Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two Decades

Davies, Michael; Jones, Rhys D.O.; Grime, Ken; Jansson‐Löfmark, Rasmus; Fretland, Adrian J.; Winiwarter, Susanne; Morgan, Paul; McGinnity, Dermot F.

doi:10.1016/j.tips.2020.03.004

Cited by 86 publications

(66 citation statements)

References 73 publications

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“…Both scaling of dose and model parameters produced human CSF exposure predictions within twofold of the exposure observed in patients with CLN2 disease. 16 , 17 The MAPE values across species were similar when scaling by dose and model parameters (21% and 28%, respectively), supporting the consistency and appropriateness of each approach.…”

Section: Discussionmentioning

confidence: 63%

Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease

Hammon

Hart

Vuillemenot

et al. 2021

Clinical Translational Sci

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Section: Discussionmentioning

confidence: 63%

Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease

Hammon

Hart

Vuillemenot

et al. 2021

Clinical Translational Sci

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“…Certain pharmacokinetic features must be followed to consider the compound as a drug. Bioavailability of absorption, the volume of distribution, the half-life for ADMET were the essential pharmacokinetics features that play a vital role in discovering a drug candidate 24 . Pharmacokinetics properties of the four compounds described as molecular weight (Mw, g/mol), the logarithm of partition coefficient (log P), number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD), number of rotatable bonds (ROT), and topological polar surface area (TPSA, Å 2 ) were calculated by using SwissADME.…”

Section: Pharmacokinetics Propertiesmentioning

confidence: 99%

In Silico Study for Similar FDA Approved Drugs as Inhibitors of SARS-CoV-2 Spike and the Host Receptor Proteins

et al. 2021

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The severe acute respiratory syndrome coronavirus 2, known as COVID-19, has been hideously increased worldwide. The disease began in Wuhan, China, around December 2019, then spread to most countries. Social distancing is the best procedure to prevent infection. Screening the available database containing millions of drug molecules or phytochemicals has become rapid and straightforward because of the computer-aided drug design (CADD) methods. In the present study, 300 phytochemicals and cellulose ether derivatives are screened through a docking study. Docking analysis showed that only four molecules (a-neohesperidin, quercetin 3-O-glucosylrutinoside, 14-ketostypodiol diacetate, and hydroxypropyl methylcellulose) were able to interact with the spike protein. However, two among them (quercetin 3-O-glucosylrutinoside and 14-ketostypodiol diacetate) could interact with the host cell receptor (ACE2) of SARS-CoV-2. The binding affinity of the four compounds is high. Still, according to Lipinski's rule of five, only 14-ketostypodiol diacetate was selected as a drug molecule due to its pharmacokinetic and ADMET properties. Screening for drug analogs to the 14-ketostypodiol diacetate detected five approved drugs. Docking analysis of these drugs with the target proteins showed that the five drugs interact with the host receptor protein, and three interact with viral spike protein. Accordingly, we suggest that molecular docking and drug analogs studies could support rapid drug development. In addition, future perspectives on therapeutic applications of 14-ketostypodiol diacetate are required for using it against SARS-CoV-2 infections.

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“…In vivo PPB studies are not only performed for the parent drug, but also the main active metabolites [27] . In non‐separative methods, spectroscopic techniques can be employed, for example, UV‐Visible (UV‐Vis), fluorescence, infrared (IR), nuclear magnetic resonance (NMR), optical rotational dispersion (ORD), and circular dichroism (CD) [28] . In addition, calorimetric approaches are used to study drug‐protein interactions, for example, isothermal titration calorimetry (ITC), and differential scanning calorimetry (DSC) [26] …”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Prediction of Pharmacokinetics Properties in Drug Design Studies: A Review

et al. 2021

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This review presents the main aspects related to pharmacokinetic properties, which are essential for the efficacy and safety of drugs. This topic is very important because the analysis of pharmacokinetic aspects in the initial design stages of drug candidates can increase the chances of success for the entire process. In this scenario, experimental and in silico techniques have been widely used. Due to the difficulties encountered with the use of some experimental tests to determine pharmacokinetic properties, several in silico tools have been developed and have shown promising results. Therefore, in this review, we address the main free tools/servers that have been used in this area, as well as some cases of application. Finally, we present some studies that employ a multidisciplinary approach with synergy between in silico, in vitro, and in vivo techniques to assess ADME properties of bioactive substances, achieving successful results in drug discovery and design.

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Improving the Accuracy of Predicted Human Pharmacokinetics: Lessons Learned from the AstraZeneca Drug Pipeline Over Two Decades

Cited by 86 publications

References 73 publications

Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease

Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease

In Silico Study for Similar FDA Approved Drugs as Inhibitors of SARS-CoV-2 Spike and the Host Receptor Proteins

Recent Advances in the Prediction of Pharmacokinetics Properties in Drug Design Studies: A Review

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