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.

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension.

The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [-9.57 (-16.22, -2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi-experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intake.

Pharmacogenetics of CYP1A2 activity and inducibility in smokers and exsmokers.

BACKGROUND: There is a high interindividual variability in cytochrome P4501A2 (CYP1A2) activity and in its inducibility by smoking, only poorly explained by known CYP1A2 polymorphisms. We aimed to study the contribution of other regulatory pathways, including transcription factors and nuclear receptors, toward this variability. METHODS: CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of them who were abstinent for 4 weeks. Participants were genotyped for 22 polymorphisms in 12 genes. RESULTS: A significant influence on CYP1A2 inducibility was observed for the NR1I3 rs2502815 (P=0.0026), rs4073054 (P=0.029), NR2B1 rs3818740 (P=0.0045), rs3132297 (P=0.036), AhR rs2282885 (P=0.040), rs2066853 (P=0.019), NR1I1 rs2228570 (P=0.037), and NR1I2 rs1523130 (P=0.044) polymorphisms. Among these, the NR1I3 rs2502815 (P=0.0045), rs4073054 (P=0.048), and NR2B1 rs3818740 (P=0.031) also influenced CYP1A2 basal activity. CONCLUSION: This is the first in-vivo demonstration of the influence of genes involved in CYP1A2 regulatory pathways on its basal activity and inducibility by smoking. These results need to be confirmed by other studies.

Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study.

BACKGROUND: (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics. METHODS: Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort. RESULTS: The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts. CONCLUSION: Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.

Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking.

BACKGROUND: Cytochrome P4501A2 (CYP1A2) presents a high interindividual variability in its activity and also in its inducibility by smoking. Cytochrome P450 oxidoreductase (POR) is an electron transfer protein that catalyzes the activity of several cytochromes P450. We aimed to study the influence of POR genetic polymorphisms on CYP1A2 activity while smoking and after smoking cessation, as well as on CYP1A2 inducibility. METHODS: CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of these smokers who were abstinent during a 4-week period. Participants were genotyped for POR rs17148944G>A, rs10239977C>T, rs3815455C>T, rs2286823G>A, rs2302429G>A, and rs1057868C>T (POR*28) polymorphisms. RESULTS: While smoking, none of the tested POR polymorphisms showed a significant influence on CYP1A2 activity. After smoking cessation, significantly higher CYP1A2 activity was found in POR rs2302429A carriers (P=0.038) and in carriers of rs17148944G-rs10239977C-rs3815455T-rs2286823G-rs2302429A-rs1057868T haplotype (P=0.038), whereas carriers of POR rs2286823A (P=0.031) and of the rs17148944G-rs10239977C-rs3815455C-rs2286823A-rs2302429G-rs1057868C haplotype (P=0.031) had decreased CYP1A2 activity. In the complete regression model, only POR rs2302429G>A showed a significant effect (P=0.017). No influence of POR genotypes or haplotypes was observed on the inducibility of CYP1A2. CONCLUSION: POR genetic polymorphisms influence CYP1A2 basal but not induced activity and do not seem to influence CYP1A2 inducibility. Future work is warranted to identify other clinical and genetic factors that may explain the variability in CYP1A2 activity and inducibility by smoking.

Using risk analysis to anticipate and mitigate failures during a hospital pharmacy relocation.

OBJECTIVES: Documented experiences of relocating hospital pharmacies are rare, but adequate preparation is vital to ensuring smooth pharmacy operation and patient safety. In the autumn of 2019, the Pharmacy of Eastern Vaud Hospitals, composed of four units (Logistics, Manufacturing, Clinical Pharmacy, and Nursing Home Supply), was relocated to a new hospital in just a few days. In this context, a failure modes, effects and criticality analysis (FMECA) was carried out before the relocation in order to anticipate any failure modes likely to affect the pharmacy's missions or patient safety during the move. METHODS: The FMECA was performed by a multidisciplinary team (pharmacists and logisticians) which analysed the complete upcoming process of relocating the pharmacy and its implications. Criticality indices (CIs) were defined based on the matrix developed by Williams et al, which sets a maximum score of 810. Every potential failure mode identified was analysed, and mitigation measures were proposed for each one. RESULTS: The analysis identified 86 potential failures. The mean initial CI calculated for the entire pharmacy relocation was 177 (min 4-max 567), but this was estimated to be reduced to 39 (-78%) after mitigation measures were identified. Within the whole pharmacy, the failures with the highest CIs were identified in the Logistics unit. Among these, the time necessary to transfer the pharmacy's drugs from their traditional alphabetical storage location to their new location using robotic, chaotic storage principles was identified as the riskiest potential failure. Indeed, the rapid availability of emergency medicines would have to be guaranteed at all times. CONCLUSIONS: The present study highlighted the relevance of using an FMECA-type evaluation to anticipate the impact of a hospital pharmacy relocation. This tool enabled pharmacy professionals to structure their potential relocation problems and reflect on mitigation measures in order to provide concerted, realistically applicable solutions before the move.

Transition of care: A set of pharmaceutical interventions improves hospital discharge prescriptions from an internal medicine ward.

BACKGROUND: Continuity of care between hospitals and community pharmacies needs to be improved to ensure medication safety. This study aimed to evaluate whether a set of pharmaceutical interventions to prepare hospital discharge facilitates the transition of care. METHODS: This study took place in the internal medicine ward and in surrounding community pharmacies. The intervention group's patients underwent a set of pharmaceutical interventions during their hospital stay: medication reconciliation at admission, medication review, and discharge planning. The two groups were compared with regards to: number of community pharmacist interventions, time spent on discharge prescriptions, and number of treatment changes. RESULTS: Comparison between the groups showed a much lower (77% lower) number of community pharmacist interventions per discharge prescription in the intervention (n=54 patients) compared to the control group (n=64 patients): 6.9 versus 1.6 interventions, respectively (p<0.0001); less time working on discharge prescriptions; less interventions requiring a telephone call to a hospital physician. The number of medication changes at different steps was also significantly lower in the intervention group: 40% fewer (p<0.0001) changes between hospital admission and discharge, 66% fewer (p<0.0001) between hospital discharge and community pharmacy care, and 25% fewer (p=0.002) between community pharmacy care and care by a general practitioner. CONCLUSION: An intervention group underwent significantly fewer medication changes in subsequent steps in the transition of care after a set of interventions performed during their hospital stay. Community pharmacists had to perform fewer interventions on discharge prescriptions. Altogether, this improves continuity of care.

Prescription of Sedative Drugs During Hospital Stay: A Swiss Prospective Study.

BACKGROUND: In recent years, the number of prescriptions for sedative drugs has increased significantly, as has their long-term use. Moreover, sedative use is frequently initiated during hospital stays. OBJECTIVES: This study aimed to describe new prescriptions of sedative drugs during hospital stays and evaluate their maintenance as discharge medication. METHODS: This observational prospective study took place in an internal medicine ward of a Swiss hospital over a period of 3 months in 2014. Demographic (age, sex, diagnosis, comorbidities) and medication data [long-term use of sedative drugs, new regular or pro re nata ('as needed') prescriptions of sedative drugs, drug-related problems] were collected. Sedative medications included: benzodiazepines, Z-drugs, antihistamines, antidepressants, neuroleptics, herbal drugs, and clomethiazole. McNemar's test was used for comparison. RESULTS: Of 290 patients included, 212 (73%) were over 65 years old and 169 (58%) were women; 34% (n = 98) were using sedative drugs long term before their hospital stay, and 44% (n = 128) had a prescription for sedative drugs at discharge-a 10% increase (p < 0.05). Sedative drugs were newly prescribed to 37% (n = 108) of patients during their stay. Among these, 37% (n = 40) received a repeat prescription at discharge. Over half of the sedative drugs were prescribed within 24 h of admission. Drug-related problems were detected in 76% of new prescriptions, of which 90% were drug-drug interactions. CONCLUSION: This study showed that hospital stays increased the proportion of patients who were prescribed a sedative drug at discharge by 10% (absolute increase). These prescriptions may generate long-term use and expose patients to drug-related problems. Promoting alternative approaches for managing insomnia are recommended.

Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly lower with varenicline for a partial decrease (HR = 0.33, 95% CI [0.12, 0.89] and HR = 0.20, 95% CI [0.04, 0.91], respectively) and nonsignificantly lower for a total cessation (HR = 0.45, 95% CI [0.20, 1.0] and HR = 0.38, 95% CI [0.14, 1.0]). When compared with the normal metabolizers determined by phenotyping, the hazard ratio for a partial decrease was similar in the normal metabolizers determined by genotyping (HR = 0.42, 95% CI [0.18, 0.94]) while it was significantly lower with varenicline for a total cessation (HR = 0.50, 95% CI [0.26, 0.98]). Women and normal nicotine metabolizers may benefit more from varenicline over nicotine replacement therapy. (PsycINFO Database Record

Clinical pharmacist's role in implementing a smoking cessation intervention in a Swiss regional hospital: an exploratory study.

BACKGROUND: Smoking cessation represents one of the best means of preventing smoking-related complications. In recent years, a majority of hospitals have implemented smoke-free policies, making support for smoker patients a necessary and indispensable task. The clinical pharmacist is well-positioned to provide this kind of support, given a good understanding of the medical condition and pharmacotherapy of hospitalized patients and the possibility to acquire specific smoking cessation training. OBJECTIVES: This study aimed to evaluate the impact of a smoking cessation intervention for hospitalized patients by a clinical pharmacist previously trained for smoking cessation counselling. SETTING: Internal medicine department of a Swiss regional hospital. METHOD: Smoker patients hospitalized in this department were included in the study from mid-September 2012 to mid-January 2013, according to the inclusion criteria. Moderate-intensity smoking cessation interventions based on smoking counselling and motivational interviewing techniques were used, and a follow-up telephone call at least 1 month after discharge was made. Patients' pharmacotherapy was analysed with regards to interactions with tobacco smoke. MAIN OUTCOME MEASURES: Motivational stage, abstinence at follow-up, change of readiness to quit between hospital visit and follow-up, patients' evaluation of the programme, pharmacotherapy interventions. RESULTS: One hundred smoker patients were screened, of whom 41 received the intervention and 40 received a follow-up contact. At least 1 month after discharge, the readiness to quit of 53 % of patients improved and 33 % of patients declared themselves abstinent. Even though 35 % of patients declared having mild to moderate withdrawal symptoms in hospital, only 15 % were interested in receiving nicotine replacement therapy. Study participants evaluated the intervention positively. CONCLUSION: A moderate-intensity smoking cessation intervention in hospitalized patients was associated with a higher quit rate than in control groups from other studies, and their readiness to quit generally improved at least 1 month after hospital discharge. A clinical pharmacist trained for smoking cessation counselling can play a key role in providing such interventions, including the assessment of pharmacotherapy interactions with tobacco smoke.

Influence of CRTC1 polymorphisms on body mass index and fat mass in psychiatric patients and the general adult population.

IMPORTANCE: There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown. OBJECTIVE: To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population. DESIGN, SETTING, AND PARTICIPANTS: Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123,865). INTERVENTION: Noninterventional studies. MAIN OUTCOME AND MEASURE: Difference in BMI and/or fat mass between CRTC1 genotype groups. RESULTS: Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (P(adjusted) = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m² lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m² lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r² = 0.7) was associated with lower BMI (sample 5, n = 123,865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02). CONCLUSIONS AND RELEVANCE: These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry.

Simultaneous determination of antidementia drugs in human plasma: procedure transfer from HPLC-MS to UPLC-MS/MS.

A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([(2)H(7)]-donepezil, [(13)C,(2)H(3)]-galantamine, [(13)C(2),(2)H(6)]-memantine, [(2)H(6)]-rivastigmine) were extracted from 250 µL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1 mm × 50 mm; 1.7 µm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4 mL/min and an overall run time of 4.5 min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300 ng/mL for donepezil, galantamine and memantine, and 0.2-50 ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients' samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.

Quantification of nicotine, cotinine, trans-3'-hydroxycotinine and varenicline in human plasma by a sensitive and specific UPLC-tandem mass-spectrometry procedure for a clinical study on smoking cessation.

A sensitive and specific ultra performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of nicotine, its metabolites cotinine and trans-3'-hydroxycotinine and varenicline in human plasma was developed and validated. Sample preparation was realized by solid phase extraction of the target compounds and of the internal standards (nicotine-d4, cotinine-d3, trans-3'-hydroxycotinine-d3 and CP-533,633, a structural analog of varenicline) from 0.5 mL of plasma, using a mixed-mode cation exchange support. Chromatographic separations were performed on a hydrophilic interaction liquid chromatography column (HILIC BEH 2.1×100 mm, 1.7 µm). A gradient program was used, with a 10 mM ammonium formate buffer pH 3/acetonitrile mobile phase at a flow of 0.4 mL/min. The compounds were detected on a triple quadrupole mass spectrometer, operated with an electrospray interface in positive ionization mode and quantification was performed using multiple reaction monitoring. Matrix effects were quantitatively evaluated with success, with coefficients of variation inferior to 8%. The procedure was fully validated according to Food and Drug Administration guidelines and to Société Française des Sciences et Techniques Pharmaceutiques. The concentration range was 2-500 ng/mL for nicotine, 1-1000 ng/mL for cotinine, 2-1000 ng/mL for trans-3'-hydroxycotinine and 1-500 ng/mL for varenicline, according to levels usually measured in plasma. Trueness (86.2-113.6%), repeatability (1.9-12.3%) and intermediate precision (4.4-15.9%) were found to be satisfactory, as well as stability in plasma. The procedure was successfully used to quantify nicotine, its metabolites and varenicline in more than 400 plasma samples from participants in a clinical study on smoking cessation.

The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution.

IMPORTANCE OF THE FIELD: The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs. AREAS COVERED IN THIS REVIEW: A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution. WHAT THE READER WILL GAIN: Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure-activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier. TAKE HOME MESSAGE: The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.