Showing papers in "Clinical Pharmacology & Therapeutics in 2007"
TL;DR: In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose‐response studies, and drug‐drug interactions.
Abstract: One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose-response studies, and drug-drug interactions.
648 citations
TL;DR: This work has shown that Persister cells play a major role in the tolerance of biofilm bacteria to antimicrobial agents, which is key to development of new therapeutic strategies.
Abstract: Biofilm formation is a crucial step in the pathogenesis of many subacute and chronic bacterial infections, including foreign body-related infections. Biofilms are difficult to eradicate with conventional antimicrobial agents. Bacterial biofilms have several potential antimicrobial resistance mechanisms. Antimicrobial resistance mechanisms may act concurrently, and in some cases, synergistically. Persister cells play a major role in the tolerance of biofilm bacteria to antimicrobial agents. Understanding the mechanisms involved in biofilm-associated antimicrobial resistance is key to development of new therapeutic strategies.
569 citations
TL;DR: Conclusions from clinical trial results that are derived from model‐based analyses rely on the model adequately describing the underlying system and without an understanding of the properties of thesediagnostics, development and use of new diagnostics, and additional information pertaining to the diagnosis, there is risk that adequate models will be rejected and inadequate models accepted.
Abstract: Conclusions from clinical trial results that are derived from model-based analyses rely on the model adequately describing the underlying system. The traditionally used diagnostics intended to provide information about model adequacy have seldom discussed shortcomings. Without an understanding of the properties of these diagnostics, development and use of new diagnostics, and additional information pertaining to the diagnostics, there is risk that adequate models will be rejected and inadequate models accepted. Thus, a diagnosis of available diagnostics is desirable.
488 citations
TL;DR: This review focuses on the recent advancements in adult stem cell biology in normal and pathological conditions and describes how these results have improved the understanding on critical and unique functions of these rare sub‐populations of multipotent and undifferentiated cells with an unlimited self‐renewal capacity and high plasticity.
Abstract: Basic and clinical research accomplished during the last few years on embryonic, fetal, amniotic, umbilical cord blood, and adult stem cells has constituted a revolution in regenerative medicine and cancer therapies by providing the possibility of generating multiple therapeutically useful cell types. These new cells could be used for treating numerous genetic and degenerative disorders. Among them, age-related functional defects, hematopoietic and immune system disorders, heart failures, chronic liver injuries, diabetes, Parkinson's and Alzheimer's diseases, arthritis, and muscular, skin, lung, eye, and digestive disorders as well as aggressive and recurrent cancers could be successfully treated by stem cell-based therapies. This review focuses on the recent advancements in adult stem cell biology in normal and pathological conditions. We describe how these results have improved our understanding on critical and unique functions of these rare sub-populations of multipotent and undifferentiated cells with an unlimited self-renewal capacity and high plasticity. Finally, we discuss some major advances to translate the experimental models on ex vivo and in vivo expanded and/or differentiated stem cells into clinical applications for the development of novel cellular therapies aimed at repairing genetically altered or damaged tissues/organs in humans. A particular emphasis is made on the therapeutic potential of different tissue-resident adult stem cell types and their in vivo modulation for treating and curing specific pathological disorders.
431 citations
TL;DR: This review focuses on zebrafish, Danio rerio, as a facile model system to study human disease and drug responses as a viable addition to established animal models by offering medium and, potentially, high throughput capabilities.
Abstract: In vivo studies represent an essential step in drug development and currently rely largely on mice, yet limitations of mammalian models motivated the search for complementary vertebrate model systems. This review focuses on zebrafish, Danio rerio, as a facile model system to study human disease and drug responses. Zebrafish are particularly suited for this purpose because they represent a vertebrate species, their genome is sequenced, and a large number of synchronously developing, transparent embryos can be produced. Zebrafish embryos are permeable to drugs and can easily be manipulated using well-established genetic and molecular approaches. Here, we summarize recent work on drug discovery and toxicity in zebrafish embryos. In addition, we provide a synopsis of current efforts to establish disease models in zebrafish focusing on neoplasia. The results of these studies highlight the potential of zebrafish as a viable addition to established animal models by offering medium and, potentially, high throughput capabilities.
414 citations
TL;DR: What constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision‐making are discussed.
Abstract: The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.
403 citations
TL;DR: OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect, and an array of drug uptake and efflux transporters are expressed in the human intestine.
Abstract: The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.
398 citations
TL;DR: It is indicated that, unexpectedly, SLCO1B1 polymorphism has a larger effect on the AUC of atorvastatin than on the more hydrophilic rosuvASTatin.
Abstract: Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 20 mg dose of atorvastatin and 10 mg dose of rosuvastatin with a washout period of 1 week. Subjects with the SLCO1B1 c.521CC genotype (n=4) had a 144% (P<0.001) or 61% (P=0.049) greater mean area under the plasma atorvastatin concentration-time curve from 0 to 48 h (AUC(0-48 h)) than those with the c.521TT (n=16) or c.521TC (n=12) genotype, respectively. The AUC(0-48 h) of 2-hydroxyatorvastatin was 100% greater in subjects with the c.521CC genotype than in those with the c.521TT genotype (P=0.018). Rosuvastatin AUC(0-48 h) and peak plasma concentration (Cmax) were 65% (P=0.002) and 79% (P=0.003) higher in subjects with the c.521CC genotype than in those with the c.521TT genotype. These results indicate that, unexpectedly, SLCO1B1 polymorphism has a larger effect on the AUC of atorvastatin than on the more hydrophilic rosuvastatin.
395 citations
TL;DR: The role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed as knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases.
Abstract: Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics and dosage requirements. Single-nucleotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Serturner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.
317 citations
TL;DR: CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite, which is associated with reduced IPA.
Abstract: Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R-138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0-24 (area under the concentration-time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.
312 citations
TL;DR: There has recently been an explosion of interest in adult stem/progenitor cells that have the potential to repair tissues, but the data present a paradox— the cells frequently repair injured tissues without much evidence of either engraftment or differentiation.
Abstract: There has recently been an explosion of interest in adult stem/progenitor cells that have the potential to repair tissues, with over 3,000 citations to publications (PubMed) and numerous announcements of clinical trials in which the cells are used to treat individuals with a broad range of diseases. At the same time, the data present a paradox-the cells originally attracted attention because of their stem-cell-like properties, but the cells frequently repair injured tissues without much evidence of either engraftment or differentiation.
TL;DR: OATP1B transporters represent the major hepatic uptake systems for atorvastatin and its active metabolites and are confirmed to have consequences for efficacy and toxicity of drugs like atorVastatin that are mainly eliminated by the hepatobiliary system.
Abstract: The inhibition of hepatic uptake transporters, such as OATP1B1, on the pharmacokinetics of atorvastatin is unknown. Here, we investigate the effect of a model hepatic transporter inhibitor, rifampin, on the kinetics of atorvastatin and its metabolites in humans. The inhibitory effect of a single rifampin dose on atorvastatin kinetics was studied in 11 healthy volunteers in a randomized, crossover study. Each subject received two 40-mg doses of atorvastatin, one on study day 1 and one on study day 8, separated by 1 week. One intravenous 30-min infusion of 600 mg rifampin was administered to each subject on either study day 1 or study day 8. Plasma concentrations of atorvastatin and metabolites were above the limits of quantitation for up to 24 h after dosing. Rifampin significantly increased the total area under the plasma concentration-time curve (AUC) of atorvastatin acid by 6.8+/-2.4-fold and that of 2-hydroxy-atorvastatin acid and 4-hydroxy-atorvastatin acid by 6.8+/-2.5- and 3.9+/-2.4-fold, respectively. The AUC values of the lactone forms of atorvastatin, 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin, were also significantly increased, but to a lower extent. An intravenous dose of rifampin substantially increased the plasma concentrations of atorvastatin and its acid and lactone metabolites. The data confirm that OATP1B transporters represent the major hepatic uptake systems for atorvastatin and its active metabolites. Inhibition of hepatic uptake may have consequences for efficacy and toxicity of drugs like atorvastatin that are mainly eliminated by the hepatobiliary system.
TL;DR: CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.
Abstract: To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.
TL;DR: Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability and may be the first report of a single dietary constituent clinically modulating drug transport.
Abstract: We showed previously that grapefruit and orange juices inhibited human enteric organic anion-transporting polypeptide (OATP)1A2 in vitro and lowered oral fexofenadine bioavailability clinically. Inhibition of OATP1A2 transport by flavonoids in grapefruit (naringin) and orange (hesperidin) was conducted in vitro. Two randomized, crossover, pharmacokinetic studies were performed clinically. In one study, 120 mg of fexofenadine was ingested with 300 ml grapefruit juice, an aqueous solution of naringin at the same juice concentration (1,200 microM), or water. In the other study, fexofenadine was administered with grapefruit juice, with or 2 h before aqueous suspension of the particulate fraction of juice containing known clinical inhibitors of enteric CYP3A4, but relatively low naringin concentration (34 microM), or with water. Naringin and hesperidin's half-maximal inhibitions were 3.6 and 2.7 microM, respectively. Fexofenadine area under the plasma drug concentration-time curves (AUCs) with grapefruit juice and naringin solution were 55% (P<0.001) and 75% (P<0.05) of that with water, respectively. Fexofenadine AUCs with grapefruit juice and particulate fractions were 57% (P<0.001), 96% (not significant (NS)), and 97% (NS) of that with water, respectively. Individuals tested in both studies (n=9 of 12) had highly reproducible fexofenadine AUC with water (r(2)=0.85, P<0.001) and extent of reduction of it with grapefruit juice (r(2)=0.72, P<0.01). Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved. Naringin appears to have sufficient safety, specificity, and sensitivity to be a clinical OATP1A2 inhibitor probe. Inherent OATP1A2 activity may be influenced by genetic factors. This appears to be the first report of a single dietary constituent clinically modulating drug transport.
University of California, San Francisco1, Stanford University2, University of Chicago3, Indiana University4, University of Florida5, University of Michigan6, Children's Hospital Oakland Research Institute7, University of North Carolina at Chapel Hill8, Vanderbilt University9, Kaiser Permanente10, University of Maryland, Baltimore11, Brigham and Women's Hospital12, University of Toronto13, Mayo Clinic14
TL;DR: This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN, including informatics, cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.
Abstract: The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.
TL;DR: This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death and could be reduced by the administration of (R)‐methadone.
Abstract: Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.
TL;DR: The most compelling data for sex‐specific medication dosing guidelines for older patients are related to volume of distribution differences, or size differences, between the sexes and to differences in glomerular filtration rates.
Abstract: Pharmacokinetic and pharmacodynamic changes occur with increasing age. Sex differences in pharmacokinetics and pharmacodynamics exist and persist at older age. The issue for the clinician is how to best treat the older patient with currently available knowledge. This communication highlights age- and sex-related differences in pharmacokinetics that should influence clinical practice and prescribing guidelines to optimize clinical responses. The most compelling data for sex-specific medication dosing guidelines for older patients are related to volume of distribution differences, or size differences, between the sexes and to differences in glomerular filtration rates.
TL;DR: It is shown in humans that habitual caffeine consumption is associated with reduced sleep quality in self‐rated caffeine‐sensitive individuals, but not in caffeine‐insensitive individuals, and a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.
Abstract: Caffeine is the most widely used stimulant in Western countries Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep
TL;DR: A semi‐mechanistic model for lean body weight (LBW) is presented that is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.
Abstract: The global epidemic of obesity has led to an increased prevalence of chronic diseases and need for pharmacological intervention. However, little is known about the influence of obesity on the drug exposure profile, resulting in few clear dosing guidelines for the obese. Here we present a semi-mechanistic model for lean body weight (LBW) that we believe is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.
TL;DR: YP2D6 genotype determined concentrations of O‐desmethyltramadol enantiomers and influenced efficacy of tramadol treatment and in PMs, non‐response rates to tramadols treatment increased fourfold compared with the other genotypes.
Abstract: The influence of CYP2D6 genotype and CYP2D6 inhibitors on enantiomeric plasma levels of tramadol and O-desmethyltramadol as well as response to tramadol was investigated. One hundred and seventy-four patients received one hundred intravenous tramadol 3 mg/kg for postoperative analgesia. Blood samples drawn 30, 90, and 180 min after administration were analyzed for plasma concentrations of the enantiomers (+)-, (-)tramadol and (+)-, (-)O-desmethyltramadol by liquid chromatography-tandem mass spectrometry. Different CYP2D6 genotypes displaying zero (poor metabolizer (PM)), one (heterozygous individual (HZ)/intermediate metabolizer (IM)), two extensive metabolizer (EM), and three (ultra rapid metabolizer (UM)) active genes were compared. Concentrations of O-desmethyltramadol differed in the four genotype groups. Median (1/3 quartile) area under the concentration-time curves for (+)O-desmethyltramadol were 0 (0/11.4), 38.6 (15.9/75.3), 66.5 (17.1/118.4), and 149.7 (35.4/235.4) ng x h/ml for PMs, HZ/IMs, EMs, and UMs (P<0.001). Comedication with CYP2D6 inhibitors decreased (+) O-desmethyltramadol concentrations (P<0.01). In PMs, non-response rates to tramadol treatment increased fourfold compared with the other genotypes (P<0.001). In conclusion, CYP2D6 genotype determined concentrations of O-desmethyltramadol enantiomers and influenced efficacy of tramadol treatment.
TL;DR: Vaporization of cannabis is a safe and effective mode of delivery of THC and further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system.
Abstract: Although cannabis may have potential therapeutic value, inhalation of a combustion product is an undesirable delivery system. The aim of the study was to investigate vaporization using the Volcano® device as an alternative means of delivery of inhaled Cannabis sativa. Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a standard cigarette. One strength (1.7, 3.4, or 6.8% tetrahydrocannabinol (THC)) and delivery system was randomly assigned for each of the 6 study days. Plasma concentrations of Δ-9-THC, expired carbon monoxide (CO), physiologic and neuropsychologic effects were the main outcome measures. Peak plasma concentrations and 6-h area under the plasma concentration–time curve of THC were similar. CO levels were reduced with vaporization. No adverse events occurred. Vaporization of cannabis is a safe and effective mode of delivery of THC. Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system.
Clinical Pharmacology & Therapeutics (2007) 82, 572–578; doi:10.1038/sj.clpt.6100200; published online 11 April 2007
TL;DR: Phenotyping for drug metabolizing enzymes and transporters is used to assess quantitatively the effect of an intervention or a condition on their activity to obtain results applicable for other substrates of the respective enzyme/transporter.
Abstract: Phenotyping for drug metabolizing enzymes and transporters is used to assess quantitatively the effect of an intervention (e.g., drug therapy, diet) or a condition (e.g., genetic polymorphism, disease) on their activity. Appropriate selection of test drug and metric is essential to obtain results applicable for other substrates of the respective enzyme/transporter. The following phenotyping metrics are recommended based on the level of validation and on practicability: CYP1A2, paraxanthine/caffeine in plasma 6 h after 150 mg caffeine; CYP2C9, tolbutamide plasma concentration 24 h after 125 mg tolbutamide; CYP2C19, urinary excretion of 4'-OH-mephenytoin 0-12 h after 50 mg mephenytoin; CYP2D6, urinary molar ratio debrisoquine/4-OH-debrisoquine 0-8 h after 10 mg debrisoquine; and CYP3A4, plasma clearance of midazolam after 2 mg midazolam (all drugs given orally).
TL;DR: The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism.
Abstract: The molecular target of rapamycin (mTOR) is central to a complex intracellular signaling pathway and is involved in diverse processes including cell growth and proliferation, angiogenesis, autophagy, and metabolism. Although sirolimus (rapamycin), the oldest inhibitor of mTOR, was discovered more than 30 years ago, renewed interest in this pathway is evident by the numerous rapalogs recently developed. These newer agents borrow from the structure of sirolimus and, although there are some pharmacokinetic differences, they appear to differ little in terms of pharmacodynamic effects and overall tolerability. Given the multitude of potential applications for this class of agents and the decrease in cost that can be expected upon the expiration of sirolimus patents, renewed focus on this agent is warranted.
TL;DR: The statistical concepts behind these methods, as well as their practical application to monitoring the safety of pharmaceutical products using spontaneous AE reports are described and examples of how these tools can be used to identify novel drug interactions and demographic risk factors for adverse drug reactions are provided.
Abstract: Robust tools for monitoring the safety of marketed therapeutic products are of paramount importance to public health. In recent years, innovative statistical approaches have been developed to screen large post-marketing safety databases for adverse events (AEs) that occur with disproportionate frequency. These methods, known variously as quantitative signal detection, disproportionality analysis, or safety data mining, facilitate the identification of new safety issues or possible harmful effects of a product. In this article, we describe the statistical concepts behind these methods, as well as their practical application to monitoring the safety of pharmaceutical products using spontaneous AE reports. We also provide examples of how these tools can be used to identify novel drug interactions and demographic risk factors for adverse drug reactions. Challenges, controversies, and frontiers for future research are discussed.
TL;DR: A biomarker consortium model will distribute cost and risk, and drive efficient execution of research and ultimately regulatory acceptance of biomarkers for specific indications.
Abstract: A consistent framework for the acceptance and qualification of biomarkers for regulatory use is needed to facilitate innovative and efficient research and subsequent application of biomarkers in drug development. One key activity is biomarker qualification, a graded, "fit-for-purpose" evidentiary process linking a biomarker with biology and clinical end points. A biomarker consortium model will distribute cost and risk, and drive efficient execution of research and ultimately regulatory acceptance of biomarkers for specific indications.
TL;DR: Looking at some converging changes taking place in the health‐care landscape that are creating a scientific and social infrastructure to enable personalized medicine, and considering how clinical pharmacology can help construct a rational personalized medicine framework are focused on.
Abstract: The market for molecular diagnostic tests is predicted to grow at extraordinary rates over the next 10 years, fueled by pharmacogenetics and the elusive dream of personalized medicine. The challenge is managing the expectations of the medical community and the public at large that have already been set by speculation, promises, and the repeated exposure to headlines about genetic discoveries. Personalized medicine is a paradigm that exists more in conceptual terms than in reality, with only a few marketed drug-test companion products and not very many actual clinical practices set up to personalize medicine in the way that supporters have intended. Nevertheless, the reality of personalized medicine has become more imminent because of the increased awareness of the shortcomings in the delivery of drugs with adequate benefit/risk to patients, a better molecular understanding of how to optimize drug selection and dosing, and an increased demand for integrating more clinically relevant genetic information into the drug development process to improve both innovation and productivity. This paper focuses on personalized medicine by (1) looking at some converging changes taking place in the health-care landscape that are creating a scientific and social infrastructure to enable personalized medicine, (2) considering challenges that need to be addressed with regard to clinical evidence standards for validating genotype-phenotype associations, and (3) considering how clinical pharmacology can help construct a rational personalized medicine framework. As therapeutic experts, clinical pharmacologists can work to assure that "good therapeutics follows good diagnostics". They are well equipped to provide timely genetic education to others and to interpret genetic data so that actionable decisions, especially about drug dosing in individual patients, can be implemented in clinical practice.
TL;DR: The lack of a time‐related increase in dose‐corrected tacrolimus exposure observed with the CYP3A4*1/CYP3A5*1 and CYP6*1B/Cyp3A 5*1 genotypes is associated with tac rolimus‐related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites.
Abstract: The impact of CYP3A and MDR1 gene single-nucleotide polymorphisms on long-term tacrolimus disposition and drug-related toxicity has not been assessed. A study was performed in 95 genotyped recipients by measuring (12 and 4 h) concentration-time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. In contrast to recipients carrying the CYP3A4*1/CYP3A5*1 or CYP3A4*1B/CYP3A5*1 genotypes, dose-corrected tacrolimus exposure almost doubled over 5 years in patients with the CYP3A4*1/ CYP3A5*3 genotype (AUC(0-12 h): from 41.7+/-18.7 to 80+/-39.2 ng h/ml/mg; P<0.05), whereas apparent oral steady-state clearance and dose requirements significantly decreased accordingly. The CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes were significantly more frequently associated with the development of biopsy-proven tacrolimus-related nephrotoxicity than the CYP3A4*1/ CYP3A5*3 genotype (37.5 vs 11.2%; P=0.03 and 42.8 vs 11.2%; P=0.02). The lack of a time-related increase in dose-corrected tacrolimus exposure observed with the CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes is associated with tacrolimus-related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites.
TL;DR: Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high‐dimensional propensity scores, within‐patient variation of drug exposure using crossover designs, and between‐provider variation in prescribing preference using instrumental variable (IV) analyses.
Abstract: Physicians and insurers need to weigh the effectiveness of new drugs against existing therapeutics in routine care to make decisions about treatment and formularies. Because Food and Drug Administration (FDA) approval of most new drugs requires demonstrating efficacy and safety against placebo, there is limited interest by manufacturers in conducting such head-to-head trials. Comparative effectiveness research seeks to provide head-to-head comparisons of treatment outcomes in routine care. Health-care utilization databases record drug use and selected health outcomes for large populations in a timely way and reflect routine care, and therefore may be the preferred data source for comparative effectiveness research. Confounding caused by selective prescribing based on indication, severity, and prognosis threatens the validity of non-randomized database studies that often have limited details on clinical information. Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high-dimensional propensity scores, within-patient variation of drug exposure using crossover designs, and between-provider variation in prescribing preference using instrumental variable (IV) analyses.
TL;DR: This new consortium, funded through Clinical and Translational Science Awards (CTSAs), begins with 12 academic health centers (AHCs) located throughout the nation.
Abstract: In the first week of October, I announced the launch of a national consortium that will transform how clinical and translational research is conducted; ultimately enabling researchers to provide new treatments more efficiently and quickly to patients. This new consortium, funded through Clinical and Translational Science Awards (CTSAs), begins with 12 academic health centers (AHCs) located throughout the nation. An additional 52 AHCs are receiving planning grants to help them prepare to apply for a CTSA.
TL;DR: The role of HLA genes, cytokine genes, and cell surface receptor genes are examined as examples of how genetic polymorphism leads to individual and population variations in immune responses to vaccines to inform the immune‐response network theory to vaccine response.
Abstract: Recent advances in the fields of immunology, genetics, molecular biology, bioinformatics, and the Human Genome Project have allowed for the emergence of the field of vaccinomics Vaccinomics encompasses the fields of immunogenetics and immunogenomics as applied to understanding the mechanisms of heterogeneity in immune responses to vaccines In this study, we examine the role of HLA genes, cytokine genes, and cell surface receptor genes as examples of how genetic polymorphism leads to individual and population variations in immune responses to vaccines In turn, this data, in concert with new high-throughput technology, inform the immune-response network theory to vaccine response Such information can be used in the directed and rational development of new vaccines, and this new golden age of vaccinology has been termed "predictive vaccinology", which will predict the likelihood of a vaccine response or an adverse response to a vaccine, the number of doses needed and even whether a vaccine is likely to be of benefit (ie, is the individual at risk for the outcome for which the vaccine is being administered?)