Approaches to higher-throughput pharmacokinetics (HTPK) in drug discovery

doi:10.1016/S1359-6446(99)01434-8

Drug Discovery Today

Volume 5, Issue 1, 1 January 2000, Pages 17-24

https://doi.org/10.1016/S1359-6446(99)01434-8 Get rights and content

Abstract

With pressure on pharmaceutical companies to reduce time-to-market and improve the success rate of new drug candidates, higher-throughput pharmacokinetic (HTPK) support has become an integral part of many drug discovery programmes. This report details the amalgamation of robotics, new sample preparation technologies and highly sensitive and selective mass spectrometric detection systems to deliver the promise of HTPK. A historical perspective on automated bioanalysis with the current approaches and future prospects for the discipline are described.

Section snippets

Pharmacokinetics in practice

The PK profile of a drug, in which the absorption, distribution, metabolism and excretion processes following in vivo administration are mathematically described, is derived from the plot of the systemic drug concentration versus time for that compound. Following either parenteral or oral administration, serial blood samples are collected as a function of time and then analyzed for drug content. The complete process is summarized in Fig. 2 and can be divided into five main areas:

•
The in vivo

Automation perspective

From the inception of modern chromatographic science, automation technologies have continuously developed, beginning with the introduction of autosamplers and microprocessor-controlled instrumentation in the late 1970s to early 1980s. This enabled the sequencing of samples, often requiring different analytical instrument characteristics, and this increased the number of samples that could be processed in a batch by enabling unattended, overnight operation. In the mid-1980s, early adopters of

Current technologies

The current options available to increase the throughput of a PK assay can be divided into the two main areas of sample preparation and experimental design, although consideration should also be given to data handling and utilization, which will also be discussed.

Limitations of HTPK

Whilst LC–MS/MS has undoubtedly brought great benefits to the analysis of biofluids, it is not without its disadvantages and is far from being a ubiquitous technique for all analytes. In particular, when dealing with the ionization of compounds in the presence of potentially interfering matrix components, ion suppression is sometimes observed, as matrix components can preferentially ionize or ion-pair with the analyte41, 42. Additionally, many components might be late eluting from the

Conclusions and future perspectives

Advances in MS currently offer many intriguing possibilities for the further development of HTPK. Triple quadrupole MS systems continue to improve in sensitivity with the development of enhanced vacuum pumping systems and ion optics. The requirement for method development is negated by improvements in selectivity and detection limits such that instrument optimization for ultimate performance is no longer required. In addition, such instrumentation allows PK investigation at more

Acknowledgements

We would like to thank our colleagues from the drug metabolism groups within Merck for many fruitful and positive discussions.

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ReviewApproaches to higher-throughput pharmacokinetics (HTPK) in drug discovery

Abstract

Section snippets

Pharmacokinetics in practice

Automation perspective

Current technologies

Limitations of HTPK

Conclusions and future perspectives

Acknowledgements

Curr. Opin. Chem. Biol.

Curr. Opin. Chem. Biol.

Trends Anal. Chem.

J. Chromatogr. A

J. Pharm. Biomed. Anal.

J. Chromatogr. B Biomed. Sci. Appl.

J. Chromatogr. A

J. Chromatogr. A

J. Pharm. Biomed. Anal.

J. Chromatogr. A

J. Chromatogr. A

Drug Discovery Today

Pharm. Sci. Technol. Today

Lab. Autom. Inf. Manage.

J. Pharm. Biomed. Anal.

J. Am. Soc. Mass Spectrom.

J. Am. Soc. Mass Spectrom.

J. Chromatogr. B Biomed. Sci. Appl.

Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964–1985)

Br. J. Clin. Pharmacol.

High-throughput screening for drug discovery

Nature

Applications of combinatorial technologies to drug discovery: 1. Background and peptide combinatorial libraries

J. Med. Chem.

Applications of combinatorial technologies to drug discovery: 2. Combinatorial organic synthesis, library screening strategies, and future directions

J. Med. Chem.

Preclinical drug metabolism in the age of high-throughput screening: an industrial perspective

Pharm. Res.

High throughput drug metabolism

Biomed. Health Res.

Review
Approaches to higher-throughput pharmacokinetics (HTPK) in drug discovery