Effects of lasmiditan on simulated driving performance: Results of two randomized, blinded, crossover studies with placebo and active controls.

OBJECTIVE: To evaluate the impact of lasmiditan, an oral, centrally-penetrant, selective serotonin 1F (5-HT1F ) receptor agonist developed for the acute treatment of migraine, on simulated driving. METHODS: Healthy adult volunteers enrolled in two randomized, placebo and active comparator-controlled, crossover studies. Study 1 (N = 90) tested lasmiditan (50-, 100-, 200-mg), alprazolam (1-mg), and placebo at 1.5 hr post-dose. Study 2 (N = 68) tested lasmiditan (100-, 200-mg), diphenhydramine (50-mg, administered 2 hr pre-assessments), and placebo at 8, 12 and 24 hr post-dose. Driving performance was assessed using a validated driving simulator employing a 100 km driving scenario. Standard deviation of lateral position (SDLP), a measure of lane position control, was the primary endpoint. RESULTS: Assay sensitivity was confirmed by increased SDLP for active comparators at 1.5- and 8-hr time points. Lasmiditan doses showed significant driving impairment versus placebo at 1.5 hr post-dose. Lasmiditan doses were non-inferior to placebo at 8 hr. Driving impairment was concentration-dependent at 1.5 hr but not at 8 hr. Common adverse events were central nervous system-related and mild-to-moderate in severity. CONCLUSIONS: Lasmiditan was associated with impaired simulated driving performance at 1.5 hr post-dose, but showed no clinically meaningful impairment at 8 hr post-dose.

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel-group, phase I study in healthy subjects.

AIM: Amiselimod (MT-1303) is a selective sphingosine 1-phosphate 1 (S1P1 ) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo. METHODS: A total of 81 healthy subjects aged 18-55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography. RESULTS: Unlike fingolimod, neither amiselimod dose exerted acute (1-6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: -4.40 bpm, 95% confidence interval -7.15, -1.66) and Day 7 in the 0.8 mg group [-3.85 bpm (-6.58, -1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [-6.49 bpm (-8.95, -4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1. CONCLUSION: The study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

Pharmacokinetics, Pharmacodynamics, Tolerability, and Food Effect of Cenerimod, a Selective S1P1 Receptor Modulator in Healthy Subjects.

The pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a potent sphingosine-1-phosphate subtype 1 receptor modulator, were investigated in three sub-studies. Two double-blind, placebo-controlled, randomised studies in healthy male subjects were performed. Cenerimod was administered either as single dose (1, 3, 10 or 25 mg; Study 1) or once daily for 35 days (0.5, 1, 2 or 4 mg; Study 2). A two-period cross-over, open-label study was performed to assess the food effect (1 mg, Study 3). The pharmacokinetic profile of cenerimod was characterised by a tmax of 5.0-6.2 h. Terminal half-life after single and multiple doses ranged from 170 to 199 h and 283 to 539 h, respectively. Food had no relevant effect on the pharmacokinetics of cenerimod. A dose-dependent decrease in lymphocyte count was observed after initiation of cenerimod and reached a plateau (maximum change from baseline: -64%) after 20-23 days of treatment. Lymphocyte counts returned to baseline values at end-of-study examination. One serious adverse event of circulatory collapse (25 mg dose group, maximum tolerated dose: 10 mg) and adverse events of mild-to-moderate intensity were reported. Treatment initiation was associated with transient decreases in heart rate and blood pressure at doses >1 and ≥10 mg, respectively.

Metabolic disposition of AZD8931, an oral equipotent inhibitor of EGFR, HER2 and HER3 signalling, in rat, dog and man.

1. This series of studies in rats, dogs and humans (Clinicaltrials.gov identifier: NCT01284595) investigated the pharmacokinetics, tissue distribution, metabolism and excretion of the EGFR, HER2 and HER3 signalling inhibitor AZD8931. 2. Single oral or intravenous doses of 2-(4-[4-(3-chloro-2-fluoro[U-(14)C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate ([(14)C]-AZD8931) were administered. 3. AZD8931 absorption was rapid in all species. Following [(14)C]-AZD8931 administration to rats, radioactivity was widely and rapidly distributed, with the highest levels in organs of metabolism and excretion (gastrointestinal tract, liver). Following oral and intravenous [(14)C]-AZD8931 administration, excretion of radioactivity by all species occurred predominantly via the bile into faeces, with <5% of the dose being eliminated in urine. In all species, AZD8931 was principally cleared by metabolism. The major route of metabolism was hydroxylation and O-demethylation in rat, and aryl ring oxidation in dog. Metabolism of AZD8931 in humans was attributed to three pathways; oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation. 4. AZD8931 is largely cleared by metabolism in the rat, dog and human. Excretory profiles indicate that there are no unique human metabolites.

Pharmacokinetic profile of micafungin when co-administered with amphotericin B in healthy male subjects.

OBJECTIVE: Micafungin and amphotericin B are antifungal agents with potent activity against a broad spectrum of fungal spp., including Candida and Aspergillus. The objective of this study was to evaluate the potential pharmacokinetic (PK) interaction of the two drugs in healthy subjects. METHODS: PK were evaluated in healthy adults in an open-label, phase I clinical trial, following separate treatments with micafungin (200 mg; days 1 - 5) and conventional amphotericin B (0.25 mg/kg; days 8 - 13) alone, and following co-administration of both drugs (days 14 - 18). RESULTS: In 20 male subjects, systemic exposure to micafungin (measured using peak plasma micafungin concentration (Cmax) and area under the plasma micafungin concentration-time curve (AUC0-τ)) were similar following coadministration of micafungin and amphotericin B (day 18; Cmax 19.1 µg/mL, AUC0-τ 232 µg×h/mL) compared with administration of micafungin alone (day 5; Cmax 18.7 µg/mL, AUC0-τ 236 µg×h/mL), suggesting that administration of amphotericin B does not affect the PK of micafungin. The exposure to amphotericin B was ~ 30% greater following co-administration of both drugs (day 18; Cmax 704 µg/mL, AUC0-τ 9157 µg×h/mL) than after administration of amphotericin B alone (day 13; Cmax 621 µg/mL, AUC0-τ 7023 µg×h/mL). Concurrent treatment with micafungin and amphotericin B was less well tolerated than when either agent was administered alone. CONCLUSIONS: PK and safety-related observations during co-administration of micafungin and amphotericin B were considered to be a consequence of accumulation of amphotericin B to a steady state, indicating that co-administration of the two drugs does not affect the PK of micafungin.

Investigation of the Effect of Lasmiditan on the Pharmacokinetics of P-Glycoprotein and Breast Cancer Resistance Protein Substrates.

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction, phase 1 clinical trial, eligible participants were adults aged 21-70 years with a body mass index of 18.5-35.0 kg/m2 . Part 1 (P-gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC0-∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0-∞ and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC0-∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates.

Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men.

AIMS: Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men. METHODS: We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01-2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03-1.0 mg TAK-683 on day 1, followed by a 0.01-2.0 mg day(-1) continuous infusion on days 2-13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days. RESULTS: TAK-683 was well tolerated up to a dose of 2.0 mg day(-1) by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day(-1) suppressed testosterone below castration level (<50 ng dl(-1)) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent. CONCLUSIONS: In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.

Studies to Assess the Utility of Serum Neurofilament Light Chain as a Biomarker in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and disabling dose-limiting toxicities of chemotherapy. We report here the results of two separate non-interventional studies (49 patients), which evaluated blood neurofilament light chain (NfL) as a biomarker of CIPN in breast cancer patients treated with paclitaxel. All patients underwent a standard treatment protocol that was established independently of the present studies. NfL was measured in serum using an ultrasensitive single-molecule array and compared with the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (CIPN20) and Total Neuropathy Score clinical version (TNSc), a clinician-reported measure of neuropathy progression. The TNSc increased with cumulative dose compared with baseline, and the NfL concentrations were also strongly associated with the cumulative dose of chemotherapy. The analysis showed a correlation between TNSc and NfL. Both TNSc and NfL showed weak to moderate associations with CIPN20 subscores, with a better association for the CIPN20 sensory compared with motor and autonomic subscores. Data from the two studies provide evidence that serum NfL has the potential to be used as a biomarker to monitor and mitigate CIPN. However, studies with additional patients planned in the ongoing clinical trial will determine the universal application of NfL as a biomarker in CIPN.

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease.

Mevidalen (LY3154207) is a positive allosteric modulator of the dopamine D1 receptor that enhances the affinity of dopamine for the D1 receptor. The safety, tolerability, motor effects, and pharmacokinetics of mevidalen were studied in patients with Parkinson disease. Mevidalen or placebo was given once daily for 14 days to 2 cohorts of patients (cohort 1, 75 mg; cohort 2, titration from 15 to 75 mg). For both cohorts, the median time to maximum concentration for mevidalen plasma concentration was about 2 hours, the apparent steady-state clearance was 20-25 L/h, and mevidalen plasma concentrations were similar between the 1st and 14th administration in cohort 1, indicating minimal accumulation upon repeated dosing. Mevidalen was well tolerated, and most treatment-emergent adverse events were mild. Blood pressure and pulse rate increased when taking mevidalen, but there was considerable overlap with patients taking placebo, and vital signs normalized with repeated dosing. In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia.

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.

Activation of the brain dopamine D1 receptor has attracted attention because of its promising role in neuropsychiatric diseases. Although efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug-like properties. Phase 1 single-ascending-dose (SAD; NCT03616795) and multiple-ascending-dose (MAD; NCT02562768) studies with the D1PAM mevidalen (LY3154207) were conducted with healthy subjects. There were no treatment-related serious adverse events (AEs) in these studies. In the SAD study, 25-200 mg administered orally showed dose-proportional pharmacokinetics (PK) and acute dose-related increases in systolic blood pressure (SBP) and diastolic blood pressure DBP) and pulse rate at doses ≥ 75 mg. AE related to central activation were seen at doses ≥ 75 mg. At 25 and 75 mg, central penetration of mevidalen was confirmed by measurement of mevidalen in cerebrospinal fluid. In the MAD study, once-daily doses of mevidalen at 15-150 mg for 14 days showed dose-proportional PK. Acute dose-dependent increases in SBP, DBP, and PR were observed on initial administration, but with repeated dosing the effects diminished and returned toward baseline levels. Overall, these findings support further investigation of mevidalen as a potential treatment for a range of neuropsychiatric disorders.

Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Pediatric Patients with Migraine.

INTRODUCTION: Lasmiditan is a selective serotonin (5-HT1F) receptor agonist approved in the US for the acute treatment ofmigraine in adults. This phase I, open-label, two-cohort study assessed the pharmacokinetics (PK), safety, and tolerability of lasmiditan in patients with migraine aged 6 to < 18 years. METHODS: Cohort 1 (15 to ≤ 40 kg) and Cohort 2 (> 40 to ≤ 55 kg) received single oral doses of lasmiditan (100 mg and 200 mg, respectively).Blood samples for the assessment of PK and safety parameters were collected over a 24-h period. Follow-up was approximately 14 days after dosing. RESULTS: Eighteen patients received lasmiditan (11 in Cohort 1, 7 in Cohort 2) and 17 patients completed the study. One patient in Cohort 2 discontinued due to adverse events. Plasma concentrations peaked at 1.5-2 h post dose and then declined, with a terminal half-life of approximately 4 h in both cohorts. While the exposure to lasmiditan was generally similar between cohorts, PK parameters, such as apparent total body clearance and volume of distribution, were greater for the 200 mg cohort relative to the 100 mg cohort. No deaths or serious adverse events were reported. The frequency and severity of adverse events (including somnolence, dizziness, and fatigue) were generally mild and similar to those in adult studies. CONCLUSION: The PK results support weight-based dosing of lasmiditan in pediatric patients with migraine and no new safety or tolerability issues were identified. These findings support further investigation of lasmiditan as a potential treatment in pediatric patients with migraine. Clinical Trial Registration Numbers NCT03988088 and EMEA-002166-PIP01-17M02.

Effects of Lasmiditan on Cardiovascular Parameters and Pharmacokinetics in Healthy Subjects Receiving Oral Doses of Propranolol.

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT1F receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with ß-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was -6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.

Abuse Potential of Lasmiditan: A Phase 1 Randomized, Placebo- and Alprazolam-Controlled Crossover Study.

Lasmiditan is a centrally penetrant, highly selective 5-hydroxytryptamine (serotonin) receptor 1F (5HT1F ) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo- and positive-controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with alprazolam and with placebo using the maximal effect score (Emax ) of the Drug-Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug-liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400-mg dose (upper 90% confidence limit on difference in least-squares [LS] means > 14 for all lasmiditan doses). Drug-liking scores for lasmiditan 400 mg were not significantly different from alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug-liking scores at lower doses (100 and 200 mg) were significantly different from alprazolam. During the treatment phase, the incidence of treatment-emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug-liking effects for lasmiditan versus placebo and versus alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.

Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies.

BACKGROUND: Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes. METHODS: In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4-10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV(1) over 4-10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031. FINDINGS: No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI -4.37 to 16.32; p=0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08-6.25] times lower in the pitrakinra group; p=0.0001). There were fewer asthma-related adverse events (p=0.069) and fewer adverse events requiring beta-agonist rescue (p=0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events. INTERPRETATION: Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers.

The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.

Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the efficacy and safety of a skin-patch vaccine containing the pathogen's heat-labile toxin (LT) in a population of travellers to Mexico and Guatemala. METHODS: In this phase 3, randomised, double-blind, placebo-controlled field trial, healthy adults (aged 18-64 years) travelling from Germany or the UK to Mexico or Guatemala were assigned in a 1:1 ratio by a dynamic electronic randomisation system to receive transcutaneous immunisation with a patch containing 37.5 µg of ETEC LT or a placebo patch. Participants, site staff, and the investigators who did the analyses were masked to group assignment. Participants were vaccinated before travel, with two patches given 14 days apart. In the destination country, participants tracked stool output in a diary and provided stool samples for pathogen identification if diarrhoea occurred. The primary endpoint was the proportion of participants with at least one episode of moderate-to-severe diarrhoea (defined as four or more unformed stools in a 24 h period) in which either or both ETEC enterotoxins (LT and heat-stable toxin [ST]) were detected. The study is registered at ClinicalTrials.gov, number NCT00993681. FINDINGS: 2036 participants were recruited and randomly assigned between Oct 14, 2009, and Aug 13, 2010, with 1016 allocated to receive the LT patch and 1020 the placebo patch. 821 participants in the LT-patch group and 823 in the placebo group received both vaccinations and were analysed in the per-protocol population. 30 (3.7%, 95% CI 2.5-5.2) participants in the LT-patch group and 46 (5.6%, 4.1-7.4) in the placebo group had moderate or severe ETEC diarrhoea (vaccine efficacy 34.6%, -2.2 to 58.9; p=0.0621). 9333 local (ie, patch-site) adverse events (including erythema, rash, pruritus, hyperpigmentation, pain, hypopigmentation, and oedema) occurred in 943 (93%) of 1015 participants in the LT-patch group, compared with 1444 local adverse events in 574 (56%) of 1019 participants in the placebo group (p<0.0001). Serious adverse events occurred in 25 participants (14 in the LT-patch group and 11 in the placebo group), with all regarded as either unrelated or possibly related to treatment. Vaccine-induced hyperpigmentation persisted for at least 180 days after vaccination in 150 (18%) of the 849 participants who received both vaccinations and returned for final assessment in the LT-patch group, compared with none of the 842 participants in the placebo group. The vaccine was immunogenic, with a post-vaccination geometric mean titre of LT-specific serum immunoglobulin G of 3400.29, compared with 315.41 in the placebo group. INTERPRETATION: Although the LT antigen was delivered effectively by the skin patch, the vaccine did not protect travellers against diarrhoea caused by ETEC or other organisms. Future vaccines against travellers' diarrhoea might need to include several antigens against various diarrhoeal pathogens, and might need to be able to generate mucosal and higher systemic immunity.

A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.

ABSTRACT: This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. TRIALS REGISTRATION: NCT01323465.

Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men.

STUDY OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men. DESIGN: Randomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics. SETTING: Sleep laboratory. PARTICIPANTS: Healthy young men between 18 and 45 years of age (22 enrolled, 19 completed). INTERVENTIONS: Periods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg. MEASUREMENTS AND RESULTS: In Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours. CONCLUSIONS: In healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

Effect of fenofibrate treatment on the low molecular weight urinary proteome of healthy volunteers.

PURPOSE: Urinary peptidome changes and discrimination for potential renal glomerular and tubular damage after 6 wk of fenofibrate treatment were evaluated in 26 healthy subjects. EXPERIMENTAL DESIGN: Peptide profiling was performed in urine samples before and after treatment using high-resolution capillary electrophoresis coupled with electrospray ionization mass spectrometry. RESULTS: A panel of 88 fenofibrate-sensitive peptides was detected with a frequency of ≥50% before and after treatment. This was reduced to 36 peptides by repeating the comparison ten times by randomly excluding samples at each time-point. Nineteen peptides were consistent and reliable biomarkers after an additional comparison with an age and sex-matched subject control group. Levels of peptides identified as fragments of Collagen α-1 (I), Collagen α-1 (XVII), Collagen α-2 (VIII) or sodium/potassium-transporting ATPase subunit gamma were reduced after fenofibrate treatment. Classification scores for renal tubular and glomerular damages determined by support vector machine based biomarker models increased after treatment but remained below pathological score cutoff values. CONCLUSIONS AND CLINICAL RELEVANCE: Fenofibrate treatment led to minor modifications of the urinary proteomic profile in a way that does not create safety issues affecting glomerular and tubular functions. Urinary peptide profiling proved to be appropriate to monitor drug pharmacological effects in a clinical setting.