Guidelines for the experimental design of pharmacokinetic studies with nanomaterials in preclinical animal models

Valic, Michael; Halim, Michael; Schimmer, Pamela; Zheng, Gang

doi:10.1016/j.jconrel.2020.04.002

Cited by 32 publications

(16 citation statements)

References 114 publications

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“…In parallel with the 3R principles, more attention has been paid in recent years to the design of pre-clinical pharmacokinetic studies [ 18 , 19 ]. Some attempts to standardize the procedures used in these studies are emerging to improve the quality of the obtained data [ 3 , 20 ]. Our work was conducted to elaborate on the impact of inter- and intra-subject variability within comparative pre-clinical studies, which is an important factor that may substantially affect the obtained results.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs

Královičová

Bartůněk

Hofmann³

et al. 2022

Pharmaceutics

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One of the major concerns for all in vivo experiments is intra- and inter-subject variability, which can be a great source of inaccuracy. The aim of this study is, therefore, to estimate the ability of parallel vs. cross-over design studies in order to describe the relative pharmacokinetic performance of the studied drug formulations. We analyzed the data from a drug development program that examined the performance of innovative abiraterone acetate formulations against the identical reference product in three stages. In stages 1–3, groups A–F were dosed with the reference product once in a parallel manner. Stage 4 was performed to evaluate the intra-individual variability (IIV) by repeated administration of the reference product to the same animals. Although the geometric mean (90% CI) values of abiraterone AUClast in groups A–F were similar to the IIV group (24.36 (23.79–41.00) vs. 26.29 (20.56–47.00) mg/mL·min·g), the results generated in the isolated parallel groups provided imprecise estimates of the true AUClast values ranging from 9.62 to 44.62 mg/mL·min·g due to chance. Notably, in 4 out of 15 possible pair comparisons between the parallel groups, the confidence intervals did not include 100%, which is the true ratio for all comparisons tested after identical formulation administration to all groups. A cross-over design can significantly improve the methodology in short-term comparative pre-clinical pharmacokinetic studies, and can provide more precise and accurate results in comparison to more traditional pre-clinical study designs.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs

Královičová

Bartůněk

Hofmann³

et al. 2022

Pharmaceutics

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“…In addition, the Gibbs free energy associated with the binding at 298, 303, 308, and 313 K was found to be negative (nearly ΔG° = −31 KJ mol −1 ). These results indicate that the strong and spontaneous binding of DF to HSA is responsible for poor pharmacokinetic profiles and is a limiting therapeutic step, or that nanocarriers could be designed to fine-tune lipophilicity, plasma protein binding, and facilitate diffusion across the membrane ( Valic et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Tissue Distribution, and Human Serum Albumin Binding Properties of Delicaflavone, a Novel Anti-Tumor Candidate

et al. 2021

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Delicaflavone (DF), a natural active ingredient from Selaginella doederleinii Hieron, has been reported to have favorable anticancer effects and is thus considered a potential anticancer agent. However, its pharmacokinetics and plasma protein binding properties remain unknown. Here, we investigated the pharmacokinetic profile of DF in rats using a validated HPLC-MS/MS methods, as well as its human serum albumin (HSA) binding properties through multi-spectroscopic and in silico methods. The results showed that DF was rapidly eliminated and had a widespread tissue distribution after intravenous administration. DF showed linear dynamics in the dose range of 30–60 mg/kg and poor oral bioavailability. The major distribution tissues of DF were the liver, lungs, and kidneys. Ultraviolet and fluorescence spectroscopy and molecular docking demonstrated that DF had a static quenching effect on HSA, with one binding site, and relatively strong binding constants. Thermodynamic analysis of the binding data revealed that hydrogen bonding and van der Waals interactions played major roles in binding. The results of this study further our understanding of the pharmacokinetic and plasma protein binding properties of the potential anticancer agent DF and shed light on pharmacological strategies that may be useful for the development of novel cancer therapeutics.

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“…Before and at predefined time points after dosing, plasma and/or tissue samples are collected to quantify the amount or concentration of the NMs. To characterize the plasma TK profile, there could be multiple experimental designs (Figure 1), including (1) a replicate blood sampling approach where each animal is sacrificed at a predefined time point and blood is collected at this single time point for each animal, (2) a staggered blood sampling approach where multiple blood samples are collected in a nondestructive manner for each subgroup of animals at different time points from either the same or a different anatomical sampling site between time points (the number of samples depends on the volume of the sample and the size of the animal), and (3) a serial or repeated blood sampling approach which nondestructively collects blood samples at all scheduled time points to derive the individual concentration–time profiles for all animals (Valic et al, 2020).…”

Section: Toxicokineticsmentioning

confidence: 99%

“…The sampling time points also need to consider the species, study objective, sampling strategy, available resources, and so on. Readers are referred to a detailed guidance by Valic et al on the TK study design of NMs (Valic et al, 2020).…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Toxicokinetics, dose–response, and risk assessment of nanomaterials: Methodology, challenges, and future perspectives

Chen

Riviere

Lin

2022

WIREs Nanomed Nanobiotechnol

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The rapid growth of nanomaterial applications has raised safety concerns for human health. A number of studies have been conducted to assess the toxicokinetics, toxicology, dose–response, and risk assessment of different nanomaterials using in vitro and in vivo animal and human models. However, current studies cannot meet the demand for efficient assessment of toxicokinetics, dose–response relationships, or the toxicological risk arising from the rapidly increasing number of newly synthesized nanomaterials. In this article, we review the methods for conducting toxicokinetics, hazard identification, dose–response, exposure, and risk assessment studies of nanomaterials, identify the knowledge gaps, and discuss the challenges remaining. We provide the rationale behind the appropriate design of nanomaterial plasma toxicokinetic and tissue distribution studies, including caveats on the interpretation and correlation of in vitro and in vivo toxicology studies. The potential of using physiologically based pharmacokinetic (PBPK) models to extrapolate toxicokinetic and toxicity findings from in vitro to in vivo and from animals to humans is discussed, and the knowledge gaps of PBPK modeling for nanomaterials are identified. While challenges still exist, there has been progress in the toxicokinetics, hazard identification, and risk assessment of nanomaterials in the past two decades. Recent advancements in the field are highlighted with relevant examples. We also share latest guidelines as well as our perspectives on future studies needed to characterize the toxicokinetics, toxicity, and dose–response relationship in support of nanomaterial risk assessment.This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

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Guidelines for the experimental design of pharmacokinetic studies with nanomaterials in preclinical animal models

Cited by 32 publications

References 114 publications

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs

Pharmacokinetics, Tissue Distribution, and Human Serum Albumin Binding Properties of Delicaflavone, a Novel Anti-Tumor Candidate

Toxicokinetics, dose–response, and risk assessment of nanomaterials: Methodology, challenges, and future perspectives

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