Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3.

PURPOSE: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).

Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment.

AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

Pharmacokinetics of fingolimod and metabolites in subjects with severe renal impairment: An open-label, single-dose, parallel-group study.

OBJECTIVE: This study assessed the pharmacokinetics and tolerability of fingolimod and its metabolites in severe renal impairment and healthy subjects. METHODS: In this single-dose, open-label study, 9 severe renal impairment subjects and 9 demographically matched healthy subjects were included. Each subject received a single oral dose of fingolimod 1.25 mg, and their blood and urine samples were assessed. The pharmacokinetics of fingolimod and its metabolites, fingolimod-phosphate (active metabolite, fingolimod-P), M2, and M3, were compared in both groups. Safety and tolerability were also assessed. RESULTS: In severe renal impairment subjects, mean±standard deviation values of Cmax (ng/mL) of fingolimod and fingolimod-P were 0.878±0.256 and 1.13±0.293 vs. 0.653±0.138 and 0.904±0.229 in healthy subjects, respectively. The overall drug exposures (AUCinf (ngxh/mL)) for fingolimod and fingolimod-P were 131±90.7 and 75.5±33.6 in severe renal impairment subjects vs. 82.3±36.9 and 65.9±30.6 in healthy subjects, respectively. t1/2 (hours) for fingolimod and fingolimod-P was comparable in severe renal impairment subjects (94±53 and 95±50) and healthy subjects (85±25 and 101±46). All adverse events were as expected for fingolimod 1.25 mg. CONCLUSIONS: The exposure to fingolimod and fingolimod-P was moderately increased (90% CI, 0.94-2.18) in severe renal impairment subjects, while half-lives and protein binding were similar to those in healthy subjects. Given that these changes are not clinically meaningful, fingolimod dose adjustment is considered unnecessary in patients with mild, moderate, or severe renal impairment.

Efficacy and Acceptability of Indapamide Sustained Release in Elderly High-Risk Hypertensive Patients : the ARGUS Study.

OBJECTIVE: To assess the efficacy and acceptability of indapamide sustained-release (SR) monotherapy in elderly high-risk patients with moderate to severe hypertension. METHODS: 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91% with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male, diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) were enrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Blood pressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the χ(2) test, analysis of variance, and the Newman-Keuls test. RESULTS: After 3 months of treatment with indapamide SR, SBP had decreased by 34 ± 3 mmHg and diastolic BP (DBP) by 12 ± 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBP reduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets were reached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. There were no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia (<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% of patients reported 'excellent' health after treatment. CONCLUSIONS: In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showed antihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-month period. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriate first-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors.

Validation of TM-2655 oscillometric device for blood pressure measurement.

OBJECTIVE: To perform validation for an arm-type oscillometric TM-2655 device (A&D Company Ltd, Tokyo, Japan) for blood pressure measurement according to the British Hypertension Society protocol. METHODS: Eighty-five study participants (33 men and 52 women) were included in the study. Mean age was 52.9+/-15.0 years, systolic blood pressure range was 84-208 mmHg and diastolic blood pressure range was 48-120 mmHg. For each participant, three readings of TM-2655 were compared with sequential auscultatory measurements by two trained independent observers. The observers used a calibrated mercury sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. RESULTS: The average difference between mercury sphygmomanometer and TM-2655 readings for systolic blood pressure was -1.0+5.2 mmHg (mean+/-SD) and for diastolic blood pressure -0.9+/-4.7 mmHg. The proportions of values agreeing to within 5, 10 and 15 mmHg were 72.5, 93.7 and 99.6% for systolic blood pressure and 78.8, 96.9 and 100% for diastolic blood pressure between the observers and the device (A/A British Hypertension Society grade). CONCLUSIONS: The TM-2655 device achieved British Hypertension Society grade A/A and therefore can be recommended for blood pressure measurement in an adult population.

Validation of the TM-2564G device for in-hospital blood pressure measurement.

OBJECTIVE: To perform clinical validation of the TM-2564G device for in-hospital blood pressure measurement according to the British Hypertension Society protocol. METHODS: The tests were carried out on 85 patients aged 19-82 years (41 male patients, mean age 50+/-19 years) with systolic blood pressure 75-219 mmHg and diastolic blood pressure 43-117 mmHg (mean 142+/-33/85+/-20 mmHg). For each patient, three readings of the TM-2564G device were compared with simultaneous auscultatory measurements by two trained independent observers. The observers used a mercury-calibrated sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. RESULTS: The average difference was -1.85 mmHg for systolic blood pressure and -1.20 mmHg for diastolic blood pressure. The standard deviation of the difference between TM-2564G and the observers' results was 4.85 and 4.16 mmHg for systolic and diastolic blood pressures, respectively. Systolic blood pressure percentage of readings agreeing to within 5 mmHg was 75.7%, 10 mmHg 95.36% and 15 mmHg 99.6%, and for DBP 82.7, 97.6 and 99.8%, respectively. CONCLUSIONS: The TM-2564G device achieved A/A British Hypertension Society grade and can be recommended for in-hospital measurement of blood pressure.

Alcohol dehydrogenase ADH2-1 and ADH2-2 allelic isoforms in the Russian population correlate with type of alcoholic disease.

The frequency ADH2-2 allele in the Moscow urban population and a correlation between the ADH2-2 allele, alcoholic dependence without cirrhosis, symptomatic alcoholic cirrhosis and status on hepatitis B and C infection have been studied. One hundred and twenty-three inhabitants of Moscow (50 healthy donors, 36 patients with alcoholic cirrhosis (subdivided into infected and uninfected by HBV and/or HCV) and 37 patients with alcoholic dependence) of a similar age/sex and drinking pattern have been analysed. The frequency of 41% for ADH2-2 allele is characteristic for an urban Moscow population. This value is intermediate between that found for Asian peoples and for Central and Western Europe. There is a negative correlation between the ADH2-2 allele and alcohol misuse (both alcoholic dependence and alcoholic cirrhosis). This correlation is expressed more in alcoholic dependence. In spite of the possession of the ADH2-2 allele (or genotype ADH2-1/2), alcohol misuse increases the risk of cirrhosis. At the same time, positive status for active hepatitis B, C or combined infection B + C (replication markers HBV-DNA or HCV-RNA) increases the risk for symptomatic alcoholic cirrhosis in alcohol abusing patients, independently of ADH2 genotype.