A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment

Nguyen, Hoa; Stamatis, Stephen D.; Kirsch, Lee E.

doi:10.1002/jps.24452

Cited by 9 publications

(4 citation statements)

References 54 publications

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“…The guidelines for degradation products state the reporting threshold for a dose less than one gram is 0.1%, the identification threshold for a dose of 10 mg to 2 g is 0.2%, and the qualification threshold for a dose of 10 mg to 100 mg is 0.5% ( Guidance for industry Q3B(R2), 2006 ). For example, the generation of any specific degradant in an amount greater than 0.5% requires further toxicity studies to assess the clinically relevant side effects associated with the degradant ( Guidance for industry Q3B(R2), 2006 ; Nguyen et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

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Section: Introductionmentioning

confidence: 99%

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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“…For brominated flame retardants, no human PBTK model has been identified, so the PBTK model for developmental exposure to BDE-47 in rats (Emond et al, 2010) has been reviewed, as a basis for a future extrapolation to humans, while for aniline and structurally related compounds a PBTK model developed for rat has been extrapolated to humans (Nguyen et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…One PBTK model that generated toxicity exposure distributions for a series of substituted anilines in rats and human was found in literature (Nguyen et al, 2015). The substituted anilines were chosen because of their structural similarity to aniline.…”

Section: Anilinesmentioning

confidence: 99%

Physiology-based toxicokinetic modelling in the frame of the European Human Biomonitoring Initiative

Sarigiannis

Karakitsios

Dominguez-Romero

et al. 2019

Environmental Research

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Given the opportunities provided by internal dosimetry modelling in the interpretation of human biomonitoring (HBM) data, the assessment of the links between exposure to chemicals and observed HBM data can be effectively supported by PBTK modelling. This paper gives a comprehensive review of available human PBTK models for compounds selected as a priority by the European Human Biomonitoring Initiative (HBM4EU). We highlight their advantages and deficiencies and suggest steps for advanced internal dose modelling. The review of the available PBTK models highlighted the conceptual differences between older models compared to the ones developed recently, reflecting commensurate differences in research questions. Due to the lack of coordinated strategies for deriving useful biomonitoring data for toxicokinetic properties, significant problems in model parameterisation still remain; these are further increased by the lack of human toxicokinetic data due to ethics issues.

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“…Sensitivity and uncertainty analysis were used to evaluate the impact of model parameters on PK tissue profiles. 37 A parameter sensitivity analysis (PSA) was performed using the GastroPlus builtin PSA module. AUC of losartan and carboxylosartan after 50-mg oral dose of losartan was simulated against various losartan OATP V max , MRP-2 V max , CYP2C9 V max , and K m , carboxylosartan OATP V max , MRP-2 V max , MRP V max values to assess the sensitivity of the model simulations of losartan and its metabolite plasma concentration profiles to variation in these transporter and metabolic Figure 3.…”

Section: Local Sensitivity Analysismentioning

confidence: 99%

Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models

Nguyen

Lin

Kimoto

et al. 2017

Journal of Pharmaceutical Sciences

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The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUC/AUC) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich-cultured hepatocytes. Human renal clearance of carboxylosartan was estimated from dog renal clearance using allometric scaling approach. All clearance mechanisms were mechanistically incorporated in a static model to predict the relative exposure of carboxylosartan versus losartan (AUC/AUC). The predicted AUC/AUC were consistent with the observed data following intravenous and oral administration of losartan. Moreover, the in vitro parameters were used as initial parameters in PBPK permeability-limited disposition models to predict the concentration-time profiles for both parent and its active metabolite after oral administration of losartan. The PBPK model was able to recover the plasma profiles of both losartan and carboxylosartan, further substantiating the validity of this approach.

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A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment

Cited by 9 publications

References 54 publications

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Physiology-based toxicokinetic modelling in the frame of the European Human Biomonitoring Initiative

Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models

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