Oral Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. DESIGN: Single-center, double-blind, randomized, five-period, five-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users. METHODS: Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. RESULTS: Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower "at this moment" drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean C max and rate of absorption (C max /T max ) values decreased, respectively, and median T max values increased, respectively. Safety was consistent with the known effects of opioid agonists. CONCLUSION: HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.

Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. DESIGN: Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. METHODS: During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. RESULTS: Insufflation of both HYD coarse and fine particles led to lower "At this Moment" Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. CONCLUSIONS: HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Evaluation of sunobinop for next-day residual effects in healthy participants.

Sunobinop is a novel, potent, selective partial agonist at nociceptin/orphanin FQ peptide (NOP) receptors. The primary objective of this randomized, double-blind, placebo-controlled study was to assess the next-day residual effects of an evening dose of sunobinop in healthy participants. Participants were randomized into 1 of 5 treatment sequences. Treatment consisted of 1 dose each of sunobinop 0.2, 0.6, 2, and 6 mg suspension and placebo suspension. Key pharmacodynamic (PD) measures included the digit symbol substitution test (DSST), Karolinska sleepiness scale (KSS), and body sway. The randomized safety population consisted of 25 participants. The DSST, KSS, and body sway showed dose-dependent effects following the administration of sunobinop, with no significant differences versus placebo at sunobinop doses <2 mg. At sunobinop 2 mg, PD effects were relatively small in magnitude and inconsistent. The last timepoint where significant differences between sunobinop 2 mg and placebo on the DSST, KSS, and body sway were observed was at 12 h, 16.5 h, and 13.5 h postdose, respectively. Sunobinop 6 mg resulted in larger and consistent PD effects, with significant differences from placebo at all timepoints up to 16.5-18 h postdose. Somnolence was the most frequently reported adverse event (AE), and all AEs were mild-to-moderate. No deaths occurred during the study or discontinuations due to an AE. Overall, a nighttime oral dose of sunobinop up to 2 mg was safe and generally well tolerated in healthy participants with limited next-day residual effects that were consistent with other sedative/hypnotic drugs.

Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants.

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study. Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Study 3 was a randomized, open-label, single-dose, 4-way crossover study of oral and sublingual sunobinop comparing morning (AM) and bedtime (PM) administration. Seventy participants were included. Systemic exposure (peak plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration [AUC0-t], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf]) of sunobinop was characterized by dose proportionality from 0.6 to 2 mg and increased less than proportionally from 3 to 30 mg. The PKs of sunobinop were similar, regardless of AM or PM administration, for both the oral and sublingual formulations. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, thereby showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination. Most treatment-emergent adverse events (TEAEs) were mild in severity; 1 severe TEAE occurred and all TEAEs resolved by the end of the studies. Sunobinop was generally well-tolerated and safe across the range of doses evaluated and presents a clinical profile suitable for continued development.

The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia.

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.

SNPTrack™ : an integrated bioinformatics system for genetic association studies.

A genetic association study is a complicated process that involves collecting phenotypic data, generating genotypic data, analyzing associations between genotypic and phenotypic data, and interpreting genetic biomarkers identified. SNPTrack is an integrated bioinformatics system developed by the US Food and Drug Administration (FDA) to support the review and analysis of pharmacogenetics data resulting from FDA research or submitted by sponsors. The system integrates data management, analysis, and interpretation in a single platform for genetic association studies. Specifically, it stores genotyping data and single-nucleotide polymorphism (SNP) annotations along with study design data in an Oracle database. It also integrates popular genetic analysis tools, such as PLINK and Haploview. SNPTrack provides genetic analysis capabilities and captures analysis results in its database as SNP lists that can be cross-linked for biological interpretation to gene/protein annotations, Gene Ontology, and pathway analysis data. With SNPTrack, users can do the entire stream of bioinformatics jobs for genetic association studies. SNPTrack is freely available to the public at http://www.fda.gov/ScienceResearch/BioinformaticsTools/SNPTrack/default.htm.

atBioNet--an integrated network analysis tool for genomics and biomarker discovery.

BACKGROUND: Large amounts of mammalian protein-protein interaction (PPI) data have been generated and are available for public use. From a systems biology perspective, Proteins/genes interactions encode the key mechanisms distinguishing disease and health, and such mechanisms can be uncovered through network analysis. An effective network analysis tool should integrate different content-specific PPI databases into a comprehensive network format with a user-friendly platform to identify key functional modules/pathways and the underlying mechanisms of disease and toxicity. RESULTS: atBioNet integrates seven publicly available PPI databases into a network-specific knowledge base. Knowledge expansion is achieved by expanding a user supplied proteins/genes list with interactions from its integrated PPI network. The statistically significant functional modules are determined by applying a fast network-clustering algorithm (SCAN: a Structural Clustering Algorithm for Networks). The functional modules can be visualized either separately or together in the context of the whole network. Integration of pathway information enables enrichment analysis and assessment of the biological function of modules. Three case studies are presented using publicly available disease gene signatures as a basis to discover new biomarkers for acute leukemia, systemic lupus erythematosus, and breast cancer. The results demonstrated that atBioNet can not only identify functional modules and pathways related to the studied diseases, but this information can also be used to hypothesize novel biomarkers for future analysis. CONCLUSION: atBioNet is a free web-based network analysis tool that provides a systematic insight into proteins/genes interactions through examining significant functional modules. The identified functional modules are useful for determining underlying mechanisms of disease and biomarker discovery. It can be accessed at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm.

Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans.

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.

ArrayTrack: an FDA and public genomic tool.

A robust bioinformatics capability is widely acknowledged as central to realizing the promises of toxicogenomics. Successful application of toxicogenomic approaches, such as DNA microarrays, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data, and the availability of functional information for data interpretation. At the FDA's National Center for Toxicological Research (NCTR), we are developing a public microarray data management and analysis software, called ArrayTrack, that is also used in the routine review of genomic data submitted to the FDA. ArrayTrack stores a full range of information related to DNA microarrays and clinical and non-clinical studies as well as the digested data derived from proteomics and metabonomics experiments. In addition, ArrayTrack provides a rich collection of functional information about genes, proteins, and pathways drawn from various public biological databases for facilitating data interpretation. Many data analysis and visualization tools are available with ArrayTrack for individual platform data analysis, multiple omics data integration, and integrated analysis of omics data with study data. Importantly, gene expression data, functional information, and analysis methods are fully integrated so that the data analysis and interpretation process is simplified and enhanced. Using ArrayTrack, users can select an analysis method from the ArrayTrack tool box, apply the method to selected microarray data, and the analysis of results can be directly linked to individual gene, pathway, and Gene Ontology analysis. ArrayTrack is publicly available online ( http://www.fda.gov/nctr/science/centers/toxicoinformatics/ArrayTrack/index.htm ) and the prospective user can also request a local installation version by contacting the authors.

Rat toxicogenomic study reveals analytical consistency across microarray platforms.

To validate and extend the findings of the MicroArray Quality Control (MAQC) project, a biologically relevant toxicogenomics data set was generated using 36 RNA samples from rats treated with three chemicals (aristolochic acid, riddelliine and comfrey) and each sample was hybridized to four microarray platforms. The MAQC project assessed concordance in intersite and cross-platform comparisons and the impact of gene selection methods on the reproducibility of profiling data in terms of differentially expressed genes using distinct reference RNA samples. The real-world toxicogenomic data set reported here showed high concordance in intersite and cross-platform comparisons. Further, gene lists generated by fold-change ranking were more reproducible than those obtained by t-test P value or Significance Analysis of Microarrays. Finally, gene lists generated by fold-change ranking with a nonstringent P-value cutoff showed increased consistency in Gene Ontology terms and pathways, and hence the biological impact of chemical exposure could be reliably deduced from all platforms analyzed.

The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies.

BACKGROUND: Reproducibility is a fundamental requirement in scientific experiments. Some recent publications have claimed that microarrays are unreliable because lists of differentially expressed genes (DEGs) are not reproducible in similar experiments. Meanwhile, new statistical methods for identifying DEGs continue to appear in the scientific literature. The resultant variety of existing and emerging methods exacerbates confusion and continuing debate in the microarray community on the appropriate choice of methods for identifying reliable DEG lists. RESULTS: Using the data sets generated by the MicroArray Quality Control (MAQC) project, we investigated the impact on the reproducibility of DEG lists of a few widely used gene selection procedures. We present comprehensive results from inter-site comparisons using the same microarray platform, cross-platform comparisons using multiple microarray platforms, and comparisons between microarray results and those from TaqMan - the widely regarded "standard" gene expression platform. Our results demonstrate that (1) previously reported discordance between DEG lists could simply result from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion with a non-stringent P-value cutoff filtering, the DEG lists become much more reproducible, especially when fewer genes are selected as differentially expressed, as is the case in most microarray studies; and (3) the instability of short DEG lists solely based on P-value ranking is an expected mathematical consequence of the high variability of the t-values; the more stringent the P-value threshold, the less reproducible the DEG list is. These observations are also consistent with results from extensive simulation calculations. CONCLUSION: We recommend the use of FC-ranking plus a non-stringent P cutoff as a straightforward and baseline practice in order to generate more reproducible DEG lists. Specifically, the P-value cutoff should not be stringent (too small) and FC should be as large as possible. Our results provide practical guidance to choose the appropriate FC and P-value cutoffs when selecting a given number of DEGs. The FC criterion enhances reproducibility, whereas the P criterion balances sensitivity and specificity.

An integrated bioinformatics infrastructure essential for advancing pharmacogenomics and personalized medicine in the context of the FDA's Critical Path Initiative.

Pharmacogenomics (PGx) is identified in the FDA Critical Path document as a major opportunity for advancing medical product development and personalized medicine. An integrated bioinformatics infrastructure for use in FDA data review is crucial to realize the benefits of PGx for public health. We have developed an integrated bioinformatics tool, called ArrayTrack, for managing, analyzing and interpreting genomic and other biomarker data (e.g. proteomic and metabolomic data). ArrayTrack is a highly flexible and robust software platform, which allows evolving with technological advances and changing user needs. ArrayTrack is used in the routine review of genomic data submitted to the FDA; here, three hypothetical examples of its use in the Voluntary eXploratory Data Submission (VXDS) program are illustrated.:

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.

OBJECTIVES: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80). METHODS: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI). RESULTS: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively. Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone. CONCLUSIONS: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

ArrayTrack: An FDA and Public Genomic Tool.

A robust bioinformatics capability is widely acknowledged as central to realizing the promises of toxicogenomics. Successful application of toxicogenomic approaches, such as DNA microarrays, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data and the availability of functional information for data interpretation. At the FDA's National Center for Toxicological Research (NCTR), we are developing a public microarray data management and analysis software, called ArrayTrack that is also used in the routine review of genomic data submitted to the FDA. ArrayTrack stores a full range of information related to DNA microarrays and clinical and nonclinical studies as well as the digested data derived from proteomics and metabonomics experiments. In addition, ArrayTrack provides a rich collection of functional information about genes, proteins, and pathways drawn from various public biological databases for facilitating data interpretation. Many data analysis and visualization tools are available with ArrayTrack for individual platform data analysis, multiple omics data integration and integrated analysis of omics data with study data. Importantly, gene expression data, functional information, and analysis methods are fully integrated so that the data analysis and interpretation process is simplified and enhanced. Using ArrayTrack, users can select an analysis method from the ArrayTrack tool box, apply the method to selected microarray data and the analysis results can be directly linked to individual gene, pathway, and Gene Ontology analysis. ArrayTrack is publicly available online ( http://www.fda.gov/nctr/science/centers/toxicoinformatics/ArrayTrack/index.htm ), and the prospective user can also request a local installation version by contacting the authors.

Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.

CONTEXT: During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed. OBJECTIVE: To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. DESIGN, SETTING, AND PARTICIPANTS: A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. INTERVENTION: Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. RESULTS: None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. CONCLUSIONS: Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.

Dose-Dependent Flux of Buprenorphine Following Transdermal Administration in Healthy Subjects.

Buprenorphine transdermal delivery system (BTDS) applied once every 7 days is indicated for the management of pain that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The 7-day flux of buprenorphine from BTDS to systemic circulation was investigated in a phase 1, 2-period crossover study with 3 randomized groups of healthy subjects receiving BTDS containing buprenorphine 5, 10, or 20 mg for 7 days preceded or followed by intravenous buprenorphine infusion (25 µg/h for 24 hours). Residual and absolute bioavailability methods were used to estimate 7-day flux of buprenorphine. Following BTDS administration, mean area under the curve of buprenorphine increased proportionally (12.6, 24.3, and 51.1 ng/[mL · h]), maximum mean plasma concentration rose with increasing dose (176, 191, and 471 pg/mL), and absolute bioavailability was 14% to 16%. Mean residual amount of buprenorphine in the BTDS after 7-day application was 4.50, 8.57, and 17.1 mg. Flux of buprenorphine was approximately 5, 10, and 20 µg/h for BTDS containing 5, 10, and 20 mg buprenorphine, respectively. BTDS was safe and well tolerated following a single 7-day application in healthy subjects. The results of this study demonstrated dose-dependent flux of buprenorphine delivered via transdermal system.

FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science.

Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through this data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.

Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. METHODS: Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. FINDINGS: Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. IMPLICATIONS: Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Microarray scanner calibration curves: characteristics and implications.

BACKGROUND: Microarray-based measurement of mRNA abundance assumes a linear relationship between the fluorescence intensity and the dye concentration. In reality, however, the calibration curve can be nonlinear. RESULTS: By scanning a microarray scanner calibration slide containing known concentrations of fluorescent dyes under 18 PMT gains, we were able to evaluate the differences in calibration characteristics of Cy5 and Cy3. First, the calibration curve for the same dye under the same PMT gain is nonlinear at both the high and low intensity ends. Second, the degree of nonlinearity of the calibration curve depends on the PMT gain. Third, the two PMTs (for Cy5 and Cy3) behave differently even under the same gain. Fourth, the background intensity for the Cy3 channel is higher than that for the Cy5 channel. The impact of such characteristics on the accuracy and reproducibility of measured mRNA abundance and the calculated ratios was demonstrated. Combined with simulation results, we provided explanations to the existence of ratio underestimation, intensity-dependence of ratio bias, and anti-correlation of ratios in dye-swap replicates. We further demonstrated that although Lowess normalization effectively eliminates the intensity-dependence of ratio bias, the systematic deviation from true ratios largely remained. A method of calculating ratios based on concentrations estimated from the calibration curves was proposed for correcting ratio bias. CONCLUSION: It is preferable to scan microarray slides at fixed, optimal gain settings under which the linearity between concentration and intensity is maximized. Although normalization methods improve reproducibility of microarray measurements, they appear less effective in improving accuracy.