Pharmaceutical industry

1 Mental Health Research Center, Eastern State Hospital, University of Kentucky, Lexington, KY, USA; 2College of Medicine, University of Kentucky, Lexington, KY, USA; 3College of Pharmacy, University of Kentucky, Lexington, KY, USA; 4Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, Medical School, University of Granada, Granada, Spain This review focuses first on the concept of pharmacogenomics and its related concepts (biomarkers and personalized prescription).

Next, the first generation of five DNA pharmacogenomic tests used in the clinical practice of psychiatry is briefly reviewed. Then the possible involvement of these pharmacogenomic tests in the exploration of early clinical proof of mechanism is described by using two of the tests and one example from the pharmaceutical industry (iloperidone clinical trials). The initial attempts to use other microarray tests (measuring RNA expression) as peripheral biomarkers for CNS disorders are briefly described.

Then the challenge of taking pharmacogenomic tests (compared to drugs) into clinical practice is explained by focusing on regulatory oversight, the methodological/scientific issues concerning diagnostic tests, and cost-effectiveness issues. Current information on medicine-based evidence and cost-effectiveness usually focuses on average patients and not the outliers who are most likely to benefit from personalized prescription. Finally, future research directions are suggested.

The future of ‘personalized prescription’ in psychiatry requires consideration of pharmacogenomic testing and environmental and personal variables that influence pharmacokinetic and pharmacodynamic drug response for each individual drug used by each patient. Neuropsychopharmacology Reviews (2009) 34, 159–172; doi:10. 1038/npp. 2008. 147; published online 17 September 2008 Keywords: pharmacogenetics; personalized iloperidone; metabolic syndrome-genetics prescription; cytochrome P450; clozapine-induced agranulocytosis

INTRODUCTION This review focuses first on the concept of pharmacogenomics and its related concepts (biomarkers and personalized prescription). Next, the first generation of five pharmacogenomic tests used as diagnostic tests in the clinical practice of psychiatry is briefly reviewed. Then the possible involvement of pharmacogenomic tests in the exploration of early clinical proof of mechanism is described by using two of these pharmacogenomic tests and one example from the pharmaceutical industry (iloperidone clinical trials).

The initial attempts to use other microarray tests (measuring RNA expression) as peripheral biomarkers for CNS disorders are briefly described. Then the challenge of taking pharmacogenomic tests to clinical practice is explained by focusing on the differences between pharmacogenomic tests and drug evaluation regarding regulatory *Correspondence: Dr J de Leon, Mental Health Research Center, Eastern State Hospital, University of Kentucky, 627 West Fourth Street, Lexington, KY 40508, USA, Tel: + 1 859 246 7563; Fax: + 1 859 246 7019, E-mail: [email protected]

edu Received 28 April 2008; revised 24 July 2008; accepted 25 July 2008 oversight, the methodological/scientific issues, and costeffectiveness issues. Finally, future research directions are suggested. The review seeks to provide more extensive information in those areas not usually described in the psychiatric literature. Several of the discussed topics are usually described in journals not frequently read by psychiatric researchers, including pharmacogenomic, clinical pharmacology, or laboratory journals.

PHARMACOGENOMICS AND RELATED CONCEPTS Many psychiatric researchers are familiar with the advances in genetic knowledge and technology; therefore this section has a small subsection covering that area and a more extensive subsection devoted to three concepts with which psychiatric researchers may not be so familiar: pharmacogenomics, biomarkers, and personalized prescription. Pharmacogenomics has been developed within the context of clinical pharmacology.

Thus, to understand how pharmacogenomic tests can be transferred to clinical practice, one must be familiar with the history and context ……………………………………………………………………………………………………………………………. Neuropsychopharmacology REVIEWS …………………………………………………………………………………………………………………………………………… Pharmacogenomics J de Leon REVIEW History of Pharmacogenomics

The development of genomic medicine and genetic testing has helped in diagnosing some relatively rare and unusual disorders, but the field of pharmacogenomics is potentially much more important; it has been proposed as the driving force for implementing genetic medicine in primary care (Emery and Hayflick, 2001; Phillips et al, 2001). Vogel (1959) coined the term pharmacogenetics. According to Pirmohamed (2001), pharmacogenetics has been defined as the study of variability in drug response due to heredity and was largely used in relation to genes determining drug metabolism.

More recently, the term pharmacogenomics is being used, which is a broader term encompassing all genes in the genome that may determine drug response. The distinction is arbitrary. Both terms are used interchangeably (Pirmohamed, 2001). Roses (2004) made an important distinction between two types of pharmacogenetics. Safety pharmacogenetics is aimed at avoiding adverse drug reactions (ADRs), which are usually called side effects in the psychiatric literature. Efficacy pharmacogenetics is meant to predict response to medication. 160 of pharmacogenomics.

The Food and Drug Administration (FDA) has used the concept of biomarkers in discussing how to approve pharmacogenomic tests, therefore the concept of biomarkers is very briefly reviewed. The concept of personalized prescription, as described here, evolved within the context of pharmacogenomics but can be applied beyond pharmacogenomics. Technological Advances and the Human Genome New technologies permitting parallel genetic testing (testing for many genetic variations) developed near the end of the 20th century (Fodor, 1997), and mapping of the human genome was completed in 2000.

Both brought hope for a new era in medicine (McKusick, 2001). One of the major technological breakthroughs that allowed the genetic revolution was the introduction of computerized genotyping systems such as the Affymetrix GeneChip (Fodor, 1997). Currently, more advanced forms of these types of DNA microarray technologies (Koch, 2004), including the Illumina BeadArray platform (Steemers and Gunderson, 2007), allow testing more than a half million SNPs at a cost of less than $1000 per sample, and further price reductions are in sight.

The importance of these new technologies can be understood when we remember that the human genome may have more than 20 000 genes and millions of variations, including the so-called single-nucleotide polymorphism (SNP). More recently, some authors have stressed that other types of genetic variations such as deletions or duplications, the so-called copy number variations (CNVs), may have been neglected (Redon et al, 2006). Moreover, other less common genetic variations such as microsatellite polymorphisms and translocations, inversions, and substitutions may have relevance in pharmacogenomics (Court, 2007).

Unfortunately, many of the current platforms and systems used for genotyping pay little attention to CNVs, even though CNVs may be important for pharmacogenomics (Ouahchi et al, 2006) and were first discovered in a pharmacogenetic gene, the cytochrome P450 2D6 (CYP2D6) (Ingelman-Sundberg et al, 2007). Autism (Sebat et al, 2007) and schizophrenia (Walsh et al, 2008) may be associated with CNVs; currently it is not known whether these described CNVs have relevance for treatment or not.

Epigenetics is increasing in importance in psychiatry (Abdolmaleky et al, 2005) and in relationship to psychiatric drug response (Sharma et al, 2006). The relevance of epigenetics for pharmacogenetic response in humans is not well understood (Nebert et al, 2008). It is important to know that it has recently been demonstrated that a fly’s drug tolerance to an anesthetic appeared to be mainly caused by epigenetic mechanisms (Wang et al, 2007).

Currently it is unclear how epigenetic changes can be tested in the clinical environment, but it has been suggested that pyrosequencing may be a technology that can be used for genetic changes including SNPs, CNVs, and also for methylation status (Marsh, 2007). ……………………………………………………………………………………………………………………………. The Concept of Biomarkers The FDA discussed the approval of pharmacogenomic tests as examples of biomarkers.

Many definitions of biomarker exist, one of which is ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological response(s) to a therapeutic intervention’ (Wagner, 2002). There are different types of biomarkers, including pharmacogenomic biomarkers (Court, 2007; Kirkwood and Hockett, 2002). In the spring of 2005, the FDA (2005) developed guidelines for pharmaceutical companies on the collection and inclusion of genetic information for drug applications.

According to the FDA, the results of genetic tests that distinguish allelic variants of two metabolic enzymes, the CYP2D6 and thiopurine S-methyltranseferase (TPMT), were considered to be well established and, therefore, valid biomarkers (testing for both enzymes is described later in this article). When submitting an investigational new drug (IND) application to the FDA, pharmaceutical companies must send relevant data on ‘valid biomarkers’, although other pharmacogenetic data can be submitted voluntarily (Salerno and Lesko, 2005).

The Concept of Personalized Prescription A term related to pharmacogenomics and frequently used by lay journals is ‘personalized prescription’, defined by a Science (1997) editorial as ‘tailoring drugs to a patient’s genetic makeup’. That editorial in 1997 predicted that personalized medicine will ‘soon’ reach clinical practice. Other more precise estimates for the generalized use of personalized prescription have been advanced: 2015 by Time magazine (Lertola, 1999) and 2020 by JAMA (Collins Neuropsychopharmacology REVIEWS.

REVIEW and McKusick, 2001). If the generalized medical use of personalized prescription is going to occur in 7–12 years, one should notice preliminary steps toward its occurrence in the first generation of pharmacogenetic tests available in psychiatry. Even business journals (Cappell et al, 2005) describe psychiatry (along with oncology) as being at the forefront in the use of pharmacogenomics in medicine. The concept of personalized prescription is really wider than pharmacogenetics or pharmacogenomics.

As a matter of fact, the first versions of two personalized prescription tests, Trastuzumab (Herceptin) and TPMT, did not involve genotyping. Oncology is fortunate to have the availability of tissue samples from tumor cells, allowing testing for very specific drug targets (proteins expressed) within the tumor cells and the use of monoclonal antibodies. Trastuzumab (Herceptin), a humanized monoclonal antibody specific to HER-2/neu, has revolutionized and personalized the management of metastatic HER-2/neu-overexpressing breast cancers (Emens, 2005).

As previously indicated, the FDA considers TPMT a ‘valid biomarker’. Although the number of subjects with low TPMT activity is small (o5% in Caucasians), the leading hospitals treating children with childhood leukemia routinely perform TPMT phenotyping before starting treatment with mercaptopurine, a TMTPmetabolized drug. This is not a genetic test, but a phenotypic test measuring red blood cell enzyme activity (Corominas and Baiget, 2004). The transition from this TPMT phenotyping test to a genotyping test may be challenging for practical reasons. Two views are prominent concerning this transition.

The more pessimistic view suggests that using genotyping for TPMT polymorphisms may only account for a small part of the TPTM phenotype (Nebert et al, 2008). Other more optimistic authors, who are trying to encourage the transition from phenotyping to genotyping in the United Kingdom, suggest that practical issues such as familiarity with the test and practice guidelines account for the wide variation in usage of TPTM phenotyping in the United Kingdom, but extensive physician education may be required for the move to genotyping (Fargher et al, 2007).

Corominas and Baiget (2004) have stressed that one difficulty in progressing toward TMTP genotyping in this area is the scarcity of drugs metabolized by this enzyme (mercaptopurine and an inactive prodrug, azathiopurine). Pharmacogenomics J de Leon …………………………………………………………………………………………………………………………………………… 161 Obviously, the genetic variables can be delineated by pharmacogenomic tests. For some drugs pharmacogenomic variables may be important; for other drugs they may have minimal importance.

Environmental variables such as co-medication or smoking may be much more important than genetic variables for some drugs. As a matter of fact, it is important to develop models to estimate the relevance of environmental variables for psychiatric medications (Botts et al, 2008; de Leon et al, 2005a, 2007b; Diaz et al, 2008). In the clinical environment, a powerful inhibitor can mimic a genetic defect and can also interact with the genetic deficit (de Leon et al, 2007b). Age and gender may be crucial personal variables in the response to some drugs. They may influence pharmacokinetic and pharmacodynamic factors (de Leon et al, 2008a, b).

In conclusion, the future of ‘personalized prescription’ in psychiatry requires consideration of pharmacogenomic testing, and also the environmental and personal variables that influence pharmacokinetic and pharmacodynamic drug response for each individual drug used by each individual patient (de Leon, 2007). Recently, Nebert et al (2008) have proposed that the pharmacogenetics of pharmacodynamic genes may be much more complicated than the pharmacogenetics of pharmacokinetic genes. They proposed that pharmacokinetic genes tend to be high-penetrance and predominantly monogenic, whereas pharmacodynamic genes tend to be more polygenic.

FIRST GENERATION OF PHARMACOGENOTIC TESTS FOR CLINICAL PRACTICE IN PSYCHIATRY The first generation of pharmacogenomic tests is available for clinical practice in psychiatry. Five pharmacogenomic tests, currently on the market or ready to be introduced in the market, have been included in published articles and are potentially useful in psychiatry. When using peer-reviewed articles to study tests marketed by private companies, one must be aware that some of these companies, as a matter of deliberate practice, do not publish ‘proprietary’ genetic associations.

As a matter of fact, three of the five tests have not published complete details concerning the genes used in them. There is no computer search strategy in PubMed that provides information on marketed pharmacogenetic tests in psychiatry. Therefore, these five tests were selected in March 2008 as described (de Leon et al, 2008c) from published articles by three authors who had extensively reviewed the pharmacogenetic literature in psychiatry for the past 10 years. That recent article (de Leon et al, 2008c) reviewed these five tests in detail from the point of view of laboratory testing; thus they are described here very briefly (Table 1).

Roche Molecular Systems Inc. , developed the first pharmacogenetic test approved by the FDA, The AmpliChip CYP 450 Test, which uses Affymetrix technology (Roche, ……………………………………………………………………………………………………………………………. Personalized Prescription Including Personal and Environmental Variables In the opinion of the author (de Leon, 2007), personalized medicine should include not only the use of tests that may or may not be pharmacogenetic, but the consideration of all scientific information valid for prescribing medication.

It must be remembered that physicians have traditionally ? practiced personalized medicine (Ruano, 2004) in their attempts to decide the best treatment for each of their patients, even though the term was not used. Clinicians need to consider genetic, environmental and personal variables when prescribing any medication. Neuropsychopharmacology REVIEWS …………………………………………………………………………………………………………………………………………… Pharmacogenomics J de Leon REVIEW

pharmacological knowledge predicts that SSRIs are not good candidates for safety pharmacogenomics; they exhibit no linear relationship between dosage and plasma concentration, wide ranges between therapeutic and toxic doses, and powerful CYP inhibition from some SSRIs (de Leon, 2007, 2008). Arranz et al (2000a) generated a lot of interest when they designed a system combining variants in the gene coding for 5-HT2A, 5-HT2C, and H2 receptors and for the serotonin transporter 5-HTT that predicts clozapine response, as this was one of the first attempts to develop a pharmacogenetic test in psychiatry.

Other authors were not able to replicate the predictive results of the test in patients from different clinical settings (Arranz et al, 1998, 2000b; Schumacher et al, 2000). The UK company LGC (2008) offers an improvement of this test, incorporating a number of yet undisclosed genetic variants. Two other pharmacogenetic tests that will be described in the next section are a pharmacogenetic test for clozapineinduced agranulocytosis, the PGxPredict : CLOZAPINE test (PGxHealth, 2008), and a test for metabolic syndrome, the PhyzioType system (Genomas, 2008).

This article does not review all pharmacogenomic studies in psychiatry, but focuses on available or soon-to-be available pharmacogenomic tests that can be used in the clinical environment and can help in the early exploration of clinical proof of mechanism. In the past few years, the STAR*D study (McMahon et al, 2006; Paddock et al, 2007; Perlis et al, 2008; Peters et al, 2008) and other studies (Binder et al, 2004; Uhr et al, 2008) have led to a boom in pharmacogenomic studies of antidepressants.

However, pharmacogenomic tests for antidepressant response will apparently not be available for clinical use soon. Genotyping for serotonin receptor and transporter variations are offered by two US laboratories (Mayo Clinic Laboratory, 2008; Pathway Diagnostics, 2008) but they have not published data supporting their use and the literature reflects the conflicting results of these gene associations with serotonin receptors (Kirchheiner et al, 2004; Serretti and Artioli, 2004), although the association with the serotonin transporter looks more promising (Serretti et al, 2007).

162 2008). The microarray contains over 15 000 oligonucleotide probes allowing testing for 20 CYP2D6 alleles, 7 CYP2D6 duplications, and 3 cytochrome P450 2C19 (CYP2C19) alleles (Table 1; de Leon, 2006; de Leon et al, 2006a). CYP2D6 metabolizes several antipsychotic and antidepressant drugs (de Leon et al, 2006b; Kirchheiner et al, 2004). CYP2D6 is highly polymorphic, meaning that more than 60 alleles and more than 130 genetic variations (by combining SNPs and CNVs) have been described for this gene, located on chromosome 22 (Ingelman-Sundberg et al, 2007, 2008).

The activity level of the CYP2D6 enzyme, called the CYP2D6 phenotype, can vary widely due to different combinations of the various CYP2D6 alleles. The most important phenotype is the poor metabolizer (PM) phenotype, which does not have active CYP2D6; some subjects have at least three active alleles and are called ultrarapid metabolizers (UMs). CYP2C19 is located on chromosome 10 and is also a polymorphic gene. Alleles with no activity and increased activity are described (Table 1; Wedlund, 2000; Sim et al, 2006). CYP2C19 metabolizes some antidepressants (de Leon et al, 2006b; Kirchheiner et al, 2004).

The AmpliChip CYP 450 Test software uses algorithms to predict the four CYP2D6 phenotypes and two CYP2C19 phenotypes. The Luminex Tag-Itt Mutation Detection Kit (de Leon, ? 2006; Melis et al, 2006; Ruano et al, 2006; Scott et al, 2007) uses the Luminex microsphere-based universal array genotyping platform. The test was originally developed by TMBiosciences which was acquired by Luminex (2008) in 2007. The Detection Kit for CYP2C19 detects the seven CYP2C19 null alleles (Table 1). It appears to be a good system for detecting PMs for both CYP2C19 and CYP2D6.

It identifies the wild-type CYP2D6 allele by genotyping 12 tested mutant alleles, as well as gene arrangements associated with deletion and duplication genotypes (Table 1). However, it does not include some of the CYP2D6 low-functioning alleles, has no phenotyping software, and does not specify which allele may be duplicated (de Leon, 2006). The Detection Kit for CYP2C9 detects five ? variants (Table 1; Ruano et al, 2006). CYP2C9 has almost no involvement in antipsychotic metabolism but may have a minor involvement for some antidepressants (Black et al, 2007).

It is possible that CYP2C9 polymorphisms may be important for patients who are deficient in other CYPs and ? are taking antidepressants (Ruano et al, 2007a). The possible applications of CYP2D6 and CYP2C19 in psychiatry have been reviewed in prior articles (de Leon et al, 2006b, 2008c), including facilitating treatment with some antipsychotic and antidepressant drugs, particularly those with a narrow therapeutic window and which are highly dependent on either of these two enzymes for their metabolism (de Leon, 2007).

Obviously, not all psychiatric drug therapy will be improved by this testing; as a matter of fact, the selective serotonin reuptake inhibitor (SSRI) drugs may not be good candidates for CYP genotyping based on currently available information (Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, 2007; Katsanis et al, 2008). As a matter of fact, …………………………………………………………………………………………………………………………….

POSSIBLE INVOLVEMENT OF PHARMACOGENOMIC TESTS FOR EXPLORING EARLY CLINICAL PROOF OF MECHANISM Pgxpredict : CLOZAPINE Test Clozapine treatment was associated with a risk of agranulocytosis estimated at 1–2%, but required weekly white blood cell monitoring and a national registry in the US have decreased the estimate to 0. 4% (Honigfeld et al, 1998). In the past, clozapine agranulocytosis was associated with HLA variants in Ashkenazi Jews (Lieberman et al, 1990).

Neuropsychopharmacology REVIEWS REVIEW Genaissance Pharmaceuticals Inc. (a pharmacogenetics company) developed a genetic test to predict clozapineinduced agranulocytosis. Genaissance Pharmaceuticals Inc. was acquired by Clinical Data (a diagnostic company) in 2005. The pharmacogenetic branch of Clinical Data (called PGxHealth) named this test PGxPredict : CLOZAPINE, but it is not currently described on their website (PGxHealth, 2008).

The author contacted a company representative, who explained the company has ‘opted to stop offering’ the first generation of the test, but she explained that PGxHealth ‘will continue to focus our resources on developing a second generation test. ’ The opinion of this author (encouraged by a reviewer request) is that the formerly available version of the test was not very helpful as it did not eliminate the need for blood monitoring in those with negative results, and patients with positive results may not have had options besides clozapine, as clozapine in the United States is mainly considered after trying all other antipsychotics.

The interesting aspect of this test is that only two of the five genes described as associated with clozapine-induced agranulocytosis were from the HLA complex (Malhotra et al, 2005). The three yet-unpublished genes may be excellent examples of leads for future proof of mechanism studies. If these genes are replicated in other studies, they may help in understanding the mechanism behind the pathophysiology of clozapine-induced agranulocytosis.

Pharmacogenomics J de Leon …………………………………………………………………………………………………………………………………………… 163 PhyzioType System Metabolic syndrome is much more frequent in psychiatric patients taking antipsychotics than in the general population (McEvoy et al, 2005; Susce et al, 2005), to the point that it is considered an epidemic (Reist et al,

2007). Genomas (2008), a personalized medicine company, has developed a patented system (Patent Application Publication US 2006/0234262A1) called the PhyzioType system ? (Ruano et al, 2007b; de Leon et al, 2008c). The system uses an ensemble of DNA markers from several genes coupled with a biostatistical algorithm to predict an individual’s risk of developing ADRs, including the antipsychotic-induced metabolic syndrome (Table 1).

The majority of antipsychotics (particularly some of the so-called atypical antipsychotics, but also some of the typicals) increase the risk of obesity, probably by increasing appetite, or by blocking brain receptors, including H1 and 5-HT2C (de Leon and Diaz, 2007; Kim et al, 2007; Meyer and Koro, 2004; Newcomer and Haupt, 2006). Some of the atypical antipsychotics (particularly olanzapine and clozapine) also appear to directly interfere with glucose (de Leon and Diaz, 2007; Newcomer and Haupt, 2006) and lipid metabolism (de Leon and Diaz, 2007; de Leon et al, 2008c, d; Meyer and Koro, 2004).

It is possible that some other antipsychotics besides olanzapine and clozapine, particularly quetiapine and phenothiazines such as chlorpromazine, also directly interfere with lipid metabolism (de Leon and Diaz, 2007; de Leon et al, 2008d; Meyer and Koro, 2004) and cause hyperlipidemia in the absence of obesity or when controlling for the effects of obesity (Birkenaes et al, 2008; de Leon et al, 2007a; Markham-Abedi and de Leon, 2006).

The PhyzioType system was used as proof of mechanism to study genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. Known physiological mechanisms were supported for three associations found in patients taking olanzapine, quetiapine, or chlorpromazine in the acetyl coenzyme A carboxylase a-SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCb (rs2241220) in the hypercholesterolemia model (de Leon et al, 2008d).

Thus, in vitro studies could be used to explore interference in lipid metabolism from clozapine, olanzapine, quetiapine, or chlorpromazine (or molecules with a similar chemical structure, such as mirtazapine; de Leon, 2008). To verify the SNPs suggested by the DNA as proof of mechanism, these molecules should interfere with lipid metabolism more so than other antipsychotic molecules. Moreover, they should specifically interfere with fatty acid metabolism at the ACCa; this would verify a possible mechanism indicating the reason some antipsychotics may cause hypertriglyceridemia.

The greater interference of these molecules than other antipsychotic molecules with NPY or ACCb, or a related mechanism involved in cholesterol synthesis regulation, would verify a possible mechanism indicating the reason some antipsychotics may cause hypercholesterolemia. These in vitro studies have not been performed. THE USE OF PHARMACOGENOMIC TESTS BY PHARMACEUTICAL COMPANIES FOR EXPLORING EARLY CLINICAL PROOF OF MECHANISM Pharmaceutical companies are using DNA microarrays in their clinical trials and are extensively using biomarkers in drug development.

Several review articles written by scientists working in pharmaceutical companies describe their potential (Ferentz, 2002; Kirkwood and Hockett, 2002; Lesko and Atkinson, 2001). However, there are no published examples of the results of the use of DNA microarrays in drug marketing for psychiatric drugs, except for iloperidone, which is described next. Iloperidone and DNA Pharmacogenomic Testing Iloperidone is a mixed 5-HT2A and D2 antagonist developed for the potential treatment of schizophrenia (Albers et al, 2008; Hesselink, 2002). Iloperidone was developed by Hoechst Marion Roussel.

After reaching Phase II trials, the company announced in May of 1996 that it had discontinued further development, and in January of 1997 it licensed the compound to Titan Pharmaceuticals. In April of 2001 Titan executed a new development and commercia……………………………………………………………………………………………………………………………. Neuropsychopharmacology REVIEWS ……………………………………………………………………………………………………………………………………………

Pharmacogenomics J de Leon REVIEW 164 lization agreement with Novartis, which predicted a possible launch in 2002 (Hesselink, 2002). This was further revised several times (Hesselink, 2002) and, finally, Vanda Pharmaceuticals acquired the drug. In 2007 Vanda Pharmaceuticals sent the FDA a new drug application ……………………………………………………………………………………………………………………………. (NDA) for iloperidone. On July 28, 2008, it announced that the FDA required more studies (Vanda Pharmacueticals, 2008).

Preliminary research that tested only one CYP2D6 null allele suggested that iloperidone is associated with a QTc Neuropsychopharmacology REVIEWS REVIEW prolongation that is related to drug levels and CYP2D6 metabolism; therefore the prolongation of QTc in CYP2D6 PMs (Nnadi and Malhotra, 2008) may be avoided simply by reducing iloperidone dosing in CYP2D6 PMs. Lavedan et al (2008a) described an attempt to use a SNP at the ciliary neurotrophic factor (CNTF) polymorphism to predict schizophrenia symptom improvement in an iloperidone clinical trial.

CNTF is a multifunctional cytokine that supports cell survival and/or differentiation (Sendtner et al, 1994). In the brain, CNTF may regulate several neurotransmitters including dopamine, serotonin, and acetylcholine, and may have neuroprotective effects (Lavedan et al, 2008a; Tolosano et al, 1996). More recently, genome-wide associations have been published identifying six SNPs associated with QTc prolongation (Volpi et al, 2008) and other six SNPs associated with efficacy (Lavedan et al, 2008b), including the neuronal PAS domain protein 3 gene (NPAS3).

The main question remaining after reading these articles is whether any of these genetic associations will be replicated in other research samples and, more importantly, in the clinical environment. Nebert et al (2008) proposed that high significance in one genome-wide association study may not be that important; replication is the most important requirement in establishing a positive association. At any rate, it is currently unknown whether the attempted rescue of iloperidone using pharmacogenomic testing will be successful or not.

It is interesting that the rescue attempt was conducted by a small company funded by a pharmacogenomic expert who left the last large pharmaceutical company that decided not to pursue the marketing of this drug. Pharmacogenomics J de Leon …………………………………………………………………………………………………………………………………………… 165.

et al, 2007; Sadee, 2002; Weinshilboum and Wang, 2004) as a significant number of Caucasians (10–15%) may have the extreme phenotypes PM or UM. There are no clear incentives for pharmaceutical companies to incorporate new pharmacogenomic knowledge of already marketed drugs. The issue gets very complicated when the drugs are generic, as companies producing generic drugs have very low margins.

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