Evaluation of methods for estimating population pharmacokinetic parameters II. Biexponential model and experimental pharmacokinetic data

Background and objectiveThe use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation as well as dose prediction, and compare this strategy to a pre-determined pharmacokinetic sampling approach.MethodsThree population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), pre-determined (i.e., scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), respectively, using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients.ResultsPharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at pre-determined times and 165 that were scavenged from those obtained as part of clinical care. All data sets were fit using a two-compartment model with first order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady state volume of distribution) as compared to the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation and showed similar results. Monte Carlo simulation based on AUC0–24/MIC using either the SC or the TR model gave similar dose prediction for ciprofloxacin.ConclusionBlood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

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Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03736-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 905-913 ◽

Cited By ~ 21

Author(s):

William W. Hope ◽

Atsunori Kaibara ◽

Michael Roy ◽

Antonio Arrieta ◽

Nkechi Azie ◽

...

Keyword(s):

Body Weight ◽

Invasive Candidiasis ◽

Phase Iii ◽

Target Range ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Two Phase ◽

Time Curve ◽

Content Type

ABSTRACTThe aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment ofCandidainfections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg · h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.

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Population Pharmacokinetic of Native Escherichia Coli Asparaginase.

Blood ◽

10.1182/blood.v114.22.4803.4803 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4803-4803

Author(s):

Stephan Borghorst ◽

Rob Pieters ◽

Hans Juergen Kuehnel ◽

Joachim Boos ◽

Georg Hempel

Keyword(s):

Escherichia Coli ◽

Interindividual Variability ◽

Treatment Protocol ◽

Volume Of Distribution ◽

Face Validity ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Published Data ◽

Pharmacokinetic Data ◽

Poppk Model

Abstract Abstract 4803 Introduction Native Escherichia Coli Asparaginase (ASNase) is an integral component in the therapy of acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL). There is a great interindividual variability in treatment intensity in patients treated with the same dose of ASNase. Population pharmacokinetics (PopPK) provides the possibility to divide the overall variability of a population in an inter- and intraindividual element and to develop more precise dosing recommendations. Furthermore, pharmacokinetic parameters can be estimated as well as possible covariates that may influence the pharmacokinetics of the drug can be identified. Patients and Methods The model building dataset consisted of 16 patients (233 samples) receiving 5000 U/m2 ASNase (Asparaginase Medac®) 8 times according to the DCOG-ALL 10 treatment protocol. Asparaginase activity was measured in a randomized clinical Phase 2 study comparing the pharmacokinetic and pharmacodynamic of a newly developed recombinant ASNase with that of the established ASNase (Asparaginase Medac®)[R. Pieters et al. Blood. 2008 Dec 15. 112(13):4832-8]. The PopPK-model was developed using NONMEM (version VI) with First Order Conditional Estimation (FOCE) method and INTERACTION option. Results A linear 2-compartmental model with a combined proportional (0.9%) and additive (48.1U/l) error model described the data adequately. The pharmacokinetic parameters estimated were: Total systemic clearance 0.135 ± 12.8% l/h/70kg, volume of distribution of the central compartment 4.27 ± 13.1% l/70kg, volume of distribution in the peripheral compartment 0.83 ± 80.4% l/70kg and intercompartmental clearance 0.058 l/h/70kg (mean ± interindividual variability). Body weight was identified as the most important covariate. Validity of the model was verified by simulating different dosages of ASNase (2500U/m2 and 10000U/m2) in induction and reinduction of the ALL-BFM treatment protocol. The median and mean ASNase activity was compared with published data [E. Ahlke et al. Br J Haematol. 1997 Mar. 96(4):675-81 and Boos et al. Eur J Cancer. 1996 Aug. 32A(9):1544-50]. Furthermore pharmacokinetic data obtained by a noncompartmental analysis [R. Pieters et al. Blood. 2008 Dec 15.112(13):4832-8] were compared with the pharmacokinetic data estimated by the PopPK model. Both procedures indicated on face validity of the PopPK model. Conclusion This PopPK analysis provides the first step in the development of a PopPK model for ASNase. Face validity of the PopPK model could be demonstrated and will be confirmed with an independent dataset. Disclosures: Pieters: Medac GmbH: Research Funding. Kuehnel:Medac GmbH: Employment. Boos:Medac GmbH: Honoraria. Hempel:Medac GmbH: Honoraria.

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Suramin: development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.1.166 ◽

1994 ◽

Vol 12 (1) ◽

pp. 166-175 ◽

Cited By ~ 25

Author(s):

D I Jodrell ◽

L M Reyno ◽

R Sridhara ◽

M A Eisenberger ◽

K H Tkaczuk ◽

...

Keyword(s):

Prostate Cancer ◽

Linear Model ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Hormone Refractory Prostate Cancer ◽

Pharmacokinetic Models ◽

Hormone Refractory

PURPOSE This study aimed to (1) develop a population pharmacokinetic model for suramin; (2) use Bayesian methods to assess suramin pharmacokinetics in individual patients; (3) use individual patients' pharmacokinetic parameter estimates to individualize suramin dose and schedule and maintain plasma suramin concentrations within predetermined target ranges; and (4) assess the feasibility of outpatient administration of suramin by intermittent, short infusions. METHODS Plasma suramin concentrations were measured by high-performance liquid chromatography (HPLC), and compartmental pharmacokinetic models were fit using a Bayesian algorithm. Population pharmacokinetic models were developed using an iterative two-stage approach. Estimates of each patient's central-compartment volume were used to calculate suramin dosage. Simulation of that patient's suramin clearance was used to predict the time of his next dose. Using this approach, plasma suramin concentration was maintained at between 200 and 300, 175 and 275, 150 and 250, or 100 and 200 microgram/mL in four sequential patient cohorts. The ability of two- and three-compartment, open, linear models to fit the pharmacokinetic data was compared. Population pharmacokinetic parameters were estimated, using both two- and three-compartment structural models in 69 hormone-refractory prostate cancer patients. RESULTS Target plasma suramin concentrations in individual patients were rapidly achieved. Concentrations were maintained within desired ranges for > or = 85% of treatment duration in all cohorts. A three-compartment, open, linear model described suramin pharmacokinetics better than did a two-compartment, open, linear model. Population pharmacokinetic estimates generated for two- and three-compartment pharmacokinetic models demonstrated modest interpatient pharmacokinetic variability and the long terminal half-life of suramin. CONCLUSION Suramin can be administered by intermittent short infusion. Adaptive-control-with-feedback dosing facilitated precise control of plasma suramin concentrations and allowed a number of different concentration ranges to be studied. This approach is expensive and labor-intensive. Although we have demonstrated the ability to control drug exposure, simpler dosing schedules require critical evaluation. Population pharmacokinetic parameters generated in men with hormone-refractory prostate cancer will facilitate rational design of such schedules.

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Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens

Frontiers in Pharmacology ◽

10.3389/fphar.2021.785893 ◽

2022 ◽

Vol 12 ◽

Author(s):

Xingchen Bian ◽

Xiaofen Liu ◽

Fupin Hu ◽

Meiqing Feng ◽

Yuancheng Chen ◽

...

Keyword(s):

Bacterial Species ◽

Bloodstream Infections ◽

Polymyxin B ◽

Multidrug Resistant ◽

Chinese Patients ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Dosing Regimens ◽

Breakpoint Determination

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42–1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5–2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75–1.5 mg/kg/12 h for P. aeruginosa and 1–1.5 mg/kg/12 h for A. baumannii and K. pneumoniae were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.

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Structured Data Entry for Reliable Acquisition of Pharmacokinetic Data

Methods of Information in Medicine ◽

10.1055/s-0038-1634673 ◽

1996 ◽

Vol 35 (03) ◽

pp. 261-264 ◽

Cited By ~ 3

Author(s):

T. Schromm ◽

T. Frankewitsch ◽

M. Giehl ◽

F. Keller ◽

D. Zellner

Keyword(s):

Text Processing ◽

Data Entry ◽

Processing System ◽

Database System ◽

Structured Data ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Probability Of Error ◽

Error Frequency ◽

Estimated Error

Abstract:A pharmacokinetic database was constructed that is as free of errors as possible. Pharmacokinetic parameters were derived from the literature using a text-processing system and a database system. A random data sample from each system was compared with the original literature. The estimated error frequencies using statistical methods differed significantly between the two systems. The estimated error frequency in the text-processing system was 7.2%, that in the database system 2.7%. Compared with the original values in the literature, the estimated probability of error for identical pharmacokinetic parameters recorded in both systems is 2.4% and is not significantly different from the error frequency in the database. Parallel data entry with a text-processing system and a database system is, therefore, not significantly better than structured data entry for reducing the error frequency.

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Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽

10.3390/biom11060909 ◽

2021 ◽

Vol 11 (6) ◽

pp. 909

Author(s):

Yurii A. Zolotarev ◽

Vladimir A. Mitkevich ◽

Stanislav I. Shram ◽

Alexei A. Adzhubei ◽

Anna P. Tolstova ◽

...

Keyword(s):

Molecular Modeling ◽

Mouse Model ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Laboratory Animals ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Bolus Administration ◽

Blood Brain ◽

The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.14 ◽

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.

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