические исследования. Although a number of typical and atypical antipsychotics (AP) have been discovered and used in psychiatric clinical practice the variability in response to AP is quite high. This variability is partially explained by a genetic heterogeneity of schizophrenia and metabolism of AP. The standard prescribed antipsychotic daily dose is not always optimal. Genetic variability of biotransformation and bioavailability of AP may significantly influence on therapeutic effect and tolerability. The aim of the study was to perform literature review of studies evaluating the correlation of CYP2D6 genetic polymorphisms and AP pharmacokinetics, effectiveness and safety. Most pharmacokinetics studies show high positive significant correlation between CYP2D6 metabolic activity, determined by CYP2D6 polymorphisms genotyping and AP pharmacokinetic parameters (AUC, elimination half-life, clearance etc.). However the majority of studies were failed to demonstrate significant correlation between CYP2D6 polymorphisms and AP effectiveness mainly due to inadequate number of patient, heterogeneous cohorts, different AP and effectiveness criteria used. Prospective studies with balanced comparison groups and large retrospective studies showed significant correlation between CYP2D6 metabolic status and the frequency of AP induced AEs (parkinsonism and tardive dyskinesia). To better assess the influence of CYP2D6 genetic polymorphisms on AP effectiveness and safety in clinical routine large prospective well designed clinical studies are needed.

EUROPEAN PAEDIATRIC ONCOLOGY OFF-PATENT MEDICINES CONSORTIUM (EPOC): A PHARMACOKINETIC STUDY OF DOXORUBICIN IN CHILDREN WITH CANCER

2015 ◽  
Vol 101 (1) ◽  
pp. e1.6-e1
Author(s):  
Miriam Krischke ◽  
Alan V Boddy ◽  
Georg Hempel ◽  
Swantje Völler ◽  
Nicolas André ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Paediatric Oncology ◽  
Patient Acceptance ◽  
Pharmacokinetic Parameters ◽  
Blood Levels ◽  
Population Pharmacokinetic ◽  
Older Children ◽  
Treatment Regimens

BackgroundDoxorubicin is a key component of a number of treatment regimens used in paediatric oncology. The pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multicentre, multinational pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after 2 administrations, with 5 samples collected in children 3 yrs. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. NT-proBNP and cardiac troponin T were measured to evaluate their role as early indicators of cardiotoxicity.Results101 children could be recruited including 27 patients less than 3 years and among those 5 infants younger than 1 year. Overall, the patient acceptance of the trial was very good.Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a lower clearance (21.1±5.8 l/h/m2) than older children (26.6±6.7 l/h/m2) (p=0.0004), after correcting for body weight. Pharmacogenetic variants, including those in transporters and drug metabolizing enzymes, had little influence on pharmacokinetic parameters.Natriuretic peptides plasma levels increased significantly shortly after doxorubicin administration, whereas cardiac troponin levels increased only with the administered cumulative anthracycline dose. Only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionThe paediatric need concerning missing PK-data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were found to be justified based on our PK analyses.

POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE

2015 ◽  
Vol 101 (1) ◽  
pp. e1.41-e1
Author(s):  
Wei Zhao ◽  
Daolun Zhang ◽  
Thomas Storme ◽  
André Baruchel ◽  
Xavier Declèves ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Haematological Malignancy ◽  
External Validation ◽  
Predictive Performance ◽  
Paediatric Population ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Risk Population ◽  
Dosing Regimen

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

scholarly journals 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S670-S671
Author(s):  
Ronald G Hall ◽  
Jotam Pasipanodya ◽  
William C Putnam ◽  
John Griswold ◽  
Sharmila Dissanaike ◽  
...  
Keyword(s):  
Human Plasma ◽  
Kidney Injury ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Full Thickness ◽  
Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients

2002 ◽  
Vol 36 (9) ◽  
pp. 1344-1350 ◽  
Author(s):  
Irene Aquerreta ◽  
Azucena Aldaz ◽  
Joaquín Giráldez ◽  
Luis Sierrasesúmaga
Keyword(s):  
High Risk ◽  
Daily Practice ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Hematologic Toxicity ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Nonhematologic Toxicity ◽  
The Relationship

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects. METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression. RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001). CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

scholarly journals Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

2009 ◽  
Vol 54 (2) ◽  
pp. 778-782 ◽  
Author(s):  
Akihiro Tanaka ◽  
Tetsuya Aiba ◽  
Takashi Otsuka ◽  
Katsuya Suemaru ◽  
Tatsuya Nishimiya ◽  
...  
Keyword(s):  
Renal Function ◽  
Cystatin C ◽  
Predictive Performance ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Serum Cystatin C ◽  
Serum Cystatin ◽  
New Model ◽  
The Mean

ABSTRACT We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoek's formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

Population Pharmacokinetics of Meropenem in Preterm Infants

2021 ◽  
Vol 76 (5) ◽  
pp. 497-505
Author(s):  
Irina B. Bondareva ◽  
Sergey K. Zyryanov ◽  
Aleksandra M. Kazanova
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Pharmacokinetic Parameter ◽  
Gestational Age ◽  
Drug Monitoring ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Variability ◽  
Older Children ◽  
Term Neonates

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

scholarly journals Staying at the crossroads: assessment of the potential of serum lithium monitoring in predicting an ideal lithium dose

2008 ◽  
Vol 30 (3) ◽  
pp. 215-221 ◽  
Author(s):  
Thiago Zaqueu Lima ◽  
Miriam Marcela Blanco ◽  
Jair Guilherme dos Santos Júnior ◽  
Carolina Tesone Coelho ◽  
Luiz Eugênio Mello
Keyword(s):  
Open Field ◽  
Lithium Chloride ◽  
Elevated Plus Maze ◽  
Lithium Concentration ◽  
Serum Lithium Concentration ◽  
Narrow Therapeutic Range ◽  
Plus Maze ◽  
Sufficient Precision ◽  
Lithium Dose ◽  
Plasmatic Concentration

OBJECTIVE: Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy. METHOD: the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255%, or 0.383% of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration. RESULTS: Animals fed with 0.255% lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50% higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration. DISCUSSION: different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement. CONCLUSION: serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.

Accuracy of predicting the vancomycin concentration in Japanese cancer patients by the Sawchuk–Zaske method or Bayesian method

2019 ◽  
Vol 26 (3) ◽  
pp. 543-548
Author(s):  
Toshihisa Nakashima ◽  
Takayuki Ohno ◽  
Keiichi Koido ◽  
Hironobu Hashimoto ◽  
Hiroyuki Terakado
Keyword(s):  
Cancer Patients ◽  
Prediction Error ◽  
Bayesian Method ◽  
Predictive Accuracy ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Squared Prediction Error ◽  
Trough Concentrations ◽  
The Mean ◽  
Mean Prediction Error

Background In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk–Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk–Zaske and Bayesian methods in Japanese cancer patients is not completely understood. Objective To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk–Zaske method and the Bayesian method in Japanese cancer patients. Methods Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Results Prediction of the trough and peak vancomycin concentrations by the Sawchuk–Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. Conclusion The Sawchuk–Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

scholarly journals The Population Pharmacokinetics of Rifampicin in Japanese Pulmonary Tuberculosis Patients

Drug Research ◽  
2020 ◽  
Vol 70 (05) ◽  
pp. 199-205
Author(s):  
Takahiro Nishimura ◽  
Haruichi Kohno ◽  
Hideaki Nagai ◽  
Daisuke Maruoka ◽  
Yuichi Koike ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Japanese Patients ◽  
Morbidity Rate ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Morbidity ◽  
Power Model ◽  
Time Data ◽  
Nonlinear Mixed Effects Model ◽  
High Morbidity Rate

AbstractIn Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration–time data were obtained from 138 patients receiving rifampicin (300–450 mg) and isoniazid (300–400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from −31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

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