Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2  = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.

Investigating the Potential of Phosphatidylcholine-Based Nano-Sized Carriers in Boosting the Oto-Topical Delivery of Caroverine: in vitro Characterization, Stability Assessment and ex vivo Transport Studies.

PURPOSE: Drug delivery into the inner ear across the intact tympanic membrane (TM) has been a challenge in the treatment of inner ear disorders. In this study, nano-sized carriers were formulated for improving the non- invasive oto-topical delivery of caroverine for the treatment of tinnitus. METHODS: Caroverine was loaded into two types of phospholipid-containing systems, namely, nano elastic vesicles (EVs) and phosphatidylcholine-based liquid crystalline nano-particles (PC-LCNPs). The prepared formulations were characterized for their drug loading, particle size, polydispersity index, zeta potential, morphological features by transmission electron microscopy (TEM), and physicochemical stability. In addition, comparative ex vivo transport study was carried out using rabbits' TM for both types of formulations. RESULTS: The findings show a significant superiority of PC-LCNPs over the EVs formulations in the drug payload (1% and 0.25%, respectively), physical stability and the efficiency of permeation across rabbits' TM. The results showed a more than twofold increase in the cumulative drug flux values of PC-LCNPs (699.58 ± 100 µg/cm2) compared to the EVs (250 ± 45 µg/cm2) across the TM. CONCLUSION: The current study revealed the smart physicochemical properties of PC-LCNPs demonstrating the potential of this carrier as a new attractive candidate for improving the non-invasive oto-topical delivery of caroverine.

Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure-QTc in patients with advanced or refractory solid tumors.

PURPOSE: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. METHODS: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. RESULTS: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval. CONCLUSIONS: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Cost-Effectiveness of Elbasvir/Grazoprevir Versus Daclatasvir Plus Asunaprevir in Patients with Chronic Hepatitis C Virus Genotype 1b Infection in China.

BACKGROUND AND OBJECTIVE: New direct-acting antivirals (DAAs) have high efficacy and tolerability in the treatment of hepatitis C virus (HCV) infection. The objective of this study was to assess the cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) versus daclatasvir plus asunaprevir (DCV + ASV) in Chinese patients with chronic HCV genotype (GT) 1b infection stratified by cirrhosis status and treatment history. METHODS: A cohort state-transition model was constructed to simulate the course of chronic HCV infection in patients stratified by cirrhosis status and treatment history. The model projected lifetime outcomes and costs in terms of HCV treatment, laboratory tests, clinical procedures, and hospitalizations. Mean age of the study cohort at baseline was 45 years, based on published sources. Sustained virologic response (SVR) rates were derived from clinical trials. Healthcare resource utilization and health utilities were extracted or estimated from published studies in Chinese populations. The stability of the base-case analysis was validated by deterministic and probabilistic sensitivity analyses. RESULTS: In each subpopulation of Chinese patients, treatment with EBR/GZR dominated treatment with DCV + ASV, with lower costs and higher quality-adjusted life-years (QALYs). Sensitivity analysis demonstrated that EBR/GZR was the cost-effective option compared to DCV + ASV in 77.4-97.4% or 94.1-100% of model simulations in Chinese treatment-naïve or treatment-experienced patients, respectively, as the cost-effectiveness threshold changed from zero to US$24,150/QALY (three times GDP per capita in China). CONCLUSIONS: Treatment with EBR/GZR was the cost-effective option for patients with chronic HCV GT1b infection in China, regardless of cirrhosis status or treatment history.

Glecaprevir/pibrentasvir expands reach while reducing cost and duration of hepatitis C virus therapy.

Hepatitis C virus (HCV) treatments have dramatically progressed from poorly tolerated, moderately successful interferon-based therapies to highly effective all-oral interferon-free regimens. While sustained virologic responses have significantly improved with fixed-dose combinations (FDC) of these direct-acting antivirals (DAA), cost remains high and certain populations of patients remain difficult to treat. Glecaprevir (GLE, an NS3/4A protease inhibitor) and pibrentasvir (PIB, NS5A inhibitor) were recently approved as a FDC therapy for HCV, and have expanded reach, reduced cost, and in certain populations, reduced HCV treatment duration. GLE/PIB is effective across all genotypes, and has been shown to be effective in HIV-infected patients, patients with chronic kidney disease, and Child-Pugh A-compensated cirrhosis. GLE/PIB is also effective for a shortened duration of 8 weeks in treatment-naive non-cirrhotic patients.

Dietary exposure assessment of cyadox based on tissue depletion of cyadox and its major metabolites in pigs, chickens, and carp.

The tissue kinetics of cyadox, an antibacterial agent used in food animals, and its major metabolites in pigs, chickens, and carp were investigated followed by a complete dietary exposure assessment to evaluate the food safety of cyadox. Cyadox and its major metabolites, bisdeoxycyadox (Cy1), 4-desoxycyadox (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), quinoxaline-2-carboxylic acid (Cy6), and 2-hydromethyl-3-hydroxy-quinoxaline (Cy12), were simultaneously quantitated with a high-performance liquid chromatography-ultraviolet (HPLC-UV) method. Pigs, chickens, and carp were fed with 150 mg/kg cyadox in feed for consecutive 60, 40, and 30 days, respectively. The residue amount of cyadox and its major metabolites in liver, kidney, muscle, and fat (skin) tissues was determined. Cy2 was below the limit of quantitation even at the withdrawal time of 6 hr, cyadox, Cy4, Cy6, and Cy12 could be detected at 6-24 hr with low level less than 50 µg/kg. By contrast, Cy1 persisted for 3 days in the kidney of pigs and chickens, and in the liver of carp. Based on these residue depletion data and previous toxicology results, the global estimated chronic dietary exposure assessment of cyadox for general population was conducted, indicating a zero withdrawal time (WDT) may be appropriate for cyadox in food animals when used in feed for prolonged administration. These results provide analytical techniques and safety standards suitable for residue monitoring of cyadox in food animals.

In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents.

A new series of N-(substituted-phenyl)-2-[5-(quinoxalin-2-yloxymethyl)-[1,3,4] oxadiazol-2-ylsulfanyl]-acetamides (5a-o) was designed and synthesised from the parent compound 2-hydroxy quinoxaline (1) through a multistep reaction sequence and was characterised by spectral and elemental analyses. All of the compounds synthesised were evaluated for their antimicrobial and antiprotozoal activities. The results revealed that quinoxaline-based 1,3,4-oxadiazoles displayed promising antibacterial, antifungal and anti-Trypanosoma cruzi activities compared with reference drugs, particularly the lead compound 5l in a short-term in vivo model in T. cruzi.

Cost-effectiveness of elbasvir/grazoprevir use in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and chronic kidney disease in the United States.

Among patients with chronic kidney disease (CKD) in the United States, HCV infection causes significant morbidity and mortality and results in substantial healthcare costs. A once-daily oral regimen of elbasvir/grazoprevir (EBR/GZR) for 12 weeks was found to be a safe and efficacious treatment for HCV in patients with CKD. We evaluated the cost-effectiveness of EBR/GZR in treatment-naïve and treatment-experienced CKD patients compared with no treatment (NoTx) and pegylated interferon plus ribavirin (peg-IFN/RBV) using a computer-based model of the natural history of chronic HCV genotype 1 infection, CKD and liver disease. Data on baseline characteristics of the simulated patients were obtained from NHANES, 2000-2010. Model inputs were estimated from published studies. Cost of treatment with EBR/GZR and peg-INF/RBV were based on wholesale acquisition cost. All costs were from a third-party payer perspective and were expressed in 2015 U.S. dollars. We estimated lifetime incidence of liver-related complications, liver transplantation, kidney transplantation, end-stage live disease mortality and end-stage renal disease mortality; lifetime quality-adjusted life years (QALY); and incremental cost-utility ratios (ICUR). The model predicted that EBR/GZR will significantly reduce the incidence of liver-related complications and prolong life in patients with chronic HCV genotype 1 infection and CKD compared with NoTx or use of peg-IFN/RBV. EBR/GZR-based regimens resulted in higher average remaining QALYs and higher costs (11.5716, $191 242) compared with NoTx (8.9199, $156 236) or peg-INF/RBV (10.2857, $186 701). Peg-IFN/RBV is not cost-effective, and the ICUR of EBR/GZR compared with NoTx was $13 200/QALY. Treatment of a patient on haemodialysis with EBR/GZR resulted in a higher ICUR ($217 000/QALY). Assuming a threshold of $100 000 per QALY gained for cost-effectiveness, use of elbasvir/grazoprevir to treat an average patient with CKD can be considered cost-effective in the United States.

The cost-effectiveness of testing for NS5a resistance-associated polymorphisms at baseline in genotype 1a-infected (treatment-naïve and treatment-experienced) subjects treated with all-oral elbasvir/grazoprevir regimens in the United States.

BACKGROUND: The presence of baseline NS5A resistance-associated variants (RAVs) impacted treatment response in HCV genotype 1a (GT1a)-infected patients treated with elbasvir/grazoprevir (EBR/GZR) for 12 weeks, but not patients treated with EBR/GZR and ribavirin (RBV) for 16 weeks. AIMS: To assess the cost-effectiveness of baseline testing for NS5A RAVs in EBR/GZR-treated patients compared without testing, and with current treatments for GT1a patients. METHODS: We simulated the course of treatment with EBR/GZR, ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) with or without RBV and natural history of disease of GT1a patients. Treatment-related data from clinical trials were used in a state-transition model of the natural history of chronic HCV GT1a infection and liver disease to project lifetime costs (US$2015) and quality-adjusted life years (QALY). Other clinical and economic inputs were estimated from published sources. We conducted base case and sensitivity analyses. RESULTS: RAVs testing-guided treatment with EBR/GZR resulted in more QALYs than EBR/GZR without testing, 3D+RBV, or LDV/SOF8. This strategy was cost-saving relative to 3D+RBV or LDV/SOF8 and was cost-effective compared with EBR/GZR without testing. LDV/SOF12 was not cost-effective compared with the EBR/GZR RAVs testing-based strategy. Treatment with EBR/GZR guided by RAVs testing is the most effective regimen among treatment-experienced patients without cirrhosis and cirrhotic patients. In sensitivity analysis, RAVs testing was cost-effective in 48-55% and 63-85% among noncirrhotic and cirrhotic patients respectively. CONCLUSIONS: RAVs testing before treatment with EBR/GZR is likely to be a cost-effective alternative to the use of EBR/GZR without testing, LDV/SOF, or 3D among GT1a treatment-naïve or treatment-experienced patients.

Assessment of thirteen-week subchronic oral toxicity of cyadox in Beagle dogs.

Cyadox (2-formylquinoxaline-N(1),N(4)-dioxide cyanocetylhydrazone) is a new antimicrobial agent and growth-promoter to be used in food-producing animals. Although its toxicity has been clearly documented in rodents, no study is available in non-rodent animals. Therefore, we studied the subchronic effects of cyadox in Beagle dogs to provide additional information with which to establish safety criteria for human exposure. For this purpose, 36 Beagle dogs, 18 males and 18 females, were divided into four groups and fed diets containing 0, 100, 450 and 2500 mg/kg of cyadox, respectively, for 13 weeks. It was found that there were no significant changes among the examined parameters, except for an increase in the level of serum potassium (K(+)) in 2500 mg/kg cyadox group in males at week 13 of the study. However, the K(+) level returned to normal during the recovery period. In conclusion, cyadox showed slight effects in Beagle dogs in the subchronic oral toxicity study. The no-observed-adverse-effect level of cyadox was considered to be 450 mg/kg diet, which equates to approximately 15.3-15.4 mg/kg b.w./day. The study provided subchronic effects of cyadox in Beagle dogs, suggesting that cyadox might present mild toxicity in non-rodents.

Assessment of caroverine as a potential chemotherapeutical agent in HNSCC cell lines.

Since the prognosis of head and neck squamous cell carcinoma (HNSCC) still remains poor, identifying novel chemotherapeutic agents is of outmost importance. The anticancer potential of quinoxalines has been described in various tumor entities. Caroverine, also a quinoxaline derivative, has been shown to suppress tumor promotion factors. The aim of this study was to evaluate the effect of caroverine on HNSCC cell lines. The HNSCC cell lines SCC9, SCC25, CAL27, and FaDu were incubated with caroverine alone or in combination with cisplatin, 5-fluorouracil (5-FU) or cetuximab. Cell viability was measured using the CCK-8 assay. The murine 3T3 fibroblast cell line was used to address tissue specificity. Apoptosis was visualized by immunohistochemistry. Caroverine showed a dose-dependent growth inhibition in all cell lines, IC50 values ranged from 75.69 to 179.80 µM. This effect was increased when caroverine was combined with cetuximab or 5-FU. Immunohistochemistry displayed more apoptosis after caroverine treatment compared to controls. Furthermore, caroverine alone had no growth inhibitory effect on 3T3 cells. For the first time, this study provides evidence that caroverine may serve as a supportive drug in the treatment of HNSCC patients.

Optical coherence tomography imaging of erythematotelangiectatic rosacea during treatment with brimonidine topical gel 0.33%: a potential method for treatment outcome assessment.

BACKGROUND: Patients with moderate to severe rosacea often seek treatment to reduce erythema and vascular markings. Few studies have looked at the effectiveness of the novel treatment, brimonidine topical gel 0.33%, trademark name Mirvaso®, in the treatment of rosacea. We report the use of optical coherence tomography (OCT) scanning to monitor the effectiveness of Mirvaso® on in vivo skin. OCT is a non-invasive optical imaging technique that can provide high-resolution imaging of vessel and cellular morphology. OCT may be useful as a pre-treatment assessment tool for identifying possible morphologic features in the skin that may serve as outcome predictors. OCT may also serve as a monitoring tool in the treatment of rosacea. OBJECTIVE: To examine and describe how OCT skin morphology changes when exposed to brimonidine topical gel 0.33% in the treatment of erythematotelangiectatic rosacea. METHODS: Normal in vivo telangiectasias and erythematous patches and papules were examined prior to treatment clinically, dermatoscopically, and through OCT scans. Brimonidine topical gel 0.33% was applied to the face and OCT images were acquired at defined time intervals: baseline; immediately (<5 minutes) after application; 4 hours after application; and after 2 weeks' once daily application. OCT morphology was then described. RESULTS: OCT imaging showed an increase in the mean gray value (MGV), a measure of dermal reflectivity, corresponding to a decrease in dermal edema. MGV measurements for the nasal telangiectasia were: baseline, MGV 10,471 (standard deviation [SD] 6,847); immediate, MGV 15,634 (SD 8,983); after 4 hours, MGV 16,357 (SD 7,647); and after 2 weeks, MGV 15,505 (SD 6,870). MGV measurements for the chin erythema were: baseline, MGV 8,850 (SD 4,969); immediate, MGV 10,799 (SD 5,266); after 4 hours, MGV 12,419 (SD 6,714); and after 2 weeks, MGV 13,395 (SD 6,170). No significant change in vessel lumen diameter was appreciated. Vessel lumen diameter for the facial papule ranged from 0.13 mm at baseline, 0.09 mm immediately after treatment, 0.09 mm after 4 hours, and 0.11 mm after 2 weeks. CONCLUSIONS: OCT scanning showed a decrease in the dermal hyporeflectivity of the dermis consistent with a decrease in dermal edema. The OCT scans obtained did not show any significant change in vessel lumen diameter. These results may reflect an increase in vascular tone, which can be attributable to the clinical improvement and decreased erythema noted in the patient. This technology could potentially be used for the non-invasive in vivo monitoring of other topical treatments.

Flexible and extended dosing of nicotine replacement therapy or varenicline in comparison to fixed dose nicotine replacement therapy for smoking cessation: rationale, methods and participant characteristics of the FLEX trial.

Quitting smoking is the single most effective strategy to reduce morbidity and premature mortality in smokers. Research has demonstrated the effectiveness of pharmacotherapy in smoking cessation, but few studies have directly compared varenicline and monotherapy nicotine replacement therapy (NRT) and none have examined varenicline and combinations of NRT products. The majority of smoking cessation trials involve carefully circumscribed populations, making their results less generalizable to those with severe medical conditions or psychiatric comorbidities. This paper reports on the rationale, methodology and participant characteristics of a randomized controlled trial designed to: (1) determine which pharmacotherapy - NRT, long term combinations of NRT, or varenicline - is most effective in achieving abstinence; (2) investigate the incidence of neuropsychiatric symptoms among participants over the course of their quit attempt; and (3) assess whether there is a significant difference in the incidence of neuropsychiatric symptoms in those receiving differing pharmacotherapies, and between those with and without psychiatric illnesses. The primary outcome was carbon monoxide confirmed abstinence from weeks 5-52 following a target quit date. Secondary outcomes included neuropsychiatric (i.e., depression, suicidal ideation, anxiety, anger) and withdrawal symptoms. Smokers (N=737) were randomly assigned to one of three treatment conditions, and were scheduled to attend 8 follow-up appointments over 12 months. All participants received 6-15 minute practical counseling sessions with nurse counselors experienced in treating tobacco dependence. We expect that the results will lead to an enhanced understanding of the efficacy of these pharmacotherapies, including those with a history of psychiatric illness.

General practitioner prescribing of single and combination nicotine replacement therapy in the UK: a retrospective database study.

BACKGROUND: Guidance in England and Wales recommends that nicotine replacement therapies (NRTs), varenicline or bupropion should be offered for smoking cessation support. Research on general practitioner (GP) NRT prescribing patterns for smoking cessation is lacking in the published literature. METHODS: UK primary care electronic health records were retrospectively analysed to identify the most common GP initiated NRT prescribing patterns, characterise people who receive NRT and determine whether NRTs given in a first quit attempt are different from subsequent attempts. RESULTS: The study population comprised 38,954 individuals in UK primary care data with a first ever NRT patch smoking cessation attempt for the period January 2008-December 2011. The majority (64.3%) received NRT patch monotherapy at first smoking cessation attempt, and the most common NRT was 21 mg/24 hours patch monotherapy (15.2%). Of the 35.7% first smoking cessation attempts which were NRT combination therapy, the most common combination was patch + inhalator (56.2%). The proportion of people who started a smoking cessation attempt with combination therapy increased from 25.7% in 2008 to 44.8% in 2011. The majority of the population had one recorded smoking cessation attempt but a significant minority (20.2% N = 7,868) started a second smoking cessation attempt. Second and third attempts, while predominantly patch monotherapy, also demonstrated an increasing use of NRT combinations over the study period (2ndepisode: 20.6%-38.2%; 3rdepisode: 20.0%-36.8%). However, a minority received only non-patch NRT during second and third NRT episodes. Taking into account the 39,068 people prescribed NRT patch during the study period with a history of NRT at baseline (excluded from the analysis), the total proportion of people prescribed NRT patch between 2008-2011 who had more than one NRT episode was 48.4% (46,936/96,986) and of 128,115 NRT users, only 14.7% (N = 18,838) were prescribed bupropion or varenicline prior to NRT use. CONCLUSIONS: The study findings represent new data describing GP NRT prescription patterns in the UK. Given the predominance of NRT patch monotherapy observed, health policy makers and service commissioners should ensure that GPs provide equality of access to all recommended smoking cessation pharmacotherapies.

A physiologically based pharmacokinetic model for the prediction of the depletion of methyl-3-quinoxaline-2-carboxylic acid, the marker residue of olaquindox, in the edible tissues of pigs.

To estimate the consumer exposure to olaquindox (OLA) residues in porcine edible tissues, a physiologically based pharmacokinetic (PBPK) model for methyl-3-quinoxaline-2-carboxylic acid (MQCA), the marker residue of OLA, was developed in pigs based on the assumptions of the flow-limited distribution, hepatic metabolism, and renal excretion. The model included separate compartments corresponding to blood, muscle, liver, kidney, adipose, and an extra compartment representing the remaining carcass. Physiological parameters were determined from literatures. Plasma protein binding, partition coefficients, and renal clearance for MQCA were determined in in vitro and in vivo studies. The metabolic conversion of OLA to MQCA was assumed as a simple, one-step process, and an apparent first-order rate constant (k) was employed to describe this metabolic process. The PBPK model was optimized and validated with plasma and tissue data from literatures and our study. Sensitivity analysis and Monte Carlo simulation were also implemented to estimate the influence of model parameters on the goodness of fit. When compared with the observed data, the PBPK model underestimated the MQCA level in all compartments at the early time points, whereas gave excellent predictions of MQCA concentration in porcine edible tissues at later time points. The correlation coefficients between the predicted and observed values were over 0.88. The consistency between the model predictions and the real residues of OLA in pigs proved the good applicability of our model in food safety risk assessment.