Make science evolve into a One Health approach to improve health and security: a white paper.

The World One Health Congresses are biennial gatherings of approximately 1500 professionals from relevant international organisations, OIE, FAO, WHO, World Bank, leading scientific experts and researchers in the field of One Health, animal production and trade, food safety, animal health, human health and environmentology/ecology, government representatives in public health, human health, food safety, environmental health and global health security. The Congress is organized by the One Health Platform. This white paper summarizes highlights of the 5th International One Health Congress in Saskatoon, Canada, June 2018 and serves as a roadmap for the future, detailing several concrete action points to be carried out in the run-up to the 6th World One Health Congress in Edinburgh, Scotland, June 2020.

Pharmacokinetic studies in women of 2 novel oral formulations of tranexamic acid therapy for heavy menstrual bleeding.

Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (≥5 µg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 µg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3-g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding.

A randomized study of the effects of food on the pharmacokinetics of once-daily extended-release hydromorphone in healthy volunteers.

This randomized, open-label, crossover study investigated the influence of food on the pharmacokinetics of extended-release hydromorphone in 30 healthy volunteers. Participants received extended-release hydromorphone 16 mg in the fasted state and immediately after a high-fat breakfast. In addition, the pharmacokinetics of a 16-mg dose of extended-release hydromorphone and a 16-mg daily dose (4 mg qid) of immediate-release hydromorphone in the fasted state were compared. Treatments were separated by washout periods of 7 to 14 days. Naltrexone was given throughout each treatment period to block the opioid effects of hydromorphone. The 90% confidence intervals (CIs) of the ratios of geometric means for maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC) for extended-release hydromorphone in the fed and fasted states were within the bioequivalence criteria range of 80% to 125%. In the fasted state, the 90% CIs of the ratios of AUC geometric means for extended-release hydromorphone and immediate-release hydromorphone were also within the bioequivalence range. Both hydromorphone treatments were well tolerated. This study shows that the bioavailability of extended-release hydromorphone is not affected by food and that the bioavailability of extended-release hydromorphone under fasting conditions is comparable with that of the immediate-release formulation when administered at the same total daily dose.

Steady-state pharmacokinetics of extended-release hydromorphone (OROS hydromorphone): a randomized study in healthy volunteers.

The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.

Pharmacokinetics of digoxin in healthy subjects receiving taranabant, a novel cannabinoid-1 receptor inverse agonist.

INTRODUCTION: Interaction studies with digoxin (Lanoxin; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant--a cannabinoid-1 receptor inverse agonist--for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction. METHODS: This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day -14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued. RESULTS: The geometric mean ratio and 90% confidence intervals for digoxin AUC(0-infinity) were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C(max)) were 1.23 (1.09, 1.40). The median time to C(max) was the same for both treatments. CONCLUSION: Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

Innovative strategies for early clinical R&D.

Developments in translational medicine and regulatory initiatives associated with the FDA's Critical Path Initiative are creating new opportunities for innovation in early clinical R&D. The introduction of the exploratory IND process allows small, 'phase 0' clinical trials to be conducted prior to traditional phase I trials - sometimes requiring considerably less chemistry, manufacturing and controls, or preclinical support. Phase 0 clinical trials involving subtherapeutic, yet pharmacologically active, dose levels can provide an early demonstration of clinical proof of concept; such demonstration is of particular importance to small pharmaceutical and early-stage biotechnology companies. However, these opportunities for rapid entry into the clinic must be balanced by a consideration of the unique risks associated with first-in-human clinical trials, and by accounting for public concerns regarding drug safety in general. This feature review discusses how innovative clinical strategies can be used effectively in early drug development.

Comparative bioequivalence study between a novel matrix transdermal delivery system of fentanyl and a commercially available reservoir formulation.

AIM: To determine the pharmacokinetics, safety and performance of a novel matrix formulation of fentanyl. METHODS: Transdermal fentanyl was administered as the novel matrix and the Durogesic reservoir formulations (24 subjects, 100 microg h(-1)) in a randomized, fully replicate, four-way crossover study. Serum concentrations of fentanyl were assayed by LC/MS/MS. Pharmacokinetic parameters of fentanyl and performance (adherence and skin irritability) were evaluated. RESULTS: Test/reference ratio (90% confidence intervals) for AUC(0-t), AUC(inf) and C(max) were 105.5% (99.4, 112.0), 105.3% (99.3, 111.6) and 111.4% (100.4, 123.6), respectively. Adherence and skin irritability results of the two formulations were similar. CONCLUSION: The two formulations are expected to result in similar efficacy for the management of severe pain.

Pharmacokinetics, tolerability, and performance of a novel matrix transdermal delivery system of fentanyl relative to the commercially available reservoir formulation in healthy subjects.

A novel transdermal formulation of fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix with a rate-controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72-hour applications of fentanyl (50 mug/h) as the novel matrix and the conventional reservoir formulations in a randomized, 2-way crossover study. Blood samples were collected, and serum concentrations of fentanyl were assayed using liquid chromatography with mass spectrometry detection. The mean area under the curve (AUCtau) and peak concentrations (C(max)) of the matrix formulation were 84 838 pg.h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUCtau and C(max) between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.

Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans.

BACKGROUND: Cyclosporine (INN, ciclosporin) is a cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) substrate whose bioavailability increases when administered with grapefruit juice. It is unknown whether pomelo, a closely related citrus fruit, interacts with cyclosporine in humans. In addition, a case study reports that cranberry juice interacts with warfarin, a drug with a narrow therapeutic range. Cranberries have a high content of flavonoids, compounds with various metabolic effects, including interaction with P-gp in vitro. Although the effect of flavonoids is less evident in vivo, cranberry juice has become a very popular beverage, and it was deemed important to investigate whether it has an effect on the disposition of cyclosporine, another drug with a narrow therapeutic range. METHODS: In an open-label, randomized, 3-way crossover study with a 14-day washout period between each dose, 12 healthy male volunteers received single oral 200-mg doses of cyclosporine according to the following regimens: 200 mg cyclosporine administered with 240 mL of pomelo juice, cranberry juice, or water under fasting conditions. Multiple whole blood samples were collected up to 36 hours after each dose. Concentrations were determined via a liquid chromatography-tandem mass spectrometry method. RESULTS: Administration of pomelo juice with cyclosporine increased the area under the curve from time 0 to the last measurable concentration (AUCt), area under the curve from time 0 to infinity (AUCinf), and maximum blood concentration (Cmax) of cyclosporine with ratios of least squares means of 119.4% (95% confidence interval [CI], 113.4%-125.8%), 118.9% (95% CI, 113.8%-124.3%), and 112.1% (95% CI, 102.3%-122.8%), respectively. All 3 variables exhibited statistically significant increases (with Bonferroni adjustment), with P = .0001 for AUCt and AUCinf and P = .0167 for Cmax; however, only the increase in AUCt was judged to be clinically significant with a 95% CI outside the 80% to 125% boundaries. Cranberry juice had no clinically significant effect on the overall disposition of cyclosporine. After administration of cyclosporine with cranberry juice, the ratios of least squares means for AUCt, AUCinf, and Cmax for cyclosporine were 95.0% (95% CI, 90.3%-100.1%), 93.4% (95% CI, 89.2%-97.8%), and 95.2% (95% CI, 86.9%-104.2%), respectively. CONCLUSION: These results suggest that pomelo juice increases the bioavailability of cyclosporine, possibly by inhibiting CYP3A or P-gp activity (or both) in the gut wall. However, drinking a glass of cranberry juice does not appear to significantly influence the disposition of cyclosporine.

Two open-label, randomized, crossover studies assessing the bioequivalence of ofloxacin administered as immediate-and extended-release formulations in healthy subjects.

BACKGROUND: Ofloxacin is a fluoroquinolone agent available as an immediate-release (IR) tablet formulation administered twice daily. An extended-release (ER) formulation of ofloxacin has been developed for oncedaily administration. OBJECTIVES: The present studies compared the pharmacokinetic (PK) and safety profiles of the ER and IR formulations of ofloxacin. METHODS: Based on specific inclusion and exclusion criteria, healthy adult male and female volunteers were selected to receive single and multiple oral doses of ofloxacin ER 400 mg QD and ofloxacin IR 200 mg BID in 2 separate open-label, randomized, crossover studies. Multiple blood samples were collected, and plasma concentrations of ofloxacin were analyzed using a high-throughput liquid chromatography system. PK parameters were calculated using noncompartmental methods. Safety was assessed in the clinical pharmacology unit based on vital signs, electrocardiograms (ECGs), and reported adverse events. The relationship of an adverse event to study drugs (definitely, probably, possibly, remotely, or unrelated) was assessed by the principal investigator. RESULTS: Forty healthy subjects were included in each study. Thirty-seven subjects (28 men, 9 women; mean age, 37 years; mean weight, 71.2 kg) completed the single-dose study, and 38 subjects (33 men, 5 women; mean age, 36 years; mean weight, 72.2 kg) completed the multiple-dose study. With the exception of 3 black subjects in each study of African-American origin, all subjects in both studies were white. The mean AUC(0-24) values for the ER formulation in the single-and multiple-dose studies (18.6 and 21.4 mg . h/L, respectively) were similar to those for the IR formulation (17.7 and 22.8 mg x h/L), with the 90% CIs falling between 80.0 and 125.0. Mean C(max) values for the ER formulation in the single- and multiple-dose studies (2.02 and 2.12 mg/L) were also similar to those for the IR formulation (1.74 and 1.85 mg/L). Under steady-state conditions, median T(max) values for the ER formulation were significantly longer than those for the IR formulation (5.00 vs 2.00 hours, respectively; P < 0.05). All vital signs and ECGs were within normal ranges during the single- and multipledose studies. Adverse events probably related to study drugs (eg, nausea, loose stools, emesis) were similar in nature and frequency between the 2 formulations. No serious adverse events were reported during either study. CONCLUSION: In these 2 trials in a selected group of healthy adult male and female volunteers, the ER and IR formulations of ofloxacin displayed a similar rate and extent of bioavailability and comparable safety profiles.

Estudo comparativo de biodisponibilidade relativa entre duas formulaçöes comerciais distintas de isotretinoína sistêmica existentes no Brasil / Comparative study of relative biovailability betwenn two Brazilian different commercial formulations of sistemic isotretinoin

Este estudo foi conduzido para avaliar a biodisponibilidade de uma nova formulação de isotretinoína sistêmica e de seu principal metabólico, a 4-oxo-ísotretinoína, relativo a um produto referência. Os dados das concentrações plasmáticas foram coletadas em 36 indivíduos sadios, em um delineamento cruzado de 2 vias, por um período de tempo de 144 horas. O plasma das amostras sanguíneas foram analisadas por um ensaio cromatográfico validado. Medidas farmacocinéticas indicadoras das taxas de absorção e eliminação dos fármacos, como concentração máxima (Cmax), área sob a curva de concentração até o tempo final de coleta t (Auc) e a área estimada até o infinito (Auc) foram analisadas sob modelo multiplicativo, isto é, utilizando log-transformado destas medidas. Os métodos para verificar a bioequivalência média entre T e R foram os intervalos de confiança e os dois testes unilaterais t. Conclui-se, então, que há bioequivalência média entre as duas formulações, baseados nos resultados obtidos pelas análises da isotretinoína e 4-oxo-isotretinoína.