Clinical trial: seven-day vonoprazan- versus 14-day proton pump inhibitor-based triple therapy for first-line Helicobacter pylori eradication.

BACKGROUND: One-week triple therapy with vonoprazan is endorsed by Japanese guidelines as an alternative to proton pump inhibitor (PPI)-based triple therapy for first-line Helicobacter pylori eradication. This contrasts with Western guidelines recommending 2-week PPI-based triple therapy. AIM: To verify the non-inferiority of 1-week vonoprazan-based triple therapy versus 2-week PPI-based triple therapy as first-line H. pylori eradication in a multiracial Asian cohort. METHODS: Randomised controlled trial of treatment-naïve patients with H. pylori infection assigned 1:1 to either 7 days amoxicillin 1 g + clarithromycin 500 mg + vonoprazan 20 mg twice per day or 14 days amoxicillin 1 g + clarithromycin 500 mg + omeprazole OR esomeprazole OR rabeprazole 20 mg twice/day. Subjects were randomly assigned to each PPI 1:1:1 Demographics, H. pylori resistance, CYP 2C19 genotype, eradication success and safety profiles were compared between groups. RESULTS: Between June 2019 and June 2021, 252 of 1097 subjects screened were randomised. 244 (age [SD] 51.7 [14.6]) received vonoprazan- (n = 119) or PPI-based (n = 125) triple therapy. Eradication rates by intention-to-treat analysis were 87.4% (vonoprazan-based triple therapy) versus 88.0% (PPI-based triple therapy. By per protocol analysis: 96.3% (vonoprazan-based triple therapy) versus 94.0% (PPI-based triple therapy). Clarithromycin resistance predicted treatment failure on multivariate analysis: RR 11.4; 95% CI [1.4-96.3], p = 0.025. No significant differences in CYP 2C19 genotypes or adverse events occurred between groups. CONCLUSION: One-week vonoprazan-based triple therapy achieved comparable efficacy to 2-week PPI-based triple therapy and was well tolerated.

Evaluation of a six-probe cocktail (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam, and digoxin) approach to estimate hepatic drug detoxification capability and dosage requirements after a single oral dosing in healthy Chinese volunteers.

The primary objectives of this study were to investigate the suitability of a 6-probe cocktail (caffeine, tolbutamide, omeprazole, dextromethorphan, midazolam, and digoxin) to be used as a tool for assessing the activity of drug metabolizing enzymes and transporters, and examine differences in the way drugs are handled among groups with different genetic regulation of these processes. This was a single-center, open-label, phase I clinical study involving 20 young, healthy Chinese volunteers (equal gender distribution). The subjects were administered a single, oral dose of the 6-probe cocktail and serum samples were collected to assess the disposition of the different probe substrates and produced metabolites. The serum samples were analyzed using ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry technology. The DNA samples were subjected to whole exome sequencing. Nineteen healthy volunteers completed the study. The 6-probe cocktail was safe and well-tolerated by all the subjects. The parent substrates and metabolites-caffeine (paraxanthine), dextromethorphan (dextrorphan), digoxin, midazolam (1-hydroxy-midazolam), omeprazole (5-hydroxy-omeprazole), and tolbutamide (4-hydroxy-tolbutamide)-were within the detectable window. Genetic variations known to alter drug metabolism (CYP2D6*10, CYP2C19*2, CYP2C19*3, and CYP2C9*3) were identified and generally correlated with phenotypic status. The 6-probe cocktail appeared to be suitable for assessing drug metabolizing activities. This, in conjunction with individual genetics, will pave the way for the implementation of personalized medicine in clinical practice. This will hopefully improve efficacy and reduce the incidence of adverse drug reactions.

A pilot study to examine the association between human gut microbiota and the host's central obesity.

BACKGROUND AND AIM: Perturbance in the composition of human gut microbiota has been associated with metabolic disorders such as obesity, diabetes mellitus, and insulin resistance. The objectives of this study are to examine the effects of ethnicity, central obesity, and recorded dietary components on potentially influencing the human gut microbiome. We hypothesize that these factors have an influence on the composition of the gut microbiome. METHODS: Subjects of Chinese (n = 14), Malay (n = 10), and Indian (n = 11) ancestry, with a median age of 39 years (range: 22-70 years old), provided stool samples for gut microbiome profiling using 16S rRNA sequencing and completed a dietary questionnaire. The serum samples were assayed for a panel of biomarkers (interleukin-6, tumor necrosis factor alpha, adiponectin, cleaved cytokeratin 18, lipopolysaccharide-binding protein, and limulus amebocyte lysate). Central obesity was defined by waist circumference cut-off values for Asians. RESULTS: There were no significant differences in Shannon alpha diversity for ethnicity and central obesity and no associations between levels of inflammatory cytokines and obesity. The relative abundances of Anaerofilum (P = 0.02), Gemellaceae (P = 0.02), Streptococcaceae (P = 0.03), and Rikenellaceae (P = 0.04) were significantly lower in the obese group. From principle coordinate analysis, the effects of the intake of fiber and fat/saturated fat were in contrast with each other, with clustering of obese individuals leaning toward fiber. CONCLUSION: The study demonstrated that there were differences in the gut microbiome in obese individuals. Certain bacterial taxa were present in lower abundance in the group with central obesity. Fiber and fat/saturated fat diets were not the key determinants of central obesity.

Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We compared the effects of weight loss induced with the glucagon-like peptide-1 agonist liraglutide, with that of lifestyle modification, followed by weight maintenance after discontinuing intervention, in obese adults with non-alcoholic fatty liver disease (NAFLD). METHODS: Thirty obese (mean age 40.7 ± 9.1 years, BMI 33.2 ± 3.6 kg/m2 , 90% male) adults with NAFLD defined as liver fat fraction (LFF) > 5% on magnetic resonance imaging without other causes of hepatic steatosis were randomized to a supervised programme of energy restriction plus moderate-intensity exercise to induce ≥ 5% weight loss (DE group, n = 15), or liraglutide 3 mg daily (LI group, n = 15) for 26 weeks, followed by 26 weeks with only advice to prevent weight regain. RESULTS: Diet and exercise and LI groups had significant (P < 0.01) and similar reductions in weight (-3.5 ± 3.3 vs -3.0 ± 2.2 kg), LFF (-8.1 ± 13.2 vs -7.0 ± 7.1%), serum alanine aminotransferase (-39 ± 35 vs -26 ± 33 U/L) and caspase-cleaved cytokeratin-18 (cCK-18) (-206 ± 252 vs -130 ± 158 U/L) at 26 weeks. At 52 weeks, the LI group significantly (P < 0.05) regained weight (1.8 ± 2.1 kg), LFF (4.0 ± 5.3%) and cCK-18 (72 ± 126 U/L), whereas these were unchanged in the DE group. CONCLUSIONS: Liraglutide was effective for decreasing weight, hepatic steatosis and hepatocellular apoptosis in obese adults with NAFLD, but benefits were not sustained after discontinuation, in contrast with lifestyle modification. Continuing the exercise learned in the structured programme contributed to the maintenance of liver fat reduction.

Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults.

OBJECTIVES: Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions. METHODS: Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days. After a 14 day washout, subjects were switched over to rifampicin (600 mg)/isoniazid (300 mg) or rifampicin (600 mg) daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters and evaluate relationships between parameters and demographic factors, and metabolic enzyme, transporter and transcriptional regulator genotypes. Allometric scaling of clearance and volume of distribution terms based on body weight was applied. RESULTS: A one-compartment model in which absorption was described by a transit absorption model best described the rifampicin data. 25-Deacetyl-rifampicin pharmacokinetic data were best described by a two-compartment model linked to the rifampicin model. None of the investigated covariates significantly influenced the disposition of rifampicin and 25-deacetyl-rifampicin. The apparent clearance of rifampicin and 25-deacetyl-rifampicin was estimated at 10.3 [relative standard error (RSE) 5.6%] and 95.8 (RSE 10%) L/h, respectively, for 70 kg adults. CONCLUSIONS: The pharmacokinetics of rifampicin and its main metabolite were characterized. Prospective studies with a larger number of participants, including patients, are needed to validate the results of this study.

Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.

We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1-day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry. The population pharmacokinetic study was conducted using NONMEM. Demographics, clinical characteristics, and genetic polymorphisms were screened as covariates. A two-compartment model for MDZ and two sequential compartments representing 1OHM and HMG best described the data. The CYP3A5*3 and total bilirubin level significantly influenced MDZ clearance. The population typical MDZ clearance for CYP3A5*3 expressers was 22% lower than non-expressers. Baseline bodyweight was a statistically significant covariate for clearance and distribution volume of 1OHM. Creatinine clearance was positively correlated with HMG clearance. Our data indicate that CYP3A5*3, total bilirubin, bodyweight, and creatinine clearance are important predictors of MDZ and metabolite pharmacokinetics. Further studies in more patients are needed to explore the links between the identified covariates and the disposition of MDZ and its metabolites.

Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers.

Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir C(max), AUC(0-12), and AUC(0-∞) were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.

Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometric method.

Raltegravir is a highly efficacious inhibitor of HIV integrase. Large pharmacokinetic variability has been reported in clinical trials and this could be due to glucuronidation of raltegravir, the only reported metabolism pathway. In order to precisely evaluate and monitor the raltegravir and raltegravir glucuronide simultaneously, a novel, sensitive and robust liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of raltegravir and raltegravir glucuronide in human plasma. A simple protein precipitation with acetonitrile was utilized for plasma sample preparation prior to analysis. Baseline chromatographic separation was achieved on a ZORBAX Eclipse XDB-C8 using gradient elution mode. The run time was 9 min at a constant flow rate of 0.4 ml/min. The mass spectrometer was operated under a positive electrospray ionization condition. Excellent linearity (r(2) ≥ 0.9997) was achieved for raltegravir and raltegravir glucuronide in the range of 2-2000 nmol/l. The average recovery of raltegravir and raltegravir glucuronide was 105.8% and 102.2%, respectively. The precision (coefficient of variation) was 1.6-6.6% for raltegravir and 2.1-6.9 for raltegravir glucuronide, respectively. The accuracy was 98.6-106.1% for raltegravir and 96.3-100.3% for raltegravir glucuronide. The plasma samples were tested to be stable after nine freeze-thaw cycles and exposure to room temperature for 24 h. This well-validated assay was applied for the quantification of raltegravir and raltegravir glucuronide in plasma samples within 24 h after a single oral dose of 400 mg raltegravir in six healthy subjects.