Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery

Stoner, Chad L.; Cleton, Adriaan; Johnson, Kjell; Oh, Doo-Man; Hallak, Hussein; Brodfuehrer, Joanne; Surendran, Narayanan; Han, Hyo-Kyung

doi:10.1016/j.ijpharm.2003.09.006

Cited by 53 publications

(27 citation statements)

References 18 publications

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“…In order to achieve a significant decrease in the attrition rates for drugs, the recent trend in drug discovery has been to access physicochemical and pharmacological information earlier in the drug discovery process (1,9,20,21). In an attempt to parallel drug discovery and early preclinical development efforts against tuberculosis, we report here two simple assays that can facilitate and improve testing of experimental compounds in the early preclinical phase.…”

Section: Discussionmentioning

confidence: 99%

“…A published survey on the causes of failure in drug development indicated that inappropriate pharmacokinetics were a major cause (19). This observation has led to an increased emphasis on pharmacokinetic input to the drug discovery process throughout the pharmaceutical industry (9,20,21).Traditional assays and models for early preclinical screening of experimental compounds against Mycobacterium tuberculosis are lengthy due to the slow-growing nature of the bacteria. In addition, many of the current in vitro and in vivo assays for drug testing against tuberculosis (TB) are not well adapted for a higher throughput approach, which is necessary for rapid screening of compound series from different drug classes.…”

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confidence: 99%

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confidence: 99%

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Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

Gruppo

Johnson

Marietta

et al. 2006

Antimicrob Agents Chemother

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The assessment of physiochemical and pharmacological properties at early stages of drug discovery can accelerate the conversion of hits and leads into candidates for further development. A strategy for streamlined evaluation of compounds against Mycobacterium tuberculosis in the early preclinical stage is presented in this report. As a primary assay to rapidly select experimental compounds with sufficient in vitro activity, the growth inhibition microtiter plate assay was devised as an alternative to current methods. This microdilution plate assay is a liquid culture method based on spectrophotometric readings of the bacillary growth. The performance of this method was compared to the performance of two established susceptibility methods using clinical available tuberculosis (TB) drugs. Data generated from all three assays were similar for all of the tested compounds. A second simple bioassay was devised to assess the oral bioavailability of compounds prior to extensive in vivo efficacy testing. The bioassay estimates drug concentrations in collected serum samples by a microdilution MIC plate method using M. tuberculosis. In the same assay, the MIC of the compound is also determined in the presence of 10% mouse serum as an indication of protein binding. The method was validated using different clinically available TB drugs, and results are discussed in this report. With these methodological advances, screening of compounds against tuberculosis in the preclinical phase will be rapid, can be adapted to semi-high-throughput screening, and will add relevant physicochemical and basic pharmacological criteria to the decision process of drug discovery.The pharmaceutical process to develop a therapeutically useful drug requires an enormous budget and amount of time, due to high attrition rates of experimental compounds in preclinical and clinical development (2, 10). Pharmaceutical companies nowadays are focusing on reducing these preclinicaldevelopment attrition rates by attempting to accurately evaluate efficacy, safety, and drug manufacturing costs much earlier in the drug discovery process. A published survey on the causes of failure in drug development indicated that inappropriate pharmacokinetics were a major cause (19). This observation has led to an increased emphasis on pharmacokinetic input to the drug discovery process throughout the pharmaceutical industry (9,20,21).Traditional assays and models for early preclinical screening of experimental compounds against Mycobacterium tuberculosis are lengthy due to the slow-growing nature of the bacteria. In addition, many of the current in vitro and in vivo assays for drug testing against tuberculosis (TB) are not well adapted for a higher throughput approach, which is necessary for rapid screening of compound series from different drug classes. Generally, compounds are first evaluated in vitro for activity against M. tuberculosis by determination of their MICs with either the BACTEC system (4, 16), the agar proportion method (7, 13, 25), or a microdilution assay mic...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

Gruppo

Johnson

Marietta

et al. 2006

Antimicrob Agents Chemother

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“…In terms of accuracy of RoE for human CL prediction, 42 out of 45 drugs fell within twofold error compared to 35 out of 45 for the SA approach (40). A recent comparative study of 68 compounds consistently showed that RoE provided better predictions than other allometric scaling methods and similar accuracies to IVIVE, especially for low lipophilic and intermediate/high clearance compounds (41). However, the performance of RoE was controversial.…”

Section: Rule Of Exponentsmentioning

confidence: 99%

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

Zou

Zheng

et al. 2012

AAPS J

107

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Abstract. Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK-or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.

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“…Providing the user with some confidence in the prediction has only been partially addressed by the efforts at providing an applicability domain using Tanimoto similarity, PCA, clustering, Mahalanobis distance, etc. (28)(29)(30)(31)(32)(33)(34)(35)(36).…”

Section: The Universementioning

confidence: 99%

Chemical Space: Missing Pieces in Cheminformatics

et al. 2010

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Cheminformatics is at a turning point, the pharmaceutical industry benefits from using the various methods developed over the last twenty years, but in our opinion we need to see greater development of novel approaches that non-experts can use. This will be achieved by more collaborations between software companies, academics and the evolving pharmaceutical industry. We suggest that cheminformatics should also be looking to other industries that use high performance computing technologies for inspiration. We describe the needs and opportunities which may benefit from the development of open cheminformatics technologies, mobile computing, the movement of software to the cloud and precompetitive initiatives.

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Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery

Cited by 53 publications

References 18 publications

Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

Chemical Space: Missing Pieces in Cheminformatics

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