A phase I, randomized, placebo-controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID-19.

Molnupiravir (MK-4482) is an oral prodrug of the antiviral ribonucleoside analog, N-hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well-tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax ), with a median time to Cmax (Tmax ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0-inf ), area under the concentration versus time curve from zero to 12 h (AUC0-12 ), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0-12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC-TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC-TP AUC0-12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0-inf was seen, supporting administration without regard to food.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults.

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.

The Bioequivalence and Effect of Food on the Pharmacokinetics of a Fixed-Dose Combination Tablet Containing Rosuvastatin and Ezetimibe in Healthy Japanese Subjects.

Certain patient populations are unable to achieve the recommended low-density lipoprotein cholesterol goals with statin monotherapy alone. Such patients may benefit from concomitant therapy with ezetimibe (EZE) 10 mg added on to a statin. To this end, fixed-dose combination (FDC) tablets containing EZE 10 mg and rosuvastatin (ROS) 2.5 mg (EZE/ROS2.5) and EZE 10 mg and ROS 5 mg (EZE/ROS5) have been developed for treatment of hypercholesterolemia. The purpose of the series of clinical studies reported herein was to evaluate the potential food effect (MK-0653H, protocol 836 (P836)) and the bioequivalence between FDC and co-administration of EZE and ROS in healthy Japanese subjects under fasted and fed conditions (MK-0653H, protocol 835 (P835) and MK-0653H, protocol 846 (P846), respectively). These studies show there is no clinically relevant food effect on EZE exposure following single oral administration of the FDC EZE/ROS5 in healthy Japanese subjects; however, ROS exposure was decreased in the fed state under conditions used to evaluate the maximum food effect. Following single oral administration of individual ROS tablets under the same conditions, the magnitude of decrease in ROS exposure was comparable to that seen with FDC, suggesting that the effect of food on ROS exposure was similar between the FDC tablet and co-administration of individual EZE and ROS tablets. The FDC EZE/ROS5 was generally well tolerated in healthy Japanese subjects under fasted and fed conditions.

Dynamic changes in three-dimensional architecture and vascular volume of transmural coronary microvasculature between diastolic- and systolic-arrested rat hearts.

BACKGROUND: The phase difference of coronary arterial and venous flows indicates the importance of intramyocardial capacitance vessels in storing diastolic flow and in discharging volume in systole. However, the anatomic and functional characteristics of the capacitance vessels are unclear. We aimed to clarify those characteristics with their transmural difference by 3D visualization of transmural microvessels under diastole and systole. METHODS AND RESULTS: We performed complete intracoronary filling of a contrast medium into Langendorff's Wistar rat hearts under (1) St Thomas-perfused diastolic arrest (D-mode) and (2) BaCl(2)-induced systolic arrest (S-mode). Precise transmural 3D architectures of capillaries and of pre- and post-capillary microvessels (ie, microvessels larger than capillaries) were visualized clearly with a confocal laser scanning microscope and x-ray microcomputed tomography (microCT), respectively. Vascular volume fraction (VF) and systolic-induced VF reduction rate from D- to S-mode were analyzed. The net capillary VF in D-mode (20.4 +/- 0.9%) was 10 times that of larger microvessels and was reduced in S-mode by 32% without capillary collapse. Systolic-induced VF reduction rate was smaller in capillaries than in larger microvessels (48%; P<0.05). The larger microvessel VF in D-mode (2.2 +/-0.2%) was reduced in S-mode, accompanied by complicated 3D deformation. CONCLUSIONS: Capillaries were relatively resistant to the systolic extravascular compression compared with pre- and post-capillary microvessels, conveniently beneficial for the myocardial oxygen delivery throughout a cardiac cycle. Nevertheless, a larger change in the absolute volume of capillaries may function as effective capacitance. On one hand, the pre- and post-capillary microvessels showed a larger phasic change in resistance, which may function to maintain the capillary patency during systole.

Comparison of pharmacokinetics of cyclosporine A in cadaveric and living-related renal transplant recipients and in an experimental rat model of renal failure.

To elucidate the differences in the cyclosporine A (CyA) PK between cadaveric and living-related renal transplantation (CRT and LRT, respectively) recipients, a retrospective cohort study of clinical PK was conducted. Data from 80 patients who received LRT (n=75) and CRT (n=5) over 4 years were included. The incidence of acute rejection in CRT recipients was over 5 times higher than that in LRT recipients. On day 14 after transplantation, the area under the blood concentration versus time curve (AUC) per dose up to 4 h in CRT recipients was 65.3 % that of LRT recipients, however, there was no difference in the blood trough levels. Unlike LRT, renal failure derived from long ischemia time was observed in CRT recipients, and it is speculated that renal failure affects the PK of CyA. Moreover, we performed intravenous. (i.v.) and intraduodenal (i.d.) PK studies of CyA using renal failure model rats prepared by renal ischemia-reperfusion (RIR rats). There were no differences in PK profiles after i.v. administration of CyA between RIR and control rats; however, AUC up to infinity (1.81+/-0.18 microg.h/ml) in RIR rats after i.d. administration was significantly lower than in control rats (5.01+/-1.78 microg.h/ml). In addition, the absorption of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in RIR rats was significantly less (69.8% and 42.8 %, respectively) than in control rats. These results suggest that the contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in RIR rats is significant, namely, there is a possibility that the reason for poor absorption of CyA in CRT recipients is increasing intestinal CYP3A activity is maybe renal injury derived from long renal ischemia. The results of this study provide a useful information for therapeutic drug monitoring of CyA in CRT recipients.

Relationship between excretion clearance of rhodamine 123 and P-glycoprotein (Pgp) expression induced by representative Pgp inducers.

P-Glycoprotein (Pgp) locates in several tissues in the living body and acts as an efflux pump for many drugs. In this study, the usefulness of intravenous rhodamine 123 (Rho123) administration as a marker for detecting the inducing effect of Pgp by drugs was identified, and the relationship between excretion clearances of Rho123 via Pgp and its expression during treatment with the representative Pgp inducers rifampicin (RFP), dexamethasone (DEX) and St. John's Wort (SJW) were examined in rat liver, intestine and kidney. After pretreatment with RFP (10 mg/kg/d) for 4 d, DEX (50 mg/kg/d) for 4 d or SJW (15 mg/kg/d) for 7 d orally, the biliary excretion of Rho123 after intravenous administration (0.2 mg/kg) increased significantly by 40%, 55% and 14%, respectively, and the intestinal excretion increased significantly by 24%, 50% and 27%, respectively, as compared with the controls. In contrast, there were no notable changes in the urinary excretion of Rho123 among rats that received these inducers. Western blot analysis with a monoclonal antibody for Pgp (C219) showed that Pgp levels in the small intestine and liver in the inducer-treated rats increased markedly as compared with the controls. In addition, there was a significant correlation between the induction levels of Pgp in the liver or small intestine and their clearance ratios (r2=0.7583, p<0.05), but not in the kidney. These observations suggest that the excretion clearances of Rho123 from blood circulation to the small intestine or to the bile after its intravenous administration are useful indicators to assess the Pgp function in the presence of Pgp inducers.

Heterogeneity of myocardial perfusion in distal coronary embolism with different particle sizes.

BACKGROUND: We hypothesized that altered myocardial perfusion distribution patterns could be seen with coronary distal emboli of different particle sizes using myocardial contrast echocardiography. METHODS: In 16 open-chest anesthetized dogs, microsphere suspensions of 9 or 500 microm in diameter were injected into the left anterior descending coronary artery until the mean left anterior descending coronary artery flow rate was reduced to less than 30% of baseline flow. During baseline conditions and after maximal embolization, real-time myocardial contrast echocardiography was performed by intravenous infusion of an echocontrast agent. RESULTS: In animals infused with 9-microm microspheres, a transmural perfusion defect was seen at the time of maximal embolization. In contrast, in animals infused with 500-microm microspheres, a subendocardial perfusion defect was observed. CONCLUSIONS: The particle size of coronary distal emboli affects myocardial perfusion distribution.

Effect of nicorandil, a K+ATP -channel opener, on coronary capillary architecture and volume after early myocardial ischemia-reperfusion--a 3-dimensional confocal laser microscopic study--.

BACKGROUND: Previous experimental and clinical studies have reported that nicorandil, an adenosine triphosphate (ATP)-sensitive K+ channel opener, exerts a beneficial effect on microvascular function and clinical outcome after myocardial ischemia. The present study assessed whether intravenous administration of nicorandil affects the 3-dimensional (3-D) architectural characteristics of capillaries and their volume after early myocardial reperfusion. METHODS AND RESULTS: Using the hearts of open-chest anesthetized rats, the left anterior descending artery was occluded for 7 min followed by reperfusion. Nicorandil or saline was infused intravenously during occlusion and reperfusion. The entire coronary microvasculature was filled with contrast medium after the hearts were arrested. Capillaries were observed 3-dimensionally by confocal laser scanning microscopy in both the control area and reperfused area of all samples. The capillary volume fraction was computed from the 3-D images. The reperfused area in both the nicorandil and saline groups showed characteristic architectural changes of the capillaries. Capillary volume fraction in the reperfused area was significantly reduced in saline group, compared with nicorandil group [12.7+/-7.2% vs 18.1 +/-5.3% (p<0.01)]. CONCLUSIONS: Intravenous nicorandil administration has a beneficial effect on capillary damage after reperfusion.

Three-dimensional microstructural abnormality of the coronary capillary network after myocardial reperfusion--comparison between 'reflow' and 'no-reflow'.

BACKGROUND: The 3-dimensional (D) structural abnormalities of the coronary capillary network and capillary volume changes after myocardial reperfusion were investigated using confocal laser scanning microscopy. METHODS AND RESULTS: Using open-chest anesthetized rats' hearts, the left anterior descending artery (LAD) was occluded for 7 min followed by reperfusion. The hearts were divided into 2 groups: (1) reperfused area stained well by intravenous indocyanine green after reperfusion (Reflow), and (2) lack of staining in the reperfused area (No-reflow). The entire coronary microvasculature was filled with contrast medium using a Langendorff's perfusion system. Capillaries were observed 3-dimensionally in the control and reperfused areas in both the Reflow and No-reflow group and the capillary volume fraction was computed from the 3-D images. The reperfused area in both groups showed decreased capillary diameter with waving and shrinkage configuration. In the No-reflow group, marked interruption of capillary network was observed. In the Reflow group the capillary volume fraction was significantly reduced in the reperfused area compared with the control area (14.8+/-4.1% vs 22.2+/-5.6%, p<0.05). Capillary volume fraction was further decreased in the No-reflow group compared with Reflow (5.3+/-1.4% vs 14.8+/-4.1%, p<0.01). CONCLUSION: The morphological changes in coronary capillaries after reperfusion were characterized by waving and shrinkage, which resulted in a reduction in capillary volume.