Explore the vast range of titles available.

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

Background and Objective The identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). Methods The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [ C max ]) was used to assess pharmacokinetic interactions. Results Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. Conclusion Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

Background Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1. Results There were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C max ) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the C max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Background Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients. Methods This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid. Discussion This study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort. Trial registration ClinicalTrials.gov , ID: NCT03982277 . Registered retrospectively on 11 June 2019.

Background and objective Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. Methods Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration ( C max ) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction. Results A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC 0–∞ and C max fell outside our acceptance criteria of 0.70–1.43. Conclusions Although TAF AUC and C max 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.

[11C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test–retest variability of cerebral [11C]Cimbi-36 PET and compare [11C]Cimbi-36 and the 5-HT2A receptor antagonist [18F]altanserin. Sixteen healthy volunteers (mean age 23.9±6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [11C]Cimbi-36; eight were scanned twice to determine test–retest variability in [11C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [18F]altanserin. Regional differences in the brain distribution of [11C]Cimbi-36 and [18F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. Test–retest variability of [11C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [11C]Cimbi-36 and [18F]altanserin (mean Pearson's r: 0.95±0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [11C]Cimbi-36 as compared to [18F]altanserin was found in the choroid plexus and hippocampus in the human brain. Excellent test–retest reproducibility highlights the potential of [11C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [11C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors. •[11C]Cimbi-36 demonstrated excellent reproducibility as a 5-HT2A receptor agonist PET radioligand in healthy volunteers.•In vivo binding of [11C]Cimbi-36 and [18F]altanserin was highly correlated demonstrating that they both image 5-HT2A receptors in the human brain•In choroid plexus and hippocampus, [11C]Cimbi-36 binding exceeded [18F]altanserin binding suggesting high density of 5-HT2C receptors here.•[11C]Cimbi-36 may be used to detect both 5-HT2A and 5-HT2C receptor binding in the human brain

Background. Boceprevir represents a new treatment option for hepatitis C (HCV)—infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs. Methods. A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10–31, plus concomitant boceprevir on days 25–31. Results. Boceprevir decreased the exposure of all PI/r, with area under the concentration—time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55–.78) for ATV/r; 0.66 (90% CI, .60–.72) for LPV/r, and 0.56 (90% CI, .51–.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUCτ) by 22%–36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUCτ was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events. Conclusions. Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug—drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.

Purpose To evaluate the plasma bioavailability of betanin and nitric oxide (NOx) after consuming beetroot juice (BTJ) and whole beetroot (BF). BTJ and BF were also analysed for antioxidant capacity, polyphenol content (TPC) and betalain content. Methods Ten healthy males consumed either 250 ml of BTJ, 300 g of BF or a placebo drink, in a randomised, crossover design. Venous plasma samples were collected pre (baseline), 1, 2, 3, 5 and 8 h post-ingestion. Betanin content in BTJ, BF and plasma was analysed with reverse-phase high-performance liquid chromatography (HPLC) and mass spectrometry detection (LCMS). Antioxidant capacity was estimated using the Trolox equivalent antioxidant capacity (TEAC) and polyphenol content using Folin–Ciocalteu colorimetric methods [gallic acid equivalents (GAE)] and betalain content spectrophotometrically. Results TEAC was 11.4 ± 0.2 mmol/L for BTJ and 3.4 ± 0.4 μmol/g for BF. Both BTJ and BF contained a number of polyphenols (1606.9 ± 151 mg/GAE/L and 1.67 ± 0.1 mg/GAE/g, respectively), betacyanins (68.2 ± 0.4 mg/betanin equivalents/L and 19.6 ± 0.6 mg/betanin equivalents/100 g, respectively) and betaxanthins (41.7 ± 0.7 mg/indicaxanthin equivalents/L and 7.5 ± 0.2 mg/indicaxanthin equivalents/100 g, respectively). Despite high betanin contents in both BTJ (~194 mg) and BF (~66 mg), betanin could not be detected in the plasma at any time point post-ingestion. Plasma NOx was elevated above baseline for 8 h after consuming BTJ and 5 h after BF ( P  < 0.05). Conclusions These data reveal that BTJ and BF are rich in phytonutrients and may provide a useful means of increasing plasma NOx bioavailability. However, betanin, the major betalain in beetroot, showed poor bioavailability in plasma.

•Venetoclax plus chemotherapy is an approved therapy in adult R/R AML patients.•Venetoclax demonstrated robust efficacy in pediatric AML in early clinical trials.•Identification of venetoclax dosing regimens in pediatric patients is needed.•Venetoclax age and weight-based dosing for pediatric patients is described herein.•The pediatric dosing scheme is projected to achieve exposures comparable to those observed in adults at 400 mg and 600 mg. This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0–6; 78·7 mg.h/L [95% CI 71·0–87·3] vs 26·0 mg.h/L [19·0–35·6]), maximum plasma concentrations (Cmax; 22·1 mg/L [19·9–24·6] vs 6·3 mg/L [4·9–8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46–0·78] vs 0·21 mg/L [0·16–0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0–6 (31·5 mg.h/L [24·1–41·1] vs 15·1 mg.h/L [12·8–17·7]), Cmax (7·4 mg/L [5·6–9·6] vs 3·9 mg/L [3·2–4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81–3·27] vs 1·52 mg/L [1·28–1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20–0·91; p=0·03). These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.