The first study in pediatric: Population pharmacokinetics of sirolimus and its application in Chinese children with immune cytopenia

The narrow therapeutic index and large inter-individual variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring (TDM) necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with immune cytopenia. The objective of this study was to characterize the PK of sirolimus in pediatric patients with immune cytopenia and to develop a population PK model in Chinese children and evaluate its utility for dose individualization. A total of 27 children with either acquired or congenital immune cytopenia aged 8.16 ± 3.60 years (range: 1–15 years) were included. TDM data for sirolimus were collected. The population PK model of sirolimus was described using the nonlinear mixed-effects modeling (Phoenix NLME 1.3 software) approach. Covariate analysis was applied to select candidate factors associated with PK parameters. The final model was validated using bootstrap (1000 runs) and visual predictive check (VPC) method. A one-compartment model with first-order absorption and elimination was developed. The outcome parameters were as follows: apparent clearance (CL/F) 5.63 L/h, apparent distribution volume (V/F) 144.16 L. Inter-individual variabilities for CL/F and V/F were 3.53% and 7.27%, respectively. The intra-individual variability of proportional error model was 22.45%. The covariate test found that body weight and total bilirubin were strongly associated with clearance; however, we did not find the relevance between the covariate and volume of distribution of sirolimus. Personalized dosage regimens were provided based on Bayesian method. The oral dose should be adjusted according to weight and total bilirubin. This is the first study to describe a population PK model of sirolimusin pediatric patients with immune cytopenia. Population pharmacokinetic (PPK) model–based dose individualization of sirolimus and the design of future clinical studies in children will be facilitated by the developed model in this study.

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A Population Pharmacokinetic Model for Vancomycin in Pediatric Patients and Its Predictive Value in a Naive Population

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.2.278-282.2000 ◽

2000 ◽

Vol 44 (2) ◽

pp. 278-282 ◽

Cited By ~ 30

Author(s):

Patrice Lamarre ◽

Denis Lebel ◽

Murray P. Ducharme

Keyword(s):

Pediatric Patients ◽

Pediatric Population ◽

Predictive Ability ◽

Volume Of Distribution ◽

Population Characteristics ◽

Rank Test ◽

Population Pharmacokinetic ◽

Good Precision ◽

Weighted Residuals ◽

Population Pk

ABSTRACT The objectives of this study were to (i) construct a population pharmacokinetic (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric patients, (ii) determine VAN PK parameters in this population, and (iii) validate the predictive ability of this model in a naive pediatric population. Data used in this study were obtained from 78 pediatric patients (under 18 years old). PK analyses were performed using compartmental methods. The most appropriate model was chosen based on the evaluation of pertinent graphics and calculation of the Akaike information criterion test. The population PK analysis was performed using an iterative two-stage method. A two-compartment PK model using age, sex, weight, and serum creatinine as covariates was determined to be the most appropriate one to describe serum VAN concentrations. The quality of fit was very good, and the distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed rank test). Fitted population PK parameters (mean ± standard deviation) were as follows: central clearance (0.1 ± 0.05 liter/h/kg), central volume of distribution (0.27 ± 0.07 liter/kg), peripheral volume of distribution (0.16 ± 0.07 liter/kg), and distributional clearance (0.16 ± 0.07 liter/kg). The predictive ability of the developed model (including the above-mentioned covariates) was evaluated in a naive population of 19 pediatric patients. The predictability was very good. Precision (±95% confidence interval [CI]) (peak, 4.1 [±1.4], and trough, 2.2 [±0.7]) and bias (±95% CI) (peak, −0.58 [±2.2], and trough, 0.63 [±1.1] mg/liter) were significantly (P < 0.05) superior to those obtained using a conventional method (precision [±95% CI]: peak, 8.03 [±2.46], and trough, 2.7 [±0.74]; bias: peak, −7.1 [±2.9], and trough, −1.35 [±1.2] mg/liter). We propose the use of this population PK model to optimize VAN clinical therapies in our institution and others with similar patient population characteristics.

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Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-25.6.528 ◽

2020 ◽

Vol 25 (6) ◽

pp. 528-539

Author(s):

Anne Chain ◽

Rebecca Wrishko ◽

Grygoriy Vasilinin ◽

Samer Mouksassi

Keyword(s):

Pediatric Patients ◽

Simulation Analysis ◽

Pediatric Population ◽

Plasma Concentrations ◽

Model Development ◽

Postoperative Nausea And Vomiting ◽

Nausea And Vomiting ◽

Fixed Dose ◽

Population Pharmacokinetic ◽

Population Pk

OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

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Pharmacokinetic and Pharmacogenetic Markers of Irinotecan Toxicity

Current Medicinal Chemistry ◽

10.2174/0929867325666180622141101 ◽

2019 ◽

Vol 26 (12) ◽

pp. 2085-2107 ◽

Cited By ~ 7

Author(s):

Roberta Zilles Hahn ◽

Marina Venzon Antunes ◽

Simone Gasparin Verza ◽

Magda Susana Perassolo ◽

Edna Sayuri Suyenaga ◽

...

Keyword(s):

Active Metabolite ◽

Drug Exposure ◽

Individual Variability ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Therapeutic Effects ◽

Severe Toxicity ◽

Pharmacokinetic Models ◽

Dose Individualization ◽

Pubmed Database

Background: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient’s body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. Methods: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. Conclusion: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.

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Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps30392 ◽

2019 ◽

Vol 22 ◽

pp. 112-121 ◽

Cited By ~ 1

Author(s):

Esther Oyaga-Iriarte ◽

Asier Insausti ◽

Lorea Bueno ◽

Onintza Sayar ◽

Azucena Aldaz

Keyword(s):

Clinical Practice ◽

Clinical Data ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Visual Predictive Check ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Optimal Sampling ◽

Multicompartmental Model ◽

Sampling Times

Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.

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Population Pharmacokinetic Model of ADVATE in Pediatric and Adult Patients with Hemophilia A.

Blood ◽

10.1182/blood.v114.22.3492.3492 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3492-3492

Author(s):

Myungshin Oh ◽

Sven Björkman ◽

Phillip Schroth ◽

Sandor Fritsch ◽

Peter Collins ◽

...

Keyword(s):

Body Weight ◽

Hemophilia A ◽

Individual Variability ◽

Patient Specific ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Data Sets ◽

Residual Variability ◽

Population Pk ◽

Variability Model

Abstract Abstract 3492 Poster Board III-429 Introduction The objective of this analysis was to characterize the population pharmacokinetic (PK) model of ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) in hemophilia A patients. This included estimation of typical population pharmacokinetic parameters and inter-individual and residual variability and identification of covariates that are significant predictors of variability in a pooled population of children and adults. Patients and Methods Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets for 52 children, aged 1 to 6 years. Population PK analysis was conducted using non-linear mixed effects modeling with the first-order integral approximation method in SAS® software (NLMIXED procedure). A two-compartment model was used as the base model and the influence of age and weight were explored. Results Two-compartment PK models with additive plus proportional residual variability model and exponential inter-individual variability model adequately described the data. Clearance (CL) is significantly correlated with age and body weight and central volume of distribution (V1) is also related with body weight. The estimated population PK parameters were (mean parameter, (inter-individual variability %)): CL (2.92 mL/kg·h, 22%), V1 (0.46 dL/kg, 5.2%), peripheral volume V2 (0.09 dL/kg) and inter-compartmental clearance Q (2.07 mL/ kg·h). Conclusions A population PK model that describes the combined PK data from adults and pediatric studies has been constructed. A significant portion of inter-individual variability in both volume and clearance can be explained by subject weight. An additional smaller effect of age on clearance but not volume was observed. A population PK model for Factor VIII could provide the clinician with advantages in designing a patient specific treatment regimen. It could provide more relevant guidance in individual patient pharmacokinetics than just incremental recovery without the burden of a full PK assessment of the patient. Disclosures: Oh: Baxter: Employment. Off Label Use: Prophylaxis is not indicated in the US. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:Bayer: Consultancy; Novo Nordisk: Consultancy; Baxter: Consultancy. Fischer:Bayer: Consultancy; Wyeth: Consultancy; Baxter: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Consultancy. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter: Employment.

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Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02678-15 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3676-3686 ◽

Cited By ~ 6

Author(s):

Man Luo ◽

Sunny Chapel ◽

Heather Sevinsky ◽

Ishani Savant ◽

Brenda Cirincione ◽

...

Keyword(s):

Pediatric Patients ◽

Pediatric Population ◽

The United States ◽

Volume Of Distribution ◽

Time Profile ◽

Pediatric Hiv ◽

Target Range ◽

Population Pharmacokinetic ◽

The European Union ◽

The Impact

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (n= 168) and one study in healthy adults (n= 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (VC), and absorption rate constant (Ka). The typical values of efavirenz apparent CL,VC, oral peripheral volume of distribution (VP), andKafor a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h−1(0.375 to 0.453 h−1), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing <10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing ≥10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing ≥3.5 to <5 kg, 150 mg QD to children weighing ≥5 to <7.5 kg, and 200 mg QD to children weighing ≥7.5 to <10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.

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Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients – population pharmacokinetic approach

Journal of Medical Biochemistry ◽

10.2478/jomb-2018-0030 ◽

2019 ◽

Vol 38 (3) ◽

pp. 323-331

Author(s):

Bojana Golubović ◽

Katarina Vučićević ◽

Dragana Radivojević ◽

Sandra Vezmar Kovačević ◽

Milica Prostran ◽

...

Keyword(s):

Liver Function ◽

Population Analysis ◽

Clinical Care ◽

External Validation ◽

Therapeutic Index ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Pharmacokinetic Variability ◽

Dose Individualization ◽

Transplant Patients

Summary Background Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients’ records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. Results The pharmacokinetic variability was partially explained with patient’s age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

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Vancomycin Prescribing Practices and Therapeutic Drug Monitoring for Critically Ill Neonatal and Pediatric Patients: A Survey of Physicians and Pharmacists in Hong Kong

Frontiers in Pediatrics ◽

10.3389/fped.2020.538298 ◽

2020 ◽

Vol 8 ◽

Author(s):

Twinny Cheuk Hin Chow ◽

Janice Yuen Shun Li ◽

Jasper Chak Ling Wong ◽

Freddie Man Hong Poon ◽

Hugh Simon Lam ◽

...

Keyword(s):

Hong Kong ◽

Critically Ill ◽

Pediatric Patients ◽

Pediatric Population ◽

Therapeutic Monitoring ◽

Therapeutic Drug ◽

Prescribing Practices ◽

Cross Sectional ◽

The Impact ◽

Trough Levels

Background: Deviations from the optimal vancomycin dosing may occur in the neonatal and pediatric population due to inconsistencies in the recommended dosing algorithms. This study aims to collect the expert opinions of clinicians who practice in the neonatal or pediatric intensive care units (NICU/PICUs) of 12 major medical centers in Hong Kong.Methods: This was a multicenter, cross-sectional study. Eligible physicians and pharmacists completed a structured questionnaire to identify the challenges they encountered when selecting the initial intermittent vancomycin dosing. They also answered questions concerning therapeutic monitoring services (TDM) for vancomycin, including the targeted trough levels for empirical vancomycin regimens administered for complicated and uncomplicated infections.Results: A total of 23 physicians and 43 pharmacists completed the survey. The top clinical parameters reported as most important for determining the initial vancomycin dosing were renal function (90.9%), post-menstrual/postnatal age (81.8%), body weight (66.7%), and suspected/documented pathogen (53.0%). Respondents reported challenges such as difficulties in determining the optimal initial dose for a targeted level (53.0%), inconsistencies between dosing references (43.9%) and a lack of clear hospital guidelines (27.3%). Half of the pharmacists (48.8%) reported that they had helped to interpret the TDM results and recommend vancomycin dose adjustments in >75% of cases. For methicillin-resistant Staphylococcus aureus infection, physicians, and pharmacists reported target trough levels of ~10–15 and 15–20 mg/L, respectively. For suspected moderate/uncomplicated Gram-positive infections physicians tended to prefer a lower trough range of 5–10 mg/L, while pharmacists preferred a range of 10–15 mg/L.Conclusions: Our results demonstrate that clinicians used varying vancomycin dosing guidelines in their practices. The multidisciplinary TDM service in Hong Kong can be improved further by establishing a standardized dosing guideline and implementing a well-structured, evidence-based service protocol. Future work includes conducting drug utilization studies to evaluate real-world antimicrobial usage patterns and the impact on tangible clinical outcomes, and developing pharmacokinetic-guided dose calculator for antimicrobials in critically ill neonates and pediatric patients.

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Application of Pharmacometrics in Pharmacotherapy: Open-Source Software for Vancomycin Therapeutic Drug Management

Pharmaceutics ◽

10.3390/pharmaceutics11050224 ◽

2019 ◽

Vol 11 (5) ◽

pp. 224 ◽

Cited By ~ 1

Author(s):

Soo Hyeon Bae ◽

Dong-Seok Yim ◽

Hyemi Lee ◽

Ae-Ryoung Park ◽

Ji-Eun Kwon ◽

...

Keyword(s):

Open Source ◽

Open Source Software ◽

Compartment Model ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Drug Management ◽

Korean Patients ◽

Population Pk ◽

R Shiny

The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for vancomycin using Korean data to improve the quality of TDM for Korean patients. A total of 220 patients (1020 observations) who received vancomycin TDM services were included in the dataset. A population PK analysis was performed using non-linear mixed effects modeling, and a covariate evaluation was conducted. A two-compartment model with first-order elimination best explained the vancomycin PK, with estimates of 2.82 L/h, 31.8 L, 11.7 L/h, and 75.4 L for CL, V1, Q, and V2, respectively. In the covariate analysis, weight correlated with the volume of the peripheral compartment, and creatinine clearance, hemodialysis, and continuous renal replacement therapy treatments contributed to the clearance of vancomycin. The results show the clear need to optimize the PK parameters used for TDM in Korean patients. Specifically, V1 should be smaller for Korean patients, and renal replacement therapies should be considered in TDM practice. This final model was successfully applied in R shiny as open-source software for Koreans.

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