Maximum Blood Concentration Research Articles

Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study

SummaryBackgroundM5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers.MethodsThis first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18–55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401).FindingsBetween Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50–1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1–7 h after dosing, and a long half-life was observed (146–193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35–55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg).InterpretationThe safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis.FundingWellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.

A New Perspective on Cancer Therapy: Changing the Treaded Path?

During the last decade, we have persistently addressed the question, “how can the innate immune system be used as a therapeutic tool to eliminate cancer?” A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.

Ecological risk assessment of heavy metal chromium in a contaminated pastureland area in the Central Punjab, Pakistan: soils vs plants vs ruminants.

Grazing animals act as a bioindicator to study the heavy metal status in the pasture lands because excessive amount of toxic metals in the animal diet either disturb their normal activity or deposit the contaminants into their tissues. The aim of this study was to appraise the chromium status in soil and pasture crops with respect to the nutritional requirement of grazing animals. Three different sites were selected to collect soil, forages, and animal samples from District Jhang. All the samples were processed through atomic absorption spectrophotometer to analyze the chromium concentration in them. Chromium concentration was varied as 0.703-4.20 mg/kg in soil, 0.45-2.85 mg/kg in forages, and 0.588-2.37 mg/kg in all collected animal samples. Both the soil and forage samples displayed the maximum chromium concentration in the Capparis decidua, whereas animal samples revealed maximum concentration in animal blood. Results of pollution load index (0.078 to 0.463 mg/kg) exhibited that all the sample values are less than unity while enrichment factor (1.57-8.25mg/kg) showed that significant level of chromium is enriched in these sites. The maximum value of daily intake (0.0007-0.0055mg/kg/day) and health risk index (0.0004-0.00370055mg/kg/day) was observed in the buffalo that feed on the Capparis decidua. Bio-concentration factor (0.398-2.09mg/kg) value was the maximum in the Medicago sativa. It is concluded that all the animal samples showed chromium concentration beyond their standards. Thus, proper measures should be taken to reduce the metal contamination in these areas that ultimately lessen the availability of toxic metals to grazing animals.

BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells

Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.

Human metabolism and kinetics of the UV absorber 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) after oral administration

2-(2H-Benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328; CAS: 25973-55-1) is an ultraviolet light (UV) absorber which belongs to the class of hydroxy phenol benzotriazoles. Therefore, UV 328 is added to plastics and other polymers due to its photostability to prevent discoloration and prolong product stability which may result in an exposure of consumers. However, information about the toxic effects on humans and the human metabolism are still lacking. In the present study, human metabolism pathways of UV 328 and its elimination kinetics were explored. For that purpose, three healthy volunteers were orally exposed to a single dose of 0.3 mg UV 328/kg bodyweight. UV 328 and its metabolites were investigated in blood and urine samples collected until 48 and 72 h after exposure, respectively. Thereby, previously published analytical procedures were applied for the sample analysis using dispersive liquid–liquid microextraction and subsequent measurement via gas chromatography coupled to tandem mass spectrometry with advanced electron ionization. UV 328 was found to be oxidized at its alkyl side chains leading to the formation of hydroxy and/or oxo function with maximum blood concentrations at 8–10 h after exposure for UV 328-6/3-OH, UV 328-4/3-OH and UV 328-4/3-CO. In contrast, a plateau for UV 328-4/3-CO-6/3-OH levels was reached around 10 h post-dosage. The highest blood levels were found for native UV 328 at 8 h after ingestion. Furthermore, biphasic elimination kinetics in blood were revealed for almost all detected metabolites. UV 328 and its metabolites did not occur in blood as conjugates. The renal elimination kinetics were very similar with the kinetics in blood. However, the prominence of the metabolites in urine was somewhat different compared to blood. In contrast, mostly conjugated metabolites occurred for renal elimination. In urine, UV 328-4/3-CO-6/3-OH was found to be the most dominant urinary biomarker followed by UV 328-6/3-OH and UV 328-4/3-OH. In total, approximately 0.1% of the orally administered dose was recovered in urine within 72 h. Although high levels of UV 328 in blood proved good resorption and high systemic availability of the substance in the human body, the urine results revealed a rather low quantitative metabolism and urinary excretion rate. Consequently, biliary excretion as part of the enterohepatic cycle and elimination via feces are assumed to be the preferred pathways instead of renal elimination.

Pharmacokinetics and Safety of a Bilastine Once-Daily, Preservative-Free, Ophthalmic Formulation.

IntroductionBilastine is a second-generation H1 antihistamine indicated for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. On the basis of the demonstrated efficacy and safety of the oral formulation, a new ophthalmic formulation of bilastine was recently developed. Previous preclinical studies had indicated that bilastine is mainly absorbed by the conjunctiva and shows low plasma concentration. The objective of this study was to evaluate the pharmacokinetics and safety of ophthalmic bilastine (6 mg/mL) after single and multiple dose administration at steady state in healthy adults.MethodsThis was an open-label, single-centre, phase I, bioavailability clinical trial. One drop of the bilastine ophthalmic formulation was administered once daily in each eye of the subjects for 5 days. Bilastine plasma concentrations were measured by HPLC–MS/MS. Adverse drug reactions were recorded for each subject during drug administration and follow-up visits.ResultsTwelve healthy subjects (age 18–55 years) were included in the study. After multiple dose administration, bilastine reached a mean (± SD) maximum blood concentrations of 2682.26 ± 1615.88 pg/mL at a median time of 2.50 h (range 1.25–4.00 h). The half-life of bilastine in plasma was 7.88 ± 6.72 h. Steady state AUC was 19,512.51 ± 9248.76 h·pg/mL. Adverse events were mild and transient, consisting mainly of dysgeusia.ConclusionsBilastine once-daily ophthalmic formulation 6 mg/mL is absorbed into the bloodstream in low amounts by the ophthalmic route. The bilastine ophthalmic formulation showed a good safety profile after multiple dose administration.

The Effect of Single-Dose Ougan Juice Application on the Pharmacokinetics of Erlotinib.

The aim of our study was to investigate the effects of single-dose Ougan (Citrus reticulata cv. Suavissima) juice application on the pharmacokinetics of erlotinib in vivo. Twelve Sprague-Dawley rats were randomly divided into the Ougan juice and control groups (n = 6 each). The rats were given a single dose of 1 mL/100 g Ougan juice or 1 mL/100 g normal saline (NS) by intragastric administration, followed by a single oral administration of 20 mg/kg erlotinib. The plasma concentration of erlotinib in rats was determined using ultra performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Erlotinib-d6 was used as the internal standard for chromatographic analysis on the UPLC BEH C18 analysis column (2.1 mm × 50 mm, 1.7 μm). The mobile phase was composed of acetonitrile and 0.1% formic acid eluting by gradient. Different pharmacokinetic (PK) parameters of erlotinib were calculated. The Ougan juice promoted the absorption of erlotinib and reduced the clearance of the drug. The area under the curve of erlotinib in the single-dose Ougan juice pretreatment group was approximately 1.87 times higher, and the maximum blood concentration (Cmax) was approximately 1.34 times higher than that in the control group. The mean residence time of erlotinib in the Ougan juice group was larger, and the clearance rate was smaller than those in the control group; the difference was statistically significant (P < 0.05). Ougan juice affected the PK spectrum of erlotinib in rats by improving the bioavailability of the drug and significantly increasing its plasma concentration.

Consistency evaluation of Chaihuang granules based on pharmacokinetics and metabolomics

Consistency evaluation of Traditional Chinese Medicinal preparations (TCMPs) with complex chemical composition is challenging. Chaihuang granules (CHG), as a well-known TCMP, consists of Chaihu (Bupleuri Radix) and Huangqin (Scutellariae Radix) extract. In this work, we used pharmacokinetics and metabolomics to evaluate consistency of CHG products from two different manufacturers. In the pharmacokinetic study, a liquid chromatography tandem mass spectrometry (LC–MS/MS) method was applied to determine the plasma concentration-time profiles of baicalin in rat plasma. Pharmacokinetic parameters, including the maximum concentration in blood (Cmax), area under the curve (AUC), the time to reach Cmax (Tmax), and half-life (T1/2), were calculated to assess the consistency preliminarily. And there was no significant difference in these pharmacokinetic parameters between the two CHG. In LC–MS-based metabolomics, the metabolic response profiles changes based on relative distance values (RDV) to different CHG products were compared. Meanwhile, the kinetic process of 31 differential endogenous metabolites that altered by CHG were determined. Metabolomics data showed the similar metabolic regulation effects to rats of the two formulations. Both pharmacokinetic and metabolomics results indicated there was no significant difference between CHG products. Furthermore, metabolic pathways significantly altered by CHG were elucidated, including phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, and sphingolipid metabolism. Pharmacokinetics combined with metabolomics could provide a comprehensive perspective for consistency evaluation of CHG.

Toxicokinetic evaluation of the common indoor air pollutant, α-pinene, and its potential reactive metabolite, α-pinene oxide, following inhalation exposure in rodents

The toxicokinetic behavior of α-pinene and its potential reactive metabolite, α-pinene oxide, was investigated following whole body inhalation exposure to 50 and 100 ppm α-pinene in rats and mice for 6 h per day for 7d. In both species and sexes, the maximum blood concentration (Cmax) increased more than proportionally while the increase in area under the concentration time curve (AUC) was proportional to the exposure concentration. When normalized to the calculated dose (D), both Cmax/D (male rats, 12.2–54.5; female rats, 17.4–74.1; male mice, 7.41–14.2; female mice, 6.59–13.0 (ng/mL)/(mg/kg)) and AUC/D (male rats, 28.9–31.1; female rats, 55.8–56.8; male mice, 18.1–19.4; female mice, 19.2–22.5 (h*ng/mL)/(mg/kg)) in rats were higher than in mice and in female rats were higher than in male rats; no sex difference was observed in mice. α-Pinene was eliminated from blood with half-lives between 12.2 and 17.4 h in rats and 6.18–19.4 h in mice. At the low dose, the ratio of α-pinene oxide to α-pinene, based on Cmax and AUC, respectively, was 0.200–0.237 and 0.279–0.615 in rats and 0.060–0.086 and 0.036–0.011 in mice demonstrating lower formation of the oxide in mice than in rats. At the high dose, the ratio decreased considerably in both species pointing to saturation of pathways leading to the formation of α-pinene oxide. α-Pinene and the oxide were quantified in the mammary glands of rats and mice with tissue to blood ratios of ≥23 demonstrating retention of these analytes in mammary glands. The findings of epoxide formation and species- and sex-differences in systemic exposure may be important in providing context and relating animal findings to human exposures.

Effect of Surface Property on the Release and Oral Absorption of Solid Sirolimus-Containing Self-microemulsifying Drug Delivery System.

The combination of self-microemulsifying drug delivery system (SMEDDS) and mesoporous silica materials favors the oral delivery of poorly water-soluble drugs (PWSD). However, the influence of the surface property of the mesopores towards the drug release and in vivo pharmacokinetics is still unknown. In this study, SBA-15 with hydroxyl groups (SBA-15-H), methyl groups (SBA-15-M), amino groups (SBA-15-A), or carboxyl groups (SBA-15-C) was combined with SMEDDS containing sirolimus (SRL). The diffusion and self-emulsifying of SMEDDS greatly improved the drug release over the raw SRL and SRL-SBA-15-R (R referred to as the functional groups). Results of drug absorption and X-ray photoelectron spectroscopy (XPS) showed strong hydrogen binding between SRL and the amino groups of SBA-15-A, which hindered the drug release and oral bioavailability of SRL-SMEDDS-SBA-15-A. The favorable release of SRL-SMEDDS-SBA-15-C (91.31 ± 0.57%) and SRL-SMEDDS-SBA-15-M (91.76 ± 3.72%) contributed to enhancing the maximum blood concentration (Cmax) and the area under the concentration-time curve (AUC0→48). In conclusion, the release of SRL-SMEDDS-SBA-15-R was determined by the surface affinity of the SBA-15-R and the interaction between the SRL molecules and the surface of SBA-15-R. This study suggested that the SMEDDS-SBA-15 was a favorable carrier for PWSD, and the surface property of the mesopores should be considered for the optimization of the SMEDDS-SBA-15.

Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.

The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1/2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1/2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.

Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users

BackgroundSmoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. Methods24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 μg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. ResultsMaximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). ConclusionIn accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.

A novel treatment strategy using continuous local antibiotic perfusion: A case series study of a refractory infection caused by hypervirulent Klebsiella pneumoniae

BackgroundConventional topical antimicrobial therapy cannot maintain a constant local concentration, resulting in uncontrolled infection and complications. We propose continuous local antibiotic perfusion (CLAP), which can maintain a constant appropriate local antibiotic concentration for a long time with less invasiveness and complications. CLAP is clearly different from traditional treatment because it uses negative pressure to direct the continuously infused antibiotic solution to the center of infection and excrete it outside the body. This study aimed to demonstrate the effectiveness of CLAP by presenting cases in which even refractory bone and soft-tissue infections caused by the hypervirulent Klebsiella pneumoniae (hvKp) could be cured without significant tissue loss and dysfunction. MethodsThis study is a case series in which four patients with limb infection due to hvKp were treated by CLAP. hvKp was defined by a positive string test. The therapy included intra-soft-tissue antibiotic perfusion and intramedullary antibiotic perfusion. Gentamicin (60 mg/50 cc) was infused continuously through dual-lumen tubes and bone marrow needles at low-flow rates (2 mL/h). Negative pressure was used to collect the antimicrobial solution and eliminate the dead space. ResultsThe infection was controlled in all four patients after a mean period of 44.3 days. The mean maximum blood concentration of gentamicin was 1.6 μg/dL, and no cases of renal dysfunction or ototoxicity occurred. After CLAP, wound closure was required in two patients and iliac bone grafting was required in one patient. As sequelae, there were one case of osteoarthritis and one case of higher brain dysfunction due to hypoxia. ConclusionsOur results suggest that intractable hvKp infections can be controlled by CLAP. CLAP may give us the option to directly control local infections with less systemic complications. Therefore, it is considered a valuable treatment for further basic and clinical research, and this research report may be a first step.

Abstract 12650: A Faster and Safe Way for Dose Escalation of Sotalol Therapy in Patients With Atrial Fibrillation or Flutter

Sotalol is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter, but recurrence is not unusual and may require dose escalation. Sotalol can cause QTc prolongation proportional to blood concentration and at times may cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, dose escalation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of 3 days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach the new maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc . Three hospital days in a telemetry bed is costly of time and resources. IV sotalol makes it possible to reduce the escalation time from 3 days to 1 day. The IV to oral dose escalation has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain the new Cmax ss target in a timeframe convenient for medical staff to supervise. Simulation for dose escalation from 80 to 120 mg bid is shown in the Figure; 75 mg IV sotalol is administered over 1 hour followed by 120 mg oral sotalol at 5 hours from start of infusion, then a second oral dose of 120 mg at 12 hours. One can target escalation from 120 to 160 mg by loading 90 mg IV over 1 hr followed by 160 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.

Abstract 12649: A Faster and Safe Way to Initiate Sotalol Therapy for Patients With Atrial Fibrillation or Flutter

Sotalol drug therapy is frequently employed to prevent the recurrence of highly symptomatic atrial fibrillation or flutter (AF, AFb). Sotalol can cause QTc prolongation that is proportional to blood concentration. Excessive concentration can cause Torsade de Pointes ventricular tachycardia (TdP). Because the risk of TdP, initiation of oral sotalol therapy is mandated by FDA to be in-hospital for a minimum of three days under ECG monitoring with facilities and personnel able to provide cardiac resuscitation. With oral administration (bid), 3 days are needed to reach maximal steady-state blood concentrations (Cmax ss) and thus maximal QTc prolongation. Three hospital days in a telemetry bed is costly and considerable expenditure of time and resources. Availability of IV sotalol makes it possible to reduce the loading time from 3 days to 1 day. The IV to oral loading regimen has been developed by model informed drug development. Serum sotalol concentrations and corresponding QTc were obtained from a previously performed bioequivalence study in healthy volunteers who received a single dose of oral and IV sotalol. NONMEM software package was used for population pharmacokinetic modeling and simulation. First Order Conditional Estimation method with Interaction (FOCE-INTER) was used for computation. We chose to administer IV sotalol over 1 hour to obtain Cmax ss target in a timeframe convenient for medical staff to supervise. The simulation for loading to the Cmax target produced by 80 mg PO bid is shown in the Figure; 60 mg IV sotalol is administered over 1 hour followed by 80 mg oral sotalol at 5 hours from start of infusion end then a second oral dose of 80 mg at 12 hours. One can target 120 mg maintenance dose by loading 90 mg IV over 1 hr followed by 120 mg oral dosing. Sotalol concentration will peak in 2-4 hours following each oral administration, thus in 21 hour there will be 3 sotalol peak concentrations. This permits evaluation of QTc response and risk of TdP all within a 1 day admission.

Characterization of Moxidectin against Strongyloides ratti: In Vitro and In Vivo Activity and Pharmacokinetics in the Rat Model.

Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30-100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of moxidectin on Strongyloides ratti larvae (L3) and adult females and the activity as well as the pharmacokinetics of moxidectin in S. ratti infected rats. In vitro, moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L3 and adults in the range of 0.08-1.44μM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 μg/kg of moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 μg/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng × h/mL. The half-life in rats was 9 h, and moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of moxidectin in the treatment of S. ratti as a model of Strongyloides spp. and, as such, supports moving moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.

Pharmacokinetic Properties of Orally Administered 4'-Cyano-2'-deoxyguanosine, a Novel Nucleoside Analog Inhibitor of the Hepatitis B Virus, in Viral Liver Injury Model Rats.

A nucleoside analog, 4'-cyano-2'-deoxyguanosine (CdG), which was developed as an inhibitor of the chronic hepatitis B virus (HBV), exhibited a superior antiviral activity against both wild-type and drugs-resistant HBV to marketed nucleoside analogs. In addition to previous pharmacokinetic studies of CdG in healthy rats, this study reports on an evaluation of the pharmacokinetic characteristics of CdG in a rat model of viral liver injury (VLI) induced by treatment with concanavalin A. Following an intravenous administration of CdG at a dose of 1 mg/kg, the plasma concentration profile of CdG in VLI model rats was found to be similar to that of healthy rats with no significant difference in kinetic parameters. However, when CdG was orally administered at a dose of 1 mg/kg, the maximum blood concentration was much lower in VLI model rats than in healthy rats. Interestingly, the amount of residual food in the stomachs in VLI model rats was significantly larger than that in healthy rats, indicating that the adsorption of CdG in the gastrointestinal tract was inhibited in the presence of food as well as other marketed nucleoside analogs. As observed in healthy rats, CdG was largely distributed to the liver compared to the kidney in the VLI model. These results suggest that liver pathology has only a minor effect on the pharmacokinetic properties of CdG, but the influence of food on CdG absorption needs to be considered.

Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: In vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate

ObjectivesAt the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in Southern Europe and America; many studies predicted a similar epidemic in Africa, as is currently seen in Europe and the United States of America. However, reported data have not confirmed these predictions. One of the hypotheses that could explain the later emergence and spread of COVID-19 pandemic in African countries is the use of antimalarial drugs to treat malaria, and specifically, artemisinin-based combination therapy (ACT).MethodsThe antiviral activity of fixed concentrations of ACT at concentrations consistent with those observed in human plasma when ACT is administered at oral doses for uncomplicated malaria treatment was evaluatedin vitro against a clinically isolated SARS-CoV-2 strain (IHUMI-3) in Vero E6 cells.ResultsMefloquine-artesunate exerted the highest antiviral activity with % inhibition of 72.1 ± 18.3 % at expected maximum blood concentration (Cmax) for each ACT drug at doses commonly administered in malaria treatment. All the other combinations, artesunate-amodiaquine, artemether-lumefantrine, artesunate-pyronaridine, or dihydroartemisinin-piperaquine, showed antiviral inhibition in the same ranges (27.1 to 34.1 %).ConclusionsAntimalarial drugs for which concentration data in the lungs are available are concentrated from 10 to 160 fold more in the lungs than in blood. Thesein vitro results reinforce the hypothesis that antimalarial drugs could be effective as an anti-COVID-19 treatment.

Localised and sustained intradermal delivery of methotrexate using nanocrystal-loaded microneedle arrays: Potential for enhanced treatment of psoriasis

Methotrexate (MTX), typically used as its sodium salt (MTX Na), is a first-line treatments for moderate to severe psoriasis, showing good efficacy. However, its systemic administration is associated with many side effects. Intradermal delivery into psoriatic tissue could offer an alternative approach. However, successful intradermal administration of MTX Na is currently precluded by its physicochemical properties. Moreover, due to its hydrophilic nature, MTX Na is swiftly cleared from the target tissue, necessitating frequent dosing which may affect patient compliance. To address these limitations, we investigated the combination of nanocrystal (NC) and dissolving microneedle (MN) technologies as an alternative approach for localised and sustained intradermal delivery of MTX Na. Poorly water-soluble MTX nanocrystals (MTX NC) were produced by a bottom-up technique with a mean particle size of 678 ± 15 nm. Sustained in vitro drug release was observed over 72 h. The MTX NC were then incorporated into the shafts of dissolving MN arrays with a drug loading of 2.48 mg/array. The MTX NC-loaded MN arrays exhibited satisfactory mechanical strength and insertion capabilities in the skin-simulant Parafilm M® and their shafts dissolved entirely in less than 20 min after insertion into excised neonatal porcine skin. Importantly, in vivo studies in Sprague Dawley rats revealed that the MN arrays were able to deposit approximately 25.1% of the loaded MTX NC in the skin, which acted, in turn, as a drug depot and released the MTX in a sustained manner over 72 h, while minimising MTX systemic exposure. Indeed, 24 h from MN application, 312.70 ± 161.95 µg/g of MTX was retained in the skin at the application site. This was approximately 322-fold higher than the amount of MTX (0.942 ± 0.59 µg/g) retained in the skin after oral administration of MTX Na. Interestingly, even after 72 h after MN application, around 12.5% of the MTX NC deposited in the skin by the MN was retained. In contrast, the maximal blood concentration of MTX achieved following MN application, was only 40% of that measured after oral administration of MTX Na. Accordingly, MTX NC-loaded dissolving MN arrays could be a promising approach for effective localised and sustained intradermal delivery of MTX as a potential enhanced treatment for psoriasis.

Safety assessment of metarrestin in dogs: A clinical candidate targeting a subnuclear structure unique to metastatic cancer cells

Pancreatic cancer is a leading cause of cancer-related deaths in the U.S. Ninety percent of patients with stage IV pancreatic cancer die within one year of diagnosis due to complications of metastasis. A metastatic potential of cancer cells has been shown to be closely associated with formation of perinucleolar compartment (PNC). Metarrestin, a first-in-class PNC inhibitor, was evaluated for its toxicity, toxicokinetics, and safety pharmacology in beagle dogs following every other day oral (capsule) administration for 28 days to support its introduction into clinical trials. The study consisted of four dose groups: vehicle; 0.25, 0.75 and 1.50 mg/kg/dose. Metarrestin reached its maximum concentration in blood at 3 h (overall median Tmax) across all doses with a mean t1/2 over 168 h of 55.5 h. Dose dependent increase in systemic exposure (Cmax and AUClast) with no sex difference was observed on days 1 and 27. Metarrestin accumulated from Day 1 to Day 27 at all dose levels and in both sexes by an overall factor of about 2.34. No mortality occurred during the dosing period; however, treatment-related clinical signs of toxicity consisting of hypoactivity, shaking/shivering, thinness, irritability, salivation, abnormal gait, tremors, ataxia and intermittent seizure-like activity were seen in both sexes at mid and high dose groups. Treatment-related effects on body weight and food consumption were seen at the mid and high dose levels. Safety pharmacology study showed no treatment-related effects on blood pressure, heart rate, corrected QT, PR, RR, or QRS intervals, or respiratory function parameters (respiratory rate, tidal volume, minute volume). There were no histopathological changes observed, with the exception of transient thymic atrophy which was considered to be non-adverse. Based primarily on clinical signs of toxicity, the No Observed Adverse Effect Level (NOAEL) in dogs was considered to be 0.25 mg/kg metarrestin after every other day dosing for 28 days with a mean of male and female Cmax = 82.5 ng/mL and AUClast = 2521 h*ng/mL, on Day 27.