Pharmacology RSS : Gourt

Pharmaceutical Legislation Changes In Europe - EMA and Member States Prepare

Preparations are underway at the European Medicines Agency together with European Member States and the European Commission, for the introduction of the new pharmacovigilance legislation in July this year. The new legislation will represent the biggest change to the legal framework since The Agency was founded in 1995...

Open Innovation Possibilities To Be Explored By Fleming Europe In Amsterdam, 26 - 27 April 2012

Major blockbuster drugs are facing the end of their era and big pharma companies are bracing for the effect in hopes that they will find a solution for their dwindling pipelines. Thus new opportunities and challenges are rising in the practice of open innovation and Fleming Europe will be there to explore them...

2nd Annual Achieving Clinical & Regulatory Excellence In Turkey, The Middle East & North Africa Conference, 11-14 June 2012, Istanbul, Turkey

NextLevel Pharma's "Advancing clinical research in Turkey, the Middle East and North Africa" conference will bring together the local regulators and ethics committees, alongside experienced investigators and study personnel, as well as clinical trial experts from pharma and CROs...

Pharmaceutical And Medical Device Market Access In Key Asian Markets Conference, 3-4 May 2012, Bangkok, Thailand

Asian markets are increasingly the focus of pharmaceutical companies who are looking for new market opportunities beyond the traditional "rich-world" countries who are facing economic stagnation...

Best Practices In Implementing Green Pharmaceutical Manufacturing Conference, 29-30 March 2012, Vienna, Austria

This unique and timely event will highlight how different frameworks and initiatives have succeeded in developing an efficient, environmentally friendly manufacturing process in the pharmaceutical industry...

Shortages Of Anti-Infective Drugs Pose Threat To Public Health And Patient Care

Shortages of key drugs used to fight infections represent a public health emergency and can put patients at risk, according to a review published in Clinical Infectious Diseases and available online*...

2nd Annual World Orphan Drug Congress USA, April 10-13 2012

Orphan drug development has become more feasible than in previous years but we've barely scratched the surface: only 367 approved orphan drugs out of 6,800 rare diseases. We need to keep the momentum going. Come April 10-13, over 300 key decision makers from orphan drug manufacturers, patient groups, payers and regulators will gather in DC at the 2nd annual World Orphan Drug Congress USA...

Seminar On Monitoring And Validating Pharmaceutical Water Systems, 22-23 February 2012, San Francisco, CA

ComplianceOnline, the leading governance, risk and compliance advisory network with over 500 experts in various regulatory subjects, today announced a seminar on The A to Z's of Microbial Control, Monitoring and Validation of Pharmaceutical Water Systems. The two day long, in-person seminar, led by well known water systems expert T.C...

Oxygen And Light Utilized In The Synthesis Of Anti-Malaria Drug

The most effective anti-malaria drug can now be produced inexpensively and in large quantities. This means that it will be possible to provide medication for the 225 million malaria patients in developing countries at an affordable price...

Clinical Outsourcing World Europe 2012, 7-8 February, Earls Court Conference Centre - London

Driving development through strategic outsourcingRegister NOW for the Clinical Outsourcing World conference to hear from the industry's BEST Outsourcing professionals including representatives from: GSK, Pfizer, AstraZeneca, Eli Lilly, Novartis, Almirall, Merck Research Laboratories and many more! Pharma & Biotech delegates- register NOW for only Â£250+vat! Please note this ...

Fake Antimalarial Medications Undermine Africa Malaria Drive

Fraudulent and substandard antimalarial drugs could be wrecking the chances of winning the war against malaria in Africa, researchers from the Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration reported in the Malaria Journal...

Blocking Cell-To-Cell Communication May Prevent Liver Damage And Improve Drug Safety

Massachusetts General Hospital (MGH) investigators have developed a novel strategy to protect the liver from drug-induced injury and improve associated drug safety...

Advances And Progress In Drug Design - Discover The Latest Developments 20-21 February 2012, Copthorne Tara Hotel, London

The number of pharmaceutical products entering the market has declined in the last decade. With the economic downturn and increasing threat from generic companies, pharmaceutical companies have never been under greater pressure to develop new innovative drugs...

Understand The Strategies And Developments In Pharmaceutical Parallel Trade, 6-7 February 2012 At The Copthorne Tara Hotel In London

SMi is proud to present their 6th annual Pharmaceutical Parallel Trade Conference, taking place on 6th & 7th February 2012 at the Copthorne Tara Hotel in London. This year's event will bring together expert speakers from different sectors within the industry, each with differing opinions and perspectives to offer...

Chemical Reaction Devized That Holds Promise For New Drug Development

A team of researchers at the California Institute of Technology (Caltech) has devised a new method for making complex molecules...

Major Advance In Understanding The Regulation Of An Important Cancer Target

Scientists at the University of Leicester have opened up a whole new approach to the therapeutic intervention for a family of anti-cancer drug targets, thanks to a completely new and unexpected finding...

Novartis' Troubles With Packaging Continue

Novartis Consumer Health announced earlier today a recall on certain OTC medicines that were badly packaged and might have broken or chipped pills, as well as incorrect product mixed into bottles of pills. Rather worrying for consumers with risks of possible wrong or overdoses of their medicine...

Novartis Recalls OTC Products Excedrin And NoDoz

Complaints of chipped and broken pills as well as inconsistent packaging have promoted Novartis Consumer Health Inc. (NCH) to recall certain lots of its products. Whilst there have been no reports of adverse effects to patients so far, Novartis has also warned of possible mixing of product. They have asked consumers to dispose of the product or return unused bottles...

New Drug Screening Identifies Chemical Agents With Potent Anti-Cancer Activity

Drugs already approved for clinical use across a variety of therapeutic categories can be screened to identify effective agents for thyroid cancer according to a recent study accepted for publication in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM). These findings could rapidly be implemented into a clinical trial to test how effective the treatment would be...

The Importance Of Compliance In Your KOL Interactions

With the recent changes to regulations about interactions with external stakeholders, it can be hard to keep up to date. Eyeforpharma spoke to Julian Jenkins, Head of Global Medical Affairs at Ferring Pharmaceuticals about how to work compliantly under the changing regulatory environment...

Discovery Of One Of The Most Porous Materials To Date Will Improve Control In Drug Delivery

The delivery of pharmaceuticals into the human body or the storage of voluminous quantities of gas molecules could now be better controlled, thanks to a study by University of Pittsburgh researchers. In a paper published online in Nature Communications, a team of chemists and colleagues from Pitt's Kenneth P...

ONSOLIS To Benefit From Approval Of Class-Wide REMS For All Transmucosal Fentanyl Products

BioDelivery Sciences International, Inc. (Nasdaq: BDSI) responded to the approval and announcement by the U.S. Food and Drug Administration (FDA) that a Risk Evaluation Mitigation Strategy (REMS) covering all transmucosal fentanyl products has been approved...

FDA Approves Shared REMS (Risk Evaluation And Mitigation Strategy) Program For All TIRF (Transmucosal Immediate Release Fentanyl) Pain Treatments

ProStrakan, Inc., a subsidiary of Kyowa Hakko Kirin Co. Ltd. (KHK), and an international specialty pharmaceutical company, announces that the U.S. Food and Drug Administration (FDA) has approved the TIRF (Transmucosal Immediate Release Fentanyl) REMS (Risk Evaluation and Mitigation Strategy) Access program...

Marinus Pharmaceuticals Experimental Epilepsy Treatment Shows Promise In Open-Label Extension Study

Marinus Pharmaceuticals, Inc., a specialty pharmaceutical company, announced that its neurosteroid ganaxolone which is currently under study for the treatment of partial onset seizures (POS), reported positive data in the open-label extension follow up to the company's Phase 2 clinical trial. The data reflects the replication of the effects seen in the double-blind study...

VIVUS Announces Date Of FDA Advisory Committee Review Of Qnexa For The Treatment Of Obesity

VIVUS, Inc. (NASDAQ: VVUS) announced that the Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) is scheduled to review the Company's New Drug Application (NDA) for Qnexa for the treatment of obesity on February 22, 2012. VIVUS resubmitted the NDA on October 17, 2011 seeking approval to market Qnexa in the United States...

Obituary: Lawrence Weaver (February)

BOOKS RECEIVED

Rosiglitazone, Myocardial Ischemic Risk, and Recent Regulatory Actions (February)

OBJECTIVE:To review the evidence surrounding rosiglitazone and ischemic cardiovascular risk and discuss the Food and Drug Administration (FDA) decision to revise safety information and restrict access to the drug.DATA SOURCES:A literature search was conducted through MEDLINE (1950-January 2012), PubMed (1966-January 2012), and International Pharmaceutical Abstracts (1970-December 2011) using the search terms rosiglitazone and cardiovascular risk. Regulatory documents from the FDA and the Center for Drug Evaluation and Research, as well as reference citations from publications identified, were reviewed.STUDY SELECTION AND DATA EXTRACTION:All articles in English identified from the data sources were evaluated for inclusion.DATA SYNTHESIS:Literature regarding rosiglitazone and ischemic cardiovascular risk has shown inconsistent results. Meta-analyses by the FDA, GlaxoSmithKline, and several independent research groups suggest an increased risk for myocardial infarction (MI), while others have not. Long-term, controlled trials not designed to evaluate cardiovascular outcomes did not find a significant increase in cardiovascular events and had low event rates overall. The RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial is the only prospective randomized trial to date designed to evaluate cardiovascular outcomes of rosiglitazone; the results were limited because of issues with study design and event adjudication. The only direct comparisons between rosiglitazone and pioglitazone are observational studies in which pioglitazone had a more favorable MI risk profile.CONCLUSIONS:Data involving rosiglitazone and an association with ischemic cardiovascular risk have yielded variable results. The FDA made the decision to restrict access to rosiglitazone in September 2010 by requiring GlaxoSmithKline to submit a risk evaluation and mitigation strategy (REMS). Drug labeling was revised in February 2011, and the rosiglitazone REMS program took full effect inNovember 2011.

Adult Epilepsy

Serum Potassium Influencing Interacting Drugs: Risk-Modifying Strategies Also Needed at Discontinuation (February)

BACKGROUND:Although the discontinuation of a medication may have important clinical consequences, there is generally much less attention given to medication surveillance when a drug is stopped than when it is started.OBJECTIVE:To investigate the consequences on serum potassium levels of discontinuing a drug that increases the serum potassium level (PID) and a drug that decreases the serum potassium level (PLD) in patients taking both.METHODS:Patients who were hospitalized in the University Medical Centre Utrecht in 2004-2009 and were using both a PID and a PLD) were included when one of these drugs was discontinued during hospitalization. Serum potassium levels measured before (potassium1) and after (potassium2) discontinuation were compared in patients who stopped the PLD and in patients who stopped the PID.RESULTS:In the group of patients who stopped the PLD (ie, continued the PID), mean serum potassium levels increased 0.19 mEq/L (range -0.9 to 1.8 mEq/L). After discontinuation of the PLD, serum potassium levels increased in 91 (59%) patients. Five patients (3.2%) developed hyperkalemia (potassium2 >5.5 mEq/L). In the group of patients who stopped the PID (ie, continued the PLD), mean serum potassium levels decreased 0.40 mEq/L (range -2.6 to 0.7 mEq/L). Serum potassium levels decreased in 61 (70%) patients after discontinuation of the PID. Fifteen patients (17%) developed hypokalemia (potassium2 <3.5 mEq/L). Results were not influenced by length of stay, age, sex, renal function, and type of medication discontinued.CONCLUSIONS:The effects of serum potassium-influencing drugs need to be monitored not only after starting but also after stopping the medication. The same may hold true for the effects of other drugs. Clinical risk management should therefore focus on the risks not only when new medication is prescribed, but also when medication is stopped.

Obstetrical Opportunities: Will Pharmacy Ever Realize Them? (February)

Based on a survey of the American College of Clinical Pharmacy Women's Health Practice and Research Network and our own experience, the pharmacy profession has limited involvement in obstetric pharmacotherapy. We believe that such involvement in pregnancies with complicated conditions can result in significant improvement of pregnancy outcomes. Moreover, we believe thisinvolvement would be welcomed by the physicians caring for these patients. This commentary documents current obstetrical pharmacy practices and proposes changes for the profession of pharmacy to consider.

Tesamorelin: A Growth Hormone-Releasing Factor Analogue for HIV-Associated Lipodystrophy (February)

OBJECTIVE:To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection.DATA SOURCES:Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites.STUDY SELECTION AND DATA EXTRACTION:All articles published in English identified from the data sources were evaluated and all pertinent information wasincluded. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans.DATA SYNTHESIS:In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvementson treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time.CONCLUSIONS:Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection.

Gabapentin Enacarbil for Treatment of Restless Legs Syndrome in Adults (February)

OBJECTIVE:To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling for gabapentin enacarbil for the treatment of restless legs syndrome (RLS) in adults.DATA SOURCES:A literature search was conducted using the terms gabapentin enacarbil, XP13512/GSK1838262, and restless legs syndrome. MEDLINE, Books@Ovid, Journals@Ovid Full Text, BIOSIS Previews, and EMED databases were the primary search sites (2004-October 2011). All English-based articles and abstracts obtained from the literature searches were reviewed. Additional information was obtained from references cited in the articles.STUDY SELECTION AND DATA EXTRACTION:All gabapentin enacarbil information related to RLS was considered. Study selection included human trials evaluating safety and efficacy of gabapentin enacarbil for the treatment of RLS.DATA SYNTHESIS:Gabapentin enacarbil is a prodrug of gabapentin that is Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe primary RLS in adults. In placebo-controlled trials, gabapentin enacarbil demonstrated efficacy in reducing the symptoms of RLS. Most clinical trials assessed gabapentin enacarbil at dosages greater than the FDA-approved 600-mg dosage. For the approved dose of 600 mg, the most commonly reported adverse effects are somnolence and dizziness.CONCLUSIONS:Clinical trials have evaluated gabapentin enacarbil for safety and efficacy in treating moderate-to-severe RLS symptoms for up to 64 weeks. It offers a pharmacokinetic advantage over gabapentin by having improved absorption and a longer duration of action, but clinically significant differences are yet to be determined. Potential disadvantages of gabapentin enacarbil include cost, concerns of suicide risk and pancreatic cancer, and a lack of data for the FDA-approved 600-mg dosage. Overall, gabapentin enacarbil is a viable therapeutic option for adults with moderate-to-severe RLS for whom more conventional therapies have failed.

Comparison of the Effects of Energy Drink Versus Caffeine Supplementation on Indices of 24-Hour Ambulatory Blood Pressure (February)

BACKGROUND:Cardiovascular events associated with energy drink consumption have been reported, but few data exist to delineate the hemodynamic effects of energy drinks.OBJECTIVE:To compare the effects of an energy drink versus caffeine supplementation on blood pressure (BP) indices as measured by 24-hour ambulatory BP monitoring (ABPM).METHODS:Healthy, nonsmoking, normotensive volunteers (aged 18-45 years) taking no medications were enrolled in a single-center, open-label, 2-period crossover pilot study. During each study period, subjects received either an energy drink (Red Bull Energy Drink, each dose containing 80 mg of caffeine and 1000 mg of taurine in an 8.3-oz serving) or a control (compounded caffeine solution, each dose containing 80 mg of caffeine solution in 8 oz of bottled water) at 0800, 1100, 1500, and 1900 hours and underwent 24-hour ABPM. The study periods were separated by a washout period (4-30 days). Mean 24-hour, daytime, and nighttimesystolic (SBP), diastolic (DBP), and mean arterial (MAP) BP; BP load; and percent nocturnal dipping were compared between study periods.RESULTS:Nine subjects (5 females, mean [SD] age 27.7 [5.0] years) completed the study. Mean 24-hour SBP (123.2 vs 117.4 mm Hg, p = 0.04), DBP (73.6 vs 68.2 mmHg, p = 0.02), and MAP (90.1 vs 84.8 mm Hg, p = 0.03) were significantly higher during energy drink supplementation versus caffeine supplementation. Daytime DBP (77.0 vs 72.0 mm Hg, p = 0.04) also was significantly higher with the energy drink versus caffeine supplementation. Trends in higher daytime SBP (127.0 vs 121.9 mm Hg, p = 0.05) and MAP (93.6 vs 88.6 mm Hg, p = 0.05) were recorded with energy drink supplementation versus caffeine supplementation. Nighttime SBP and DBP oads were significantly higher with the energy drink, but nocturnal dippingdid not differ significantly between study periods.CONCLUSIONS:Single-day energy drink supplementation increased mean 24-hour and daytime BP compared to caffeine control in this pilot study. Additional research is warranted to better understand the hemodynamic effects of energy drinkconsumption.

The Role of Mannitol as a Nephroprotectant in Patients Receiving Cisplatin Therapy (February)

OBJECTIVE:To review the efficacy and safety of concomitant mannitol administration with cisplatin therapy to reduce the incidence of nephrotoxicity.DATA SOURCES:A literature search was performed via MEDLINE, PubMed, and the Cochrane Library (1945-august 2011) using the terms mannitol, cisplatin, nephrotoxicity, and forced diuresis. Reference citations from the publications identified were also reviewed.STUDY SELECTION AND DATA EXTRACTION:The search was limited to studies conducted in humans. All studies in which mannitol was used for forced diuresis with cisplatin therapy were evaluated.DATA SYNTHESIS:Cisplatin therapy can lead to transient and permanent renal impairment. Molecular and histologic changes occur in the renal tubules, which contribute to nephrotoxicity. The adverse effect profile of cisplatin is well documented, but the prevention strategies to alleviate renal impairment due to treatment are less understood. Mannitol plus hydration has been used for several years to alleviate toxicity associated with cisplatin therapy. However, the data for mannitol administration have not been convincing. When the use of mannitol and hydration is compared directly to hydration alone, mannitol shows no benefit. In some patients, not only was mannitol not protective, its administration was associated with worsening renal function.CONCLUSIONS:Although mannitol plus hydration is used to decrease cisplatin-induced nephrotoxicity, there are no compelling data that the addition of mannitol is more nephroprotective than the use of hydration alone. Appropriate hydration remains the most reasonable strategy to reduce the incidence of cisplatin-induced nephrotoxicity.

AUTHORS' REPLY

Evaluating Outcomes Associated with Alternative Dosing Strategies for Piperacillin/Tazobactam: A Qualitative Systematic Review (February)

OBJECTIVE:To perform a qualitative systematic review of the evidence comparing traditional strategies against prolonged intermittent or continuous infusion strategies for piperacillin/tazobactam, based on clinical and pharmacodynamic outcomes.DATA SOURCES:MEDLINE (1950-September 2011), EMBASE (1980-September 2011), and International Pharmaceutical Abstracts (1970-September 2011) were searched, using the terms piperacillin, tazobactam, pharmacokinetics, pharmacodynamics, dosing, and infusion. Reference lists from relevant publications were also reviewed.STUDY SELECTION AND DATA EXTRACTION:Articles evaluating the administration of piperacillin/tazobactam to adults and comparing at least 2 dosing regimens (1 of which included the traditional, manufacturer-recommended 30-minute infusion; the other, a prolonged or continuous infusion strategy) were included. Prespecified clinical outcomes of interest included mortality, clinical cures, and adverse events. The pharmacodynamic endpoint of interest was percent time of unbound drug concentration remaining above the minimum inhibitory concentration.DATA SYNTHESIS:Twelve studies were included in this review, 7 of which assessed clinical outcomes and 5 that assessed pharmacodynamic endpoints using Monte Carlo simulations. Prolonged or continuous infusions of piperacillin/tazobactam consistently achieved higher pharmacodynamic endpoints than did traditional infusions. The association of prolonged or continuous infusions with improved clinical outcomes, however, is unclear. Two retrospective studies found improved mortality rates with prolonged infusions (1 in a subgroup of patients with higher APACHE II [Acute Physiology and Chronic Health Evaluation II] scores), while another retrospective study found improved clinical cure rates with continuous infusions in patients with ventilator-associated pneumonia. These clinical benefits have not been substantiated in prospective randomized trials. No study has provided evidence of reduced adverse effects with prolonged or continuous infusions.CONCLUSIONS:The limited evidence available does not firmly support widespread adoption of administering piperacillin/tazobactam as prolonged intermittent or continuous infusions to improve clinical outcomes despite the achievement of higher pharmacodynamic targets in simulated studies. Retrospective studies indicate that critical care patients are the subgroup most likely to benefit from these dosing strategies. Well-designed prospective clinical trials are required to confirm potential benefits observed in retrospective studies.

Bevacizumab for the Treatment of Neovascular Age-Related Macular Degeneration (February)

OBJECTIVE:To review data regarding the efficacy and safety of bevacizumab for the treatment of neovascular age-related macular degeneration (nARMD).DATA SOURCES:Literature was searched using MEDLINE (1976-September 2011) and EMBASE (1973-September 2011). Search terms included bevacizumab, Avastin, neovascular macular degeneration, age-related macular degeneration, vascular endothelial growth factor, intravitreal, and safety. Reference citations were reviewed for relevant information.STUDY SELECTION AND DATA EXTRACTION:All randomized clinical trials published in English with data assessing the safety and efficacy of bevacizumab for nARMD were evaluated.DATA SYNTHESIS:The only Food and Drug Administration-approved treatments for nARMD are photodynamic therapy (PDT) with verteporfin, intravitreal pegaptanib, and ranibizumab. However, bevacizumab has gained attention as a potential agent in treating nARMD and is now widely used in practice. PDT with verteporfin and pegaptanib has shown only stabilization of visual acuity (VA). When the efficacy of bevacizumab was compared to these therapies, bevacizumab clinically and statistically improved VA outcomes. When compared to ranibizumab, which has also been shown to improve VA, bevacizumab showed no significant difference in VA outcomes and was associated with a decrease in average annual cost of $22,805.CONCLUSIONS:Bevacizumab administered intravitreally is appropriate for prevention of vision loss and recovery of VA in patients with nARMD. Although further analysis of long-term effects of bevacizumab on VA and safety is needed, it is potentially a more cost-effective option than ranibizumab for the treatment of nARMD.

Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook and Computer Simulations

Prediction of Warfarin Dose Reductions in Puerto Rican Patients, Based on Combinatorial CYP2C9 and VKORC1 Genotypes (February)

BACKGROUND:The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.OBJECTIVE:To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.METHODS:A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.RESULTS:Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-rangeINR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in anextreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.CONCLUSIONS:This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.

Comment: Generic Substitution of Antiepileptic Drugs: A Systematic Review of Prospective and Retrospective Studies (February)