Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors.

Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366 .

Excretion stereoselectivity of triticonazole in rat urine and faeces.

The purpose of this study was to study the excretion stereoselectivity of triticonazole enantiomers in rat urine and faeces. Six male Sprague-Dawley (SD) rats were administrated 50 mg/kg rac-triticonazole. Rats urine and faeces were separately and quantitatively collected at the following intervals: 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 h. The faeces samples were homogenized in an aqueous solution containing 0.2% DMSO at the ratio of 1 g: 40 mL. An aliquot of 100 µL rats urine or faeces homogenate was spiked and mixed with 6.0 µL of 1.00 µg/mL flusilazole as an internal standard. The triticonazole enantiomers in urine and faeces were determined by using an HPLC/MS-MS after samples preparation. The excreted amounts of enantiomers in the urine showed a significant difference (P < 0.05) except for 3-6 h. The cumulative excretion rate (Xu0→24) in urine was 26.43 ± 0.08% and 37.58 ± 0.11% for R-(-)- and S-(+)-triticonazole, respectively, indicating high enantioselectivity (P < 0.001). The cumulative excretion rate (Xu0→72) in faeces was 6.93 ± 0.03% and 6.77 ± 0.03% for R-(-)- and S-(+)-triticonazole, respectively, without a difference. The results showed that the total cumulative percentage of triticonazole enantiomers accounted for in urine and faeces was 64.00 ± 0.13% and 13.70 ± 0.32%, the urinary excretion of R-(-)- and S-(+)-triticonazole were significantly different and S-(+)-triticonazole was preferentially excreted. However, the faecal excretion of the enantiomers showed no difference.

Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies.

AIMS: A population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient-specific and concurrent medication factors on pevonedistat PK. METHODS: Data were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed-effects modelling. The final model was evaluated using visual predictive checks and other goodness-of-fit criteria. RESULTS: A linear 2-compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK. CONCLUSIONS: The clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38-3 m2 ) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA-based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK.

Effect of CYP3A inhibitors on the pharmacokinetics of pevonedistat in patients with advanced solid tumours.

AIMS: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. METHODS: Patients received single doses of intravenous pevonedistat 8 mg m-2 , alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m-2 , alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre- and post-infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. RESULTS: The ratios of geometric mean area under the concentration-time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03-1.19) and 1.14 (33; 1.07-1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1-2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. CONCLUSIONS: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.

[Simultaneous determination of seven bioactive compounds and pharmacokinetics in rat plasma after oral administration of Yindan Xinnaotong Ruanjiaonang by UPLC-MS/MS].

To estabish ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of quercetin(QCT), isorhamnetin(ISR), kaempferol(KMF), ginkgolide A(GA), ginkgolide B(GB), ginkgolide C(GC) and bilobalide(BB) in rat plasma and investigate the pharmacokinetic process of seven compounds after oral administration of Yindan Xinnaotong Ruanjiaonang, The results indicated that all calibrations curves showed good linearity (r≥0.997 1). RSD of intra-day and inter-day precisions were all within 11%. The matrix effects and extraction recovery were in the range of 93.28%-103.6% and 72.43%-95.77% respectively. The peak concentration (Cmax) of QCT, ISR, KMF, GA, GB, GC and BB were (45.02±11.28), (49.90±13.82), (27.85±8.38), (76.31±18.19), (76.54±15.43), (35.35±10.28), (48.70±12.34) µg•L⁻¹, respectively. The peak time (tmax) of seven constituents were (0.33±0.11), (0.50±0.23), (0.33±0.14), (0.75±0.29), (1.0±0.35), (1.5±0.23), (0.75±0.50) h, respectively. UPLC-MS/MS method established in this research was proved to be so rapid and sensitive that it can be applied to the pharmacokinetic study of seven bioactive constituents in Yindan Xinnaotong Ruanjiaonang.

A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma.

Purpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50-278 mg/m(2) on schedule A; 11 patients received pevonedistat 157 mg/m(2) on schedule B. The schedule A MTD was 209 mg/m(2): dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10 h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5 months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.

Population pharmacokinetics of peramivir in healthy volunteers and influenza patients.

UNLABELLED: Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. SUBJECTS: Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

Influenza viral load and peramivir kinetics after single administration and proposal of regimens for peramivir administration against resistant variants.

We estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (Cmax) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

A Microfluidic Diffusion Cell for Fast and Easy Percutaneous Absorption Assays.

PURPOSE: Percutaneous absorption assays of molecules for pharmaceutical and cosmetology purposes are important to determine the bioavailability of new compounds, once topically applied. The current method of choice is to measure the rate of diffusion through excised human skin using a diffusion cell. This method however entails significant drawbacks such as scarce availability and poor reproducibility of the sample, low sampling rate, and tedious assay setup. METHODS: The objective of the present work is to propose an alternative method that overcomes these issues by integrating an experimental model of the skin (artificial stratum corneum) and online optical sensors into a microfluidic device. RESULTS: The measurement of the diffusion profile followed by the calculation of the permeability coefficients and time lag were performed on seven different molecules and obtained data positively fit with those available from literature on human skin penetration. The coating of the lipid mixture to generate the artificial stratum corneum also proved robust and reproducible. The results show that the proposed device is able to give fast, real-time, accurate, and reproducible data in a user-friendly manner, and can be produced at a large scale. CONCLUSION: These assets should help both the cosmetics and pharmaceutics fields where the skin is the target or a pathway of a formulated compound, by allowing more candidate molecules or formulations to be assessed during the various stages of their development.

Pharmacokinetics of peramivir after single intravenous doses in healthy Chinese subjects.

1.The aim of the study was to evaluate the pharmacokinetics of peramivir after single intravenous (i.v.) doses in healthy Chinese subjects. 2.In a cross-over study, 12 subjects were given 300 and 600 mg peramivir by i.v. infusion. Blood and urine samples were collected at 17 designated time points and 7 designated intervals up to 36 h post-dose. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. 3.After single i.v. doses of 300 and 600 mg peramivir, Cmax and AUC0-t of peramivir were 21.4 ± 3.7, 41.1 ± 5.3 mgcL(-1) and 55.90 ± 10.62, 112.1 ± 13.2 mgch L(-1), respectively. Cmax and AUC increased in proportion to the dose. Within 12 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 and 600 mg peramivir were 84.31 ± 11.75% and 88.10 ± 7.39%, respectively. 4.In healthy Chinese subjects, peramivir displayed linear pharmacokinetics in the range of 300-600 mg, and was primarily excreted via urine as unchanged drug.

[Absolute bioavailability of ginkgolide compounds in rats].

To investigate the pharmacokinetic characteristics and absolute bioavailability of ginkgolide A (GA), ginkgolide B (GB) and bilobalide (BB) in rats. In this experiment, a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/ MS) method was established to determine the plasma concentrations of GA, GB and BB in rats after rats were administrated with the three drugs through ig and iv respectively. The main pharmacokinetic parameters and absolute bioavailability of three ginkgolide compounds were obtained by using pharmacokinetic software DAS 2. 0. After the inject of GA, GB and BB, the results showed Cmax at (513.9 ± 116.9), (701.3 ± 76.0), (5,255.6 ± 476.8) µg · L(-1) and AUC0.24h of (960.9 ± 268.5), (779.5 ± 140.6), (7,409.3 ± 1,181.1) µg · h · L(-1), respectively; after the oral administration, the results showed Cmax at (522.9 ± 39.9), (146.8 ± 31.6), (2,711.9 ± 588.9) µg · L(-1) and AUC0-24 h of (1,760.4 ± 300.7), (636.6 ± 180.3), (16,651.4 ± 1,306.5) µg · h · L(-1), respectively. The absolute bioavailability of GA, GB and BB in rats was (61.1 ± 10.4)%, (27.2 ± 7.7)%, (56.2 ± 4.4)%, respectively. The method established in this experiment has a good specificity and sensitivity and so can be used to study the pharmacokinetics and absolute bioavailability of GA, GB and BB in rats.

Peramivir pharmacokinetics in a patient receiving continuous veno-venous hemodiafiltration during the 2009 H1N1 influenza A pandemic.

OBJECTIVE: Peramivir is a neuraminidase inhibitor having activity against various influenza A and B subtypes. The main route of elimination is the kidney and a dose reduction is justified for multiple-day therapy when the creatinine clearance is < 50 mL/min. Before the 2009 influenza pandemic, dosing guidelines did not exist for patients receiving continuous renal replacement therapy (CRRT). This case report provides data on the dialysis membrane saturation coefficient (SA) and pharmacokinetic parameters of peramivir in a 29-year-old female receiving continuous veno-venous hemodiafiltration (CVVHDF), a mode of CRRT. METHODS: Plasma and effluent samples were collected to calculate the saturation coefficient, plasma half-life, maximum and minimum plasma concentrations, and area under the plasma drug concentration-time curve (AUC) for peramivir. CVVHDF was performed using a Prisma pump and an AN69 filter. During peramivir sampling, the dialysate flow rate was 16.7 mL/min. The mean total ultrafiltrate produced was 14.2 mL/min. To calculate a saturation coefficient (SA), simultaneous sampling of blood and effluent was performed. Pre- and post-filter as well as effluent samples were obtained 4.5 and 8.5 hours following the 3rd dose of 480 mg. Plasma concentrations were also obtained at several time points and the AUC estimated from 0 to 24 hours (AUC0-24). RESULTS: The maximum plasma concentration (C30min) was 19,477 ng/mL, the minimum plasma concentration (Cmin) 2,750 ng/mL, and AUC0-24 196,166 ng x h/mL. The estimated plasma half-life was 8.2 hours with a log-linear decrease over the 24-hour period suggesting significant extracorporeal clearance. The calculated SA was 0.98, similar to an estimated SA of 1. CONCLUSION: Peramivir is readily cleared by CVVHDF having a calculated SA close to 1. The maximum and minimum plasma concentrations, AUC0-24, and plasma half-life was similar to those previously reported. These data will be useful in determining appropriate peramivir dosing regimens for severely ill influenza patients with acute renal impairment managed by CVVHDF.

Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza A virus infection.

Peramivir is a new neuraminidase inhibitor for intravenous administration that was first introduced in clinical practice in Japan. We conducted a multicenter, open-label, uncontrolled study in children with influenza virus infection ranging in age from ≥28 days to <16 years during the 2009 pandemic A (H1N1) influenza epidemic to evaluate the efficacy, safety, and pharmacokinetics of peramivir in children after intravenous infusion of 10 mg/kg (600 mg maximum) once daily. Among the 106 children (125 days to 15 years old) confirmed to have been infected with the pH1N1 virus by the PCR who were treated with peramivir, the median time to alleviation of symptoms was 29.1 h (95% confidence interval = 22.1 to 32.4), and the proportion of the 106 children who were virus positive was 78.2% on day 2 after the start of treatment and had decreased to 7.1% on day 6. The results of the safety evaluation among 117 patients enrolled in this study showed that adverse events and adverse drug reactions were reported in 62.4 and 29.1%, respectively, of the patients. All of the adverse events and adverse drug reactions resolved or improved rapidly. A population pharmacokinetic analysis was performed on the basis of 297 observed plasma concentration data obtained from 115 children with influenza virus infection. Peramivir exposure in children was within the range of levels within which the efficacy and safety was confirmed in adults, and it is considered that peramivir is clinically and virologically effective and safe in children with pH1N1 virus infection.

Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine.

Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10-44 mg/m2, with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m2 for co-administration with azacitidine 75 mg/m2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients.Trial registration: clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468.

Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients.

Influenza virus infections are known to persist longer in patients with underlying diseases, including respiratory tract diseases, and tend to become complicated by secondary influenza-associated infections, such as pneumonia. To assess the efficacy and safety of the novel anti-influenza virus drug peramivir in high-risk patients, we conducted a clinical trial of patients with diabetes or chronic respiratory tract diseases and patients being treated with drugs that suppress immune function. In this multicenter, uncontrolled, randomized, double-blind study, peramivir was intravenously administered at 300 or 600 mg/day for 1 to 5 days, as needed. Efficacy was investigated in 37 patients (300 mg, n = 18 patients; 600 mg, n = 19 patients). The median durations of influenza illness were 68.6 h (90% confidence interval, 41.5 to 113.4 h) overall, 114.4 h (90% confidence interval, 40.2 to 235.3 h) in the 300-mg group, and 42.3 h (90% confidence interval, 30.0 to 82.7 h) in the 600-mg group. The hazard ratio for the 600-mg group compared to the 300-mg group was 0.497 (90% confidence interval, 0.251 to 0.984), and the duration of influenza illness was significantly shorter in the 600-mg group than in the 300-mg group. Among the 42 patients in the safety analysis set, adverse events occurred in 73.8% and adverse drug reactions in 33.3%. No adverse events were particularly problematic clinically, and all patients recovered quickly from all events. The measured blood drug concentrations showed no tendency toward accumulation. Drug accumulation with repeated doses was thus considered to be of little concern. Intravenous peramivir appears to offer a potentially useful treatment for high-risk patients in the future.

Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration.

OBJECTIVE: To report a sieving coefficient for peramivir in a patient receiving continuous venovenous hemofiltration (CVVH). CASE SUMMARY: An 18-year-old male presented with chills, myalgias, and dyspnea and was hospitalized. Nasal secretions were positive for influenza by rapid antigen test at an outside facility and oseltamivir was commenced. Oral absorption was predicted to be unreliable, and intravenous peramivir was accessed as an emergency investigational new drug applicaiton (eIND). CVVH was initiated after the development of acute renal failure, with blood samples collected to determine peramivir concentrations. DISCUSSION: Peramivir, an intravenous investigational neuraminidase inhibitor with activity against influenza viruses, has limited data for dosing in the setting of CVVH. A single patient received 600 mg of peramivir intravenously and had blood and ultrafiltrate concentrations measured serially. A sieving coefficient of approximately 0.9 was identified. CONCLUSIONS: Peramivir is well cleared by CVVH, and drug exposure is potentially predictable based on flow rates. Further study is necessary.

ADMET profile and virtual screening of plant and microbial natural metabolites as SARS-CoV-2 S1 glycoprotein receptor binding domain and main protease inhibitors.

In an attempt to search for selective inhibitors against the SARS-CoV-2 which caused devastating of lives and livelihoods across the globe, 415 natural metabolites isolated from several plants, fungi and bacteria, belonging to different classes, were investigated. The drug metabolism and safety profiles were computed in silico and the results showed seven compounds namely fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxin B and D, and stagonolide K were predicted to having considerable absorption, metabolism, distribution and excretion parameters (ADME) and safety indices. Molecular docking against the receptor binding domain (RBD) of spike glycoprotein (S1) and the main protease (Mpro) exposed the compounds having better binding affinity to main protease as compared to the S1 receptor binding domain. The docking results were compared to an antiviral drug penciclovir reportedly of clinical significance in treating the SARS-CoV-2 infected patients. The results demonstrated the test compounds jasmonic acid, putaminoxins B and D bound to the HIS-CYS catalytic dyad as well as to other residues within the MPro active site with much greater affinity than penciclovir. The findings of the study suggest that these compounds could be explored as potential SARS-CoV-2 inhibitors, and could further be combined with the experimental investigations to develop effective therapeutics to deal with the present pandemic.

The CUL3/neddylation inhibitor MLN4924 reduces ethanol-induced locomotor sensitization and inflammatory pain allodynia in mice.

Heterologous sensitization of adenylyl cyclase (AC) is defined by an enhanced cAMP response following persistent activation of Gαi/o-coupled receptors. This phenomenon was first observed in cellular models, and later reported in animal models of inflammatory pain or following chronic exposure to drugs of abuse including opioids and cocaine. Recently, we used genome-wide siRNA screening to identify Cullin3 signaling as a mediator of AC sensitization in cellular models. We also showed that pharmacological inhibition of Cullin3 with the neddylation inhibitor, MLN4924, abolished heterologous sensitization of several AC isoforms, including AC1, AC2, AC5, and AC6. Because ACs, especially AC1, have been implicated in alcohol-induced locomotor sensitization and inflammatory pain, we assessed the potential activity of MLN4924 in both murine models. We found that MLN4924 (30 mg/kg, i.p.) accumulated in the brain and reduced both locomotor sensitization induced by repeated alcohol administration and allodynia in an inflammatory pain model. Based on our previous findings that MLN4924 potently blocks AC sensitization in cellular models, we propose that the activity of MLN4924 in both animal models potentially occurs through blocking AC sensitization. Our findings provide the basis for understanding the molecular mechanism and yield a new pathway for drug development for pathological disorders associated with AC sensitization.

Enhanced anti-amnestic effect of donepezil by Ginkgo biloba extract (EGb 761) via further improvement in pro-cholinergic and antioxidative activities.

ETHNOPHARMACOLOGICAL RELEVANCE: EGb 761 is a standardized dry extract of Ginkgo biloba L. leaves traditionally used by Eastern Asia and has been associated with beneficial effects on neurodegeneration disorders, including Alzheimer's disease. AIM OF THE STUDY: Since beneficial interactions between EGb 761 and donepezil have been observed in previous clinical studies, the current study was proposed aiming to further explore related mechanisms from both pharmacokinetics and pharmacodynamics aspects. MATERIALS AND METHODS: Pharmacodynamic interactions were studied in scopolamine-induced cognitive impairment rats received two-weeks treatment of vehicle, EGb 761 and/or donepezil by the Morris water maze test and ex vivo evaluation of biomarkers of cholinergic transmission and oxidative stress in rat brain. In the meantime, pharmacokinetic profiles of donepezil and bilobalide were obtained and compared among all treatment groups. In addition, impact of the bioavailable EGb 761 components on donepezil brain penetration was evaluated with the hCMEC/D3 cell monolayer model. RESULTS: Scopolamine-induced rats with co-treatment of EGb 761 and donepezil had significantly improved cognitive function in the Morris water maze test with increased brain levels of superoxide dismutase and decreased brain levels of acetylcholinesterase and malondialdehyde than that with treatment of only EGb 761 or donepezil. Despite such beneficial pharmacodynamics outcomes, the two-week co-treatment of EGb 761 and donepezil did not alter the plasma pharmacokinetics and brain uptake of donepezil or bilobalide, which was further verified in the hCMEC/D3 monolayer model. CONCLUSION: Co-administration of EGb 761 and donepezil exerted better anti-amnestic effect via further enhanced pro-cholinergic and antioxidative effects of EGb 761 or donepezil in scopolamine-induced cognitive impairment rat without alteration in their systemic/brain exposure.