Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process

Author(s):

Kelly E. Caudle, Teri E. Klein, James M. Hoffman, Daniel J. Muller, Michelle Whirl-Carrillo, Li Gong, Ellen M. McDonagh, Katrin Sangkuhl, Caroline F. Thorn, Matthias Schwab, Jose A.G. Agundez, Robert R. Freimuth, Vojtech Huser, Ming Ta Michael Lee, Otito F. Iwuchukwu, Kristine R. Crews, Stuart A. Scott, Mia Wadelius, Jesse J. Swen, Rachel F. Tyndale, C. Michael Stein, Dan Roden, Mary V. Relling, Marc S. Williams and Samuel G. JohnsonPages 209-217 (9)

Abstract:

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.

Keywords:

Clinical practice guideline, guideline, pharmacogenetics, pharmacogenomics.

Affiliation:

262 Danny Thomas Place MS: 313, Memphis, TN 38105, USA.

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A 30-years Review on Pharmacokinetics of Antibiotics: Is the Right Time for Pharmacogenetics?

Author(s):

Lorena Baietto, Silvia Corcione, Giovanni Pacini, Giovanni Di Perri, Antonio D’Avolio and Francesco Giuseppe De RosaPages 581-598 (18)

Abstract:

Drug bioavailability may vary greatly amongst individuals, affecting both efficacy and toxicity: in humans, genetic variations account for a relevant proportion of such variability. In the last decade the use of pharmacogenetics in clinical practice, as a tool to individualize treatment, has shown a different degree of diffusion in various clinical fields.

In the field of infectious diseases, several studies identified a great number of associations between host genetic polymorphisms and responses to antiretroviral therapy. For example, in patients treated with abacavir the screening for HLA-B*5701 before starting treatment is routine clinical practice and standard of care for all patients; efavirenz plasma levels are influenced by single nucleotide polymorphism (SNP) CYP2B6-516G>T (rs3745274). Regarding antibiotics, many studies investigated drug transporters involved in antibiotic bioavailability, especially for fluoroquinolones, cephalosporins, and antituberculars. To date, few data are available about pharmacogenetics of recently developed antibiotics such as tigecycline, daptomycin or linezolid. Considering the effect of SNPs in gene coding for proteins involved in antibiotics bioavailability, few data have been published.

Increasing knowledge in the field of antibiotic pharmacogenetics could be useful to explain the high drug inter-patients variability and to individualize therapy. In this paper we reported an overview of pharmacokinetics, pharmacodynamics, and pharmacogenetics of antibiotics to underline the importance of an integrated approach in choosing the right dosage in clinical practice.

Keywords:

Metabolism, pharmacology, pharmacogenomic, single nucleotide polymorphism (SNP), tailored therapy, therapeutic drug monitoring (TDM), transporter, treatment.

Affiliation:

Department of Medical Sciences, University of Turin, Infectious Diseases at Amedeo di Savoia Hospital, Corso Svizzera 164, 10149. Turin, Italy.

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Preclinical Pharmacokinetics, Pharmacodynamics and Safety of Sucroferric Oxyhydroxide

Author(s):

Mario Cozzolino, Felix Funk, Viatcheslav Rakov, Olivier Phan and Isaac TeitelbaumPages 953-965 (13)

Abstract:

Sucroferric oxyhydroxide (VELPHORO®) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of 59Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity.

Keywords:

Chronic kidney disease (CKD), dialysis, hyperphosphataemia, phosphate, phosphate binder, preclinical, sucroferric oxyhydroxide.

Affiliation:

Department of Health Sciences, University of Milan, Renal Division, San Paolo Hospital, Via A. Di Rudinì, 8 20142 Milan, Italy.

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Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Author(s):

Derek W. Edwardson, Rashmi Narendrula, Simon Chewchuk, Kyle Mispel-Beyer, Jonathan P.J. Mapletoft and Amadeo M. ParissentiPages 412-426 (15)

Abstract:

Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.

Keywords:

Anthracyclines, anti-tumor effects, cardiotoxicity, deoxyaglycone, hydroxylation, metabolites, optimization, semi-quinone, therapeutic index.

Affiliation:

Dept. of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON P3E 2C6, Canada.

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Digestive Enzyme Supplementation in Gastrointestinal Diseases

Author(s):

Gianluca Ianiro, Silvia Pecere, Valentina Giorgio, Antonio Gasbarrini and Giovanni CammarotaPages 187-193 (7)

Abstract:

Background: Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage.

Methods: This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discussion of the use of pancreatic enzymes, lactase ( -galactosidase) and conjugated bile acids, and also exploring the future perspective of digestive enzyme supplementation.

Results: Currently, the animal-derived enzymes represent an established standard of care, however the growing study of plant-based and microbe-derived enzymes offers great promise in the advancement of digestive enzyme therapy.

Conclusion: New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not specifically related to enzyme deficiency, whereas the combination of different enzymes might constitute an intriguing therapeutic option in the future.

Keywords:

Bile acids, celiac disease, enzyme supplementation, gastrointestinal disease, lactose intolerance, pancreatic insufficiency.

Affiliation:

Department of Medical Sciences, Division of Internal Medicine, Gastroenterology and Liver Unit, Catholic University, School of Medicine and Surgery, A. Gemelli Hospital Rome, Italy, Largo A. Gemelli 8, IT-00168 Rome, Italy.

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