Background
Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We ...investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.
Methods
The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.
Results
In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (
n
= 31) or 100 mg (
n
= 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (
n
= 227) or deferred treatment (
n
= 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.
Conclusion
Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection.
ClinicalTrials.gov identifier
NCT02203149.
Aims
Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion‐transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to ...OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters.
Methods
The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems.
Results
Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration–time curve were 5.7‐ and 7.6‐fold for pitavastatin and 4.4‐ and 3.3‐fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3.
Conclusions
The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
Coronavirus disease 2019 (COVID‐19) global pandemic is caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) viral infection, which can lead to pneumonia, lung injury, and death in ...susceptible populations. Understanding viral dynamics of SARS‐CoV‐2 is critical for development of effective treatments. An Immune‐Viral Dynamics Model (IVDM) is developed to describe SARS‐CoV‐2 viral dynamics and COVID‐19 disease progression. A dataset of 60 individual patients with COVID‐19 with clinical viral load (VL) and reported disease severity were assembled from literature. Viral infection and replication mechanisms of SARS‐CoV‐2, viral‐induced cell death, and time‐dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Disease severity are tested as a covariate to model parameters. The IVDM was fitted to the data and parameters were estimated using the nonlinear mixed‐effect model. The model can adequately describe individual viral dynamics profiles, with disease severity identified as a covariate on infected cell death rate. The modeling suggested that it takes about 32.6 days to reach 50% of maximum cell‐based immunity. Simulations based on virtual populations suggested a typical mild case reaches VL limit of detection (LOD) by 13 days with no treatment, a moderate case by 17 days, and a severe case by 41 days. Simulations were used to explore hypothetical treatments with different initiation time, disease severity, and drug effects to demonstrate the usefulness of such modeling in informing decisions. Overall, the IVDM modeling and simulation platform enables simulations for viral dynamics and treatment efficacy and can be used to aid in clinical pharmacokinetic/pharmacodynamic (PK/PD) and dose‐efficacy response analysis for COVID‐19 drug development.
Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the ...safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4‐part, open‐label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once‐daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24‐hour area under the concentration‐time curve of GZR was increased by approximately 15‐fold (geometric mean ratio 90%CI 15.21 12.83; 18.04); the concentration of EBR was increased approximately 2‐fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio 90%CI 1.43 1.24; 1.64). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.
Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density ...lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this ...unmet medical need, MK‐1654, a half‐life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo‐controlled, single‐site, double‐blind trial of MK‐1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK‐1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK‐1654 was generally well‐tolerated in Japanese adults. There were no serious drug‐related adverse events (AEs) reported in any MK‐1654 recipient and no discontinuations due to any AEs in the study. The half‐life of MK‐1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose‐dependent manner among participants who received MK‐1654. These data support the development of MK‐1654 for use in Japanese infants.
Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV ...infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary.
Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV NCT04086472. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population.
The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants.
An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.
Approximately 3.5 million children and adolescents worldwide are chronically infected with HCV. This study uses pharmacokinetic modeling to identify pediatric doses of elbasvir/grazoprevir (EBR/GZR) ...that achieve plasma concentrations similar to those seen in adults receiving the approved fixed-dose combination regimen of EBR/GZR.
We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to <18 years with chronic HCV genotype 1 or 4 infection (NCT03379506). Pharmacokinetic data were used to bridge efficacy and safety data from adults to children in a stepwise (oldest to youngest) manner. A total of 57 participants were enrolled: cohort 1 (aged 12 to <18 y), n=22; cohort 2 (aged 7 to <12 y), n=17; and cohort 3 (aged 3 to <7 y), n=18.
Steady-state plasma exposures were achieved by week 4 for EBR and GZR in all cohorts and daily dosing achieved geometric mean steady-state area under the concentration-time curve at 0-24 hours that fell within comparability bounds established for adults. All participants achieved sustained virologic response 12 weeks after completing treatment (ie, undetectable HCV RNA 12 wk following completion of treatment). Headache (n=4), fatigue (n=4), and nausea (n=2) were the most common treatment-related adverse events (all mild or moderate); no participant discontinued because of an adverse event.
Pediatric EBR/GZR pharmacokinetic models were successfully developed based on complex adult population pharmacokinetic models. At appropriate age-related doses, EBR/GZR is safe and effective in pediatric and adolescent participants with HCV infection.
Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. ...These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance‐associated substitutions. This post‐hoc analysis assessed 12‐week sustained viral response (SVR12) and pharmacokinetics of fixed‐dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self‐reported PPI use. Data were derived from six phase 3 EBR/GZR trials with treatment‐naive or treatment‐experienced genotype 1‐ or 4‐infected patients, with or without compensated cirrhosis. Baseline PPI use was defined as ≥7 consecutive days of use between study days –7 and 7. Bivariate analyses assessed PPI use and factors associated with SVR12 with sex, age (continuous and dichotomous), cirrhosis status, prior treatment status, baseline HCV RNA (continuous and dichotomous), HCV genotype, and baseline resistance‐associated substitutions as variables in the models. Overall, 12% (162/1,322) of EBR/GZR‐treated patients reported baseline PPI use. Of those, 96% achieved SVR12. In patients without PPI use, 97% achieved SVR12. PPI use was not a predictive factor in achieving SVR12 based on a univariate analysis (P = 0.188). In the bivariate models, none of the interaction terms involving PPI use were statistically significant. There was no significant effect of PPI usage, regardless of adjustment for considered factors. The estimated area under the curve and maximum concentration values for EBR were comparable among patients with and without reported PPI use. Conclusion: These results demonstrate that PPI use with EBR/GZR had no clinically significant effect on SVR12 rates in genotype 1/4‐infected patients with or without compensated cirrhosis. (clinicaltrials.gov identifiers: NCT02092350, NCT02105467, NCT02105662, NCT02105688, NCT02105701, NCT02358044) (Hepatology Communications 2017;1:757–764)
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