PRECISION DRUGS
Karel Petrak, D. Phil.

Abstract
Precision medicine is an approach to prevent and treat diseases that takes into account people’s individual variations in genes, environment, and lifestyle. In the first approximation, precision medicine may provide a more accurate diagnosis of the disease such as cancer, but may not offer improved therapies.

The aim of drug targeting is to generate pharmacologically effective drug concentration at the site of disease while keeping a very low/minimal drug concentration in the rest of the body. Targeted drugs could be the “precision drugs” needed to bring precision medicine into the clinical practice. However, a new paradigm needs to be adopted to make “precision drugs” a reality.

Introduction
More than 100 years ago, Professor Paul Ehrlich discovered Salvarsan, an arsenic compound that killed syphilis-causing bacterium; however, the compound was also harmful to human host [1]. Prof. Ehrlich prophesized in 1906 that chemists “would soon be able to produce substances that would seek out specific disease-causing agents” [2]. He used the term “magische kugel”, a “magic bullet”.

Very few drugs have been developed so far to act as “magic bullets”, with a notable exception of antibodies having therapeutic effect [3-4]. Conventional drug-development process produces drugs that distribute broadly throughout the body and act on their pharmacological targets associated not only with the disease but also the normal cells. Consequently, both desirable and undesirable drug effects are elicited. The vision of Paul Ehrlich inspired, excited and motivated scientists over a century. One of the approaches that have been given a considerable effort over many years has been to deliver, “target” existing drugs to specific disease sites. These efforts have been largely unsuccessful [5-6]. Looking for “magic bullets” is a flawed concept – we cannot rely on “magic”, and thinking of an “intelligent” bullet is an oxymoron. Instead, we need to adopt the concept of “precision drugs”.

Precision Medicine is a medical-research area aiming to amass population genetic data with the aim of “discovering genetic causes of disease and finding new drugs that will target dangerous mutations” [7]. The aim of precision medicine is to “generate the scientific evidence needed to move the concept of precision medicine into clinical practice” [8-9]. The issue that is not being addressed as yet is that putting into practice the mechanistic and diagnostic findings of precision medicine will require the availability and use of corresponding precision drugs, precision therapeutic agents.

In the first approximation, precision medicine may provide a more accurate diagnosis of the disease such as cancer, but may not have the means to offer an improved therapy. Targeting cells in which a precisely diagnosed mechanism drives disease, such as for example any particular cancer, will very likely need “precision drugs” / “precision medications” that are yet to be developed.

In a recent publication [10] I critically reviewed this topic and concluded that the most plausible paradigm for the future development of site-specific drug-delivery systems is to combine monoclonal antibodies (or other targeting entities such receptor ligands, etc.) with drugs that meet the pharmacokinetic and pharmacodynamic requirements of this application. A new paradigm needs to be adopted that centers on “self-targeting carriers” such as antibodies combined with “high-potency” drugs specifically selected or developed de novo that fully meet the specific pharmacokinetic requirements of targeted drug delivery.

References
1. Michael P. Sherman. Historical Perspective: Perinatal Profiles: Elie Metchnikoff: Probiotic Pioneer. NeoReviews 2011;12;e495-e497.
http://neoreviews.aappublications.org/content/12/9/e495.full
2. http://www.chemheritage.org/discover/online-resources/chemistry-in-history/themes/pharmaceuticals/preventing-and-treating-infectious-diseases/ehrlich.aspx
3. Scott AM, Wolchok JD and Lloyd J. Old LJ. Antibody therapy of cancer. Nature Reviews Cancer 12, 278-287 (April 2012) | doi:10.1038/nrc3236.
4. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-monoclonal-antibodies
5. Petrak, K. Nanotechnology and site-targeted drug delivery. J. Biomater. Sci. in Special Issue on Nanobiomaterials (Vasif Hasirci and Karel Petrak, Eds.), vol. 17, no. 11, pp. 1209-1221 (2006).
6. Petrak, K. Targeted Drug Delivery––Quo Vadis? Drug Development Research Volume 73, Issue 2, pages 59–65, March 2012. Article first published online: 29 DEC 2011. DOI: 10.1002/ddr.20492.
7. http://www.nih.gov/precisionmedicine/
8. http://www.nih.gov/precisionmedicine/infographic-printable.pdf
9. http://ghr.nlm.nih.gov/handbook/precisionmedicine/initiative
10. Petrak K., Precision Medicine and Site-specific Drug Delivery. Archives in Cancer Research, Volume 3, Issue 3 (in press).

Postscript
Precision Medicine will need Precision Drugs. I am keen to discuss, collaborate with or mentor anyone interested in working towards this goal. KP