Population pharmacokinetics and exposure-response analyses of varenicline in adolescent smokers.

Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC24 ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC24 (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.

Pharmacokinetic comparisons of two different varenicline formulations in humans: Varenicline tartrate versus varenicline oxalate
.

BACKGROUND AND OBJECTIVE: Varenicline is an effective drug for smoking cessation. The aim of the present study was to compare the pharmacokinetics and safety profiles of two different varenicline formulations (varenicline tartrate (reference) and varenicline oxalate (test)), each containing 1 mg varenicline base in humans. MATERIALS AND METHODS: A randomized, open-label, two-sequence, two-period, single-dose crossover study with a 2-week washout period was conducted with 30 healthy male participants. Blood samples for the pharmacokinetic analysis of varenicline were collected up to 96 hours following the administration of each drug. Pharmacokinetic parameters were also calculated, including the peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) as well as AUC from time zero to infinity (AUCinf). ANOVA for pharmacokinetic equivalence was assessed using log-transformed Cmax and AUC values, and the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were assessed as well. The safety profiles were also assessed. RESULTS: 27 participants completed the study. No significant differences were found for any pharmacokinetic parameters of varenicline between the two formulations. The observed average values of Cmax, AUClast, and AUCinf were 4.46 ng/mL, 97.68 ng×h/mL, and 101.60 ng×h/mL for reference and 4.54 ng/mL, 97.10 ng×h/mL, and 100.97 ng×h/mL for test, respectively. The GMRs and 90% CIs for Cmax, AUClast, and AUCinf were 1.0106 (0.9626 - 1.0610), 0.9904 (0.9540 - 1.0282), and 0.9885 (0.9517 - 1.0268), respectively. No clinically relevant changes were observed in the physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were found. CONCLUSION: The results of the present study reveal that varenicline oxalate and varenicline tartrate have similar pharmacokinetic characteristics as varenicline, and that these two formulations exhibit pharmacokinetic equivalence to meet the regulatory criteria. Both varenicline formulations were generally well tolerated.

Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population.

PURPOSE: The abstinence rate to tobacco after varenicline treatment is moderate and might be partially affected by variability in varenicline concentrations. This study aimed at characterizing the sources of variability in varenicline pharmacokinetics and to relate varenicline exposure to abstinence. METHODS: The population pharmacokinetic analysis (NONMEM®) included 121 varenicline concentrations from 82 individuals and tested the influence of genetic and non-genetic characteristics on apparent clearance (CL/F) and volume of distribution (V/F). Model-based average concentrations over 24 h (Cav) were used to test the impact of varenicline exposure on the input rate (Kin) expressed as a function of the number of cigarettes per day in a turnover model of 373 expired carbon monoxide levels. RESULTS: A one-compartment model with first-order absorption and elimination appropriately described varenicline concentrations. CL/F was 8.5 L/h (coefficient of variation, 26%), V/F was 228 L, and the absorption rate (ka) was fixed to 0.98 h-1. CL/F increased by 46% in 100-kg individuals compared to 60-kg individuals and was found to be 21% higher in UGT2B7 rs7439366 TT individuals. These covariates explained 14% and 9% of the interindividual variability in CL/F, respectively. No influence of varenicline Cav was found on Kin in addition to the number of cigarettes. CONCLUSIONS: Body weight mostly and to a smaller extent genetic polymorphisms of UGT2B7 can influence varenicline exposure. Dose adjustment based on body weight and, if available, on UGT2B7 genotype might be useful to improve clinical efficacy and tolerability of varenicline.

Vareniclina: pasado, presente y futuro / Varenicline: past, present and future

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Determining the pharmacokinetics of nicotinic drugs in the endoplasmic reticulum using biosensors.

Nicotine dependence is thought to arise in part because nicotine permeates into the endoplasmic reticulum (ER), where it binds to nicotinic receptors (nAChRs) and begins an "inside-out" pathway that leads to up-regulation of nAChRs on the plasma membrane. However, the dynamics of nicotine entry into the ER are unquantified. Here, we develop a family of genetically encoded fluorescent biosensors for nicotine, termed iNicSnFRs. The iNicSnFRs are fusions between two proteins: a circularly permutated GFP and a periplasmic choline-/betaine-binding protein engineered to bind nicotine. The biosensors iNicSnFR3a and iNicSnFR3b respond to nicotine by increasing fluorescence at [nicotine] <1 µM, the concentration in the plasma and cerebrospinal fluid of a smoker. We target iNicSnFR3 biosensors either to the plasma membrane or to the ER and measure nicotine kinetics in HeLa, SH-SY5Y, N2a, and HEK293 cell lines, as well as mouse hippocampal neurons and human stem cell-derived dopaminergic neurons. In all cell types, we find that nicotine equilibrates in the ER within 10 s (possibly within 1 s) of extracellular application and leaves as rapidly after removal from the extracellular solution. The [nicotine] in the ER is within twofold of the extracellular value. We use these data to run combined pharmacokinetic and pharmacodynamic simulations of human smoking. In the ER, the inside-out pathway begins when nicotine becomes a stabilizing pharmacological chaperone for some nAChR subtypes, even at concentrations as low as ∼10 nM. Such concentrations would persist during the 12 h of a typical smoker's day, continually activating the inside-out pathway by >75%. Reducing nicotine intake by 10-fold decreases activation to ∼20%. iNicSnFR3a and iNicSnFR3b also sense the smoking cessation drug varenicline, revealing that varenicline also permeates into the ER within seconds. Our iNicSnFRs enable optical subcellular pharmacokinetics for nicotine and varenicline during an early event in the inside-out pathway.

Immediate release tablet formulation of varenicline salicylate and comparative pharmacokinetic study in human volunteers.

PURPOSE: To develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference. MATERIALS AND METHODS: The characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug-excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared. RESULTS: VRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m2/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing f 2 values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and area under the curve from 0 to infinity (AUCinf), were compared. The values of 90% CI were 0.972-1.035 for Cmax and 0.982-1.075 for AUCinf, which was indicative of the bioequivalence of both products. CONCLUSION: VRC-S-containing F4 tablet might be a good candidate for smoking cessation treatment.

Debate 4: ¿Funciona vareniclina a dosis bajas? A favor / Debate 4: Does varenicline work at low doses? For

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Debate 4: ¿Funciona vareniclina a dosis bajas? En contra / Debate 4: Does varenicline work at low doses? Against

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Improvement of the association between self-reported pill count and varenicline levels following exclusion of participants with misreported pill count: A commentary on Peng et al. (2017).

INTRODUCTION: We previously reported poor associations between salivary varenicline and pill counts, and a substantial overestimation of adherence by pill counts in "Measures and predictors of varenicline adherence in the treatment of nicotine dependence" (Peng et al., 2017). We have since conducted supplementary analyses characterizing, and then excluding, individuals with established inaccurate pill count recall. METHODS: Based on published varenicline pharmacokinetics (including drug levels, and the long half-life) and our detection limits, conservatively we should be able to detect varenicline in anyone who took at least one pill during the 48h prior to saliva collection; thus, those reporting 1 or more pills in this time frame but who had undetectable salivary varenicline were deemed to have inaccurate pill count recall. Correlations between pill counts and salivary varenicline, and Receiver Operating Characteristics curve analyses were conducted following exclusion of participants with inaccurate pill count recall. RESULTS: Nearly 20% of our participants (N=67/376) had inaccurate self-reported pill counts. These participants were younger, non-white, lower income, and unmarried (evaluated using chi-square or Mann-Whitney U test). Following exclusion of these individuals, the correlations between salivary varenicline and pill count improved and the area under the curve (AUC) of pill counts for discriminating adherence improved modestly. CONCLUSION: When the 20% of individuals with inaccurate pill count recall were excluded, an improved association between self-reported pill count and salivary varenicline was observed, albeit still weak. A substantial overestimation of adherence by pill counts relative to salivary varenicline is still observed even after exclusion of almost 20% of the group having established inaccurate reporting suggesting that these individuals, with identifiable inaccuracies, were only part of the overestimation of adherence.

The effect of varenicline and nicotine patch on smoking rate and satisfaction with smoking: an examination of the mechanism of action of two pre-quit pharmacotherapies.

OBJECTIVES: In recent years, there has been growing research interest in using nicotine replacement medications to aid smoking reduction prior to a quit attempt. Gaining a better understanding of how treatments influence smoking reduction may allow for better tailoring of treatments and, ultimately, better cessation outcomes. The objective of the current study was to test the effects of the pre-quit use of varenicline and nicotine patch on smoking rate and satisfaction with smoking. METHODS: All participants were required to attend up to five study visit sections. Participants (n = 213) who were interested in quitting were randomised (open-label) to receive either pre-quit patch or varenicline (both treatments started 2 weeks prior to an assigned quit day, followed by 10 weeks post-quit) or standard patch (10 weeks starting from an assigned quit day). Participants used modified smartphones to monitor their smoking in real time for 4 weeks. RESULTS: Participants in the two pre-quit treatment groups reported significant reductions in both their satisfaction with smoking (p < 0.001) and smoking rate (p < 0.001) from baseline to the end of pre-quit period; participants in the standard patch group did not. The observed reduction of smoking rate was associated with the satisfaction with smoking (p < 0.01), although the mediation effect of satisfaction was small. CONCLUSIONS: Pre-quit treatment caused reductions in satisfaction with smoking and smoking rate. Satisfaction was associated with changes in smoking rate, but the relationship was weak. As such, monitoring reductions in satisfaction do not appear to be a viable method of evaluating responsiveness to treatment.

The discriminative stimulus effects of i.v. nicotine in rhesus monkeys: Pharmacokinetics and apparent pA2 analysis with dihydro-ß-erythroidine.

Quantitative analysis of antagonism is infrequently used to identify nAChRs mediating behavioral effects. Here, nicotine (0.032 mg/kg i.v.) was established as a discriminative stimulus in rhesus monkeys responding under a fixed ratio 5 schedule; pharmacokinetics and underlying nAChR mechanism(s) were examined. When measured up to 4 h in venous blood, the training dose resulted in the following mean pharmacokinetic parameters: nicotine Cmax = 71.7 ng/ml, t1/2 = 116 min, and clearance = 6.25 ml/min/kg; cotinine Cmax = 191 ng/ml; and 3OH-cotinine Cmax = 63 ng/ml. The ED50 value of nicotine to produce discriminative stimulus effects was 0.013 mg/kg. Epibatidine and varenicline increased drug-lever responding to 97% and 95%, respectively (ED50 values = 0.00015 and 0.031 mg/kg, respectively), whereas cocaine, midazolam, and morphine produced no more than 28% drug-appropriate responding. Mecamylamine and dihydro-ß-erythroidine (DHßE) dose-dependently attenuated the discriminative stimulus effects of the nicotine training dose, whereas methyllycaconitine (MLA) did not. DHßE (0.1 and 0.32) produced rightward shifts of the nicotine and varenicline dose-response functions; Schild plots fitted through individual data resulted in slopes that were not different from unity; the apparent pA2 calculated for DHßE did not significantly differ in the presence of nicotine (6.58) or varenicline (6.45). Compared to human cigarette smoking, nicotine blood levels after 0.032 mg/kg nicotine i.v. took a similar time to reach maximal concentration, levels at Cmax were similar to smoking 2-3 cigarettes, while average nicotine levels were comparable to smoking 5-6 cigarettes. Apparent pA2 analysis with DHßE under these conditions is consistent with nicotine and varenicline acting through the same nAChRs to produce discriminative stimulus effects.

Agonistas parciales, moduladores bioquímicos con múltiples aplicaciones / Partial agonists: biochemical modulators with multiple applications

En general, los diferentes tratados de farmacología se organizan en torno a una clasificación anatómica-terapéutica-química. Los tratados de «química farmacéutica» suelen organizarse, además, poniendo énfasis en la naturaleza química de los fármacos, así como en los procesos bioquímicos involucrados en su acción. En otras ocasiones, cuando se contempla la fitoterapia desde un punto de vista botánico, como hace la «botánica medicinal», la exposición se realiza mediante un viaje a través de los diferentes taxones que contienen especies con relevancia terapéutica. En cambio, en este artículo de revisión se va a hablar de un grupo de fármacos que, desde los enfoques expositivos anteriores, no tienen mucho que ver pero que, sin embargo, poseen mecanismos farmacodinámicos muy similares, a pesar de que actúen sobre diferentes receptores. Se trata de los agonistas (y antagonistas) parciales. Lógicamente no se revisarán todos en este artículo, sino aquellos que al autor le han parecido más curiosos e interesantes para ilustrar su relación mutua en cuanto al funcionamiento farmacodinámico: vareniclina, buprenorfina, diazepinonas, aripiprazol, memantina. Este es el objetivo de este artículo: la revisión de un grupo de fármacos desde un punto de vista novedoso, como es su mecanismo de acción farmacodinámico común. Entre las conclusiones, está la indicación de este tipo de fármacos cuando se va a intervenir en sistemas bioquímicos y fisiológicos tan complicados que las funciones a tratar no deben ni inhibirse ni potenciarse desmedidamente, sino simplemente modularse. Este es el caso de muchas dolencias que afectan al sistema nervioso (AU)

In general the different treatises of pharmacology are organised around an anatomical-therapeutic-chemical classification. Treatises about «medicinal chemistry» are organised, not only around this, but also emphasise the chemical nature of the drugs, as well as the biochemical processes involved in their action. Furthermore, when herbal medicine is contemplated from a botanical point of view, as does the «medical botany», exposure is performed by a journey through the different taxa containing species with therapeutic relevance. Nevertheless, in this review article a group of drugs is discussed that, from the previous points of view, do not have anything to do with each other. However, they have very similar pharmacodynamic mechanisms, despite acting on different receptors. These are partial agonists (and antagonists). Obviously not all of these will be reviewed in this article, but those more interesting to illustrate their relationship in terms of pharmacodynamic performance: varenicline, buprenorphine, diazepinones, aripiprazole, memantine. This is the purpose of this article: A review of a group of drugs from a novel point of view, such as their common pharmacodynamic mechanism of action. Among the conclusions, is the indication of these drugs to intervene in such complicated biochemical and physiological systems that functions to be treated should neither be inhibited nor enhanced, but simply modulated. This is the case of many diseases that affect the nervous system (AU)

Chronic treatment with varenicline changes expression of four nAChR binding sites in mice.

INTRODUCTION: Chronic treatment with nicotine is known to increase the α4ß2-nAChR sites in brain, to decrease α6ß2-nAChR sites and to have minimal effect on α3ß4-and α7-nAChR populations. Varenicline is now used as a smoking cessation treatment, with and without continued smoking or nicotine replacement therapy. Varenicline, like nicotine, upregulates the α4ß2-nAChR sites; however, it is not known whether varenicline treatment changes expression of the other nAChR subtypes. METHODS: Using a mouse model, chronic treatments (10 days) with varenicline (0.12  mg/kg/h) and/or nicotine (1 mg/kg/hr), alone or in combination, were compared for plasma and brain levels of drugs, tolerance to subsequent acute nicotine and expression of four subtypes of nAChR using autoradiography. RESULTS: The upregulation of α4ß2-nAChR sites elicited by chronic varenicline was very similar to that elicited by chronic nicotine. Treatment with both drugs somewhat increased up-regulation, indicating that these doses were not quite at maximum effect. Similar down-regulation was seen for α6ß2-nAChR sites. Varenicline significantly increased both α3ß4-and α7-nAChR sites while nicotine had less effect on these sites. The drug combination was similar to varenicline alone for α3ß4-nAChR sites, while for α7 sites the drug combination was less effective than varenicline alone. Varenicline had small but significant effects on tolerance to acute nicotine. CONCLUSIONS: Effects of varenicline in vivo may not be limited to the α4ß2*-nAChR subtype. In addition, smoking cessation treatment with varenicline may not allow receptor numbers to be restored to baseline and may, in addition, change expression of other receptor subtypes.

Vareniclina. Un año después / Varenicline. One year later

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