Population pharmacokinetic rationale for intravenous contezolid acefosamil followed by oral contezolid dosage regimens.

Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.

A Phase 1 pharmacokinetic study of a single-dose bioadhesive clindamycin 2% gel for bacterial vaginosis.

OBJECTIVES: To evaluate pharmacokinetics (PK) of a single dose of an investigational 2% clindamycin phosphate vaginal gel in healthy women by assessment of plasma and vaginal clindamycin concentrations over 7 days, and assess safety. METHODS: Single-centre, Phase 1, single-dose PK study. Blood and vaginal samples were collected daily and safety was evaluated through to Day 7. RESULTS: Twenty-one subjects were enrolled; 20 completed the study. Plasma clindamycin concentrations demonstrated quantifiable values in all subjects through to 24 h post-dose, remaining above the limits of quantification (LOQ) through to 48 h for the majority of subjects. Systemic exposure (AUC0-t) was 1179 (range 62-3822) h·ng/mL. Arithmetic mean AUC0-24 was 818 (range 51-3287) h·ng/mL. Vaginal clindamycin phosphate levels were relatively high 24 h following administration in 15/21 subjects (6 subjects had values >400 µg/g and 9 had values of 100-400 µg/g). The levels dropped in most participants to below the LOQ 2 days following dosing. In a few participants, levels remained elevated for several days. Maximal amounts of vaginal clindamycin occurred on Day 2 with a mean value of 30.3 µg. One treatment-emergent adverse event (TEAE) of moderate-severity headache not related to study drug was reported and resolved on Day 1. No TEAEs were related to physical examinations, pelvic examinations, laboratory values or vital signs. CONCLUSIONS: The vaginal concentrations of clindamycin phosphate plus the clindamycin plasma profile over time are consistent with release of drug from the investigational gel over 24 to 72 h. A single dose was well tolerated.

Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects.

INTRODUCTION: Cligosiban is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AIM: Three clinical studies investigated the pharmacokinetics (including effect of food and formulation), central penetration, safety, and tolerability of single oral doses of cligosiban in healthy subjects. METHODS: Study 1 was a double-blind, randomized, placebo-controlled, crossover design in 3 cohorts of 10 subjects each. Single doses of 0.3-2,400 mg cligosiban were administered as aqueous solutions or dispersions under fasting and fed (800 mg only) conditions. Studies 2 and 3 were open-label, randomized, crossover designs in 12 subjects each. Study 2 investigated 800 mg cligosiban administered as capsules and aqueous dispersion under fasting conditions, and capsules under fed conditions. Study 3 investigated 1,600 mg cligosiban administered as caplets and aqueous dispersion under fasting conditions, and caplets under fed conditions. MAIN OUTCOME MEASURES: Blood sampling for cligosiban assay and safety assessments were conducted throughout all studies. Cerebrospinal fluid (CSF) samples for cligosiban assay were collected in study 2. RESULTS: Cligosiban was rapidly absorbed under fasting conditions with peak concentrations generally occurring within 1-2 hours post-dose regardless of formulation. Maximum observed plasma concentration (Cmax) and area under the concentration time curve extrapolated to infinity (AUC0-∞) increased approximately dose-proportionally from 0.3-10 mg, but sub-proportionally from 30-2,400 mg. Cligosiban exposure was similar when administered as a dispersion or capsule (800 mg) under fasted conditions, but higher (87% increase) when administered as a caplet compared to the dispersion (1,600 mg). Food decreased the rate of absorption for all 3 formulations (median time to Cmax 3-6 hours compared to 1-2 hours fasted) but increased the extent of absorption (Cmax and AUC0-∞ increased by 75-149% and 33-49%, respectively). Cligosiban was detected in CSF at concentrations approximately 40% of unbound plasma concentrations. Cligosiban was well tolerated at all doses. CLINICAL IMPLICATIONS: Cligosiban is well tolerated over a wide dose range, and has the pharmacokinetic properties to be taken as required prior to sexual intercourse in men with PE and to antagonize the oxytocin receptor in the brain and spinal cord. STRENGTHS & LIMITATIONS: Three controlled trials show similar toleration and pharmacokinetic data. Cligosiban in CSF indicates its likely presence in all central nervous system tissue. These data need to be investigated and confirmed in multiple-dose studies prior to investigation in phase-II studies in men with PE. CONCLUSION: Cligosiban had a good safety/tolerability profile at doses predicted to be therapeutic or supra-therapeutic and a pharmacokinetic profile appropriate for "as-needed" dosing for men with PE. Osterloh IH, Muirhead GJ, Sultana S, et al. Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects. J Sex Med 2018;15:1547-1557.

Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open-label, drug-drug interaction study.

AIMS: The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure. METHODS: This phase 1, open-label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5-day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4. RESULTS: Coadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of probenecid were 128.7% (121.9-135.7%) and 176.1% (171.9-180.3%), respectively. The geometric mean ratios of Cmax and AUC(0-t) (90% CI) with and without coadministration of cimetidine were 117.1% (111.0-123.6%) and 143.7% (140.3-147.2%), respectively. Mean (standard deviation) renal clearance of mirogabalin (l h-1 ) was substantially slower after probenecid [6.67 (1.53)] or cimetidine [7.17 (1.68)] coadministration, compared with mirogabalin alone [11.3 (2.39)]. Coadministration of probenecid or cimetidine decreased mirogabalin mean (standard deviation) apparent total body clearance [10.5 (2.33) and 12.8 (2.67) l h-1 , respectively, vs. 18.4 (3.93) for mirogabalin alone]. CONCLUSIONS: A greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs. a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2-fold), no a priori dose adjustment is recommended.

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

BACKGROUND: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort). RESULTS: PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding. CONCLUSIONS: This study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Efficacy and safety of AVP-21D9, an anthrax monoclonal antibody, in animal models and humans.

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.).

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects.

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis.

A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of once daily ragweed pollen AIT.Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled,dose-escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 units of Ambrosia artemislifolia major allergen 1 [Amb a 1 U],without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 Amb a 1-U was not initiated. Fifty-three subjects were randomized (AIT,n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate(5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was 24 ≤ hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed-specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups ≥ 24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT 24

Pharmacokinetics and safety of FV-100, a novel oral anti-herpes zoster nucleoside analogue, administered in single and multiple doses to healthy young adult and elderly adult volunteers.

FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Comparing the Pharmacokinetics of 2 Novel Intravenous Tramadol Dosing Regimens to Oral Tramadol: A Randomized 3-Arm Crossover Study.

Tramadol is a dual-mechanism (opiate and monoamine reuptake inhibition) analgesic. Intravenous (IV) tramadol has been widely prescribed outside the United States. However, there have not been studies comparing the pharmacokinetics (PK) of IV dosing regimens to that of oral tramadol. In this phase 1, open-label, single investigational center, 3-treatment, 3-period, multidose crossover study, we compared 2 novel IV dosing regimens (IV tramadol 75 mg and IV tramadol 50 mg) to oral tramadol 100 mg given every 6 hours (the highest approved oral dosage in the United States) Compared to the oral regimen, IV tramadol 50 mg administered at hours 0, 2, and 4 and every 4 hours thereafter reached initial tramadol peak serum concentration (Cmax ) more rapidly, while resulting in similar overall steady-state Cmax and area under the plasma concentration-time curve. IV tramadol 75 mg administered at hours 0, 3, and 6 and every 6 hours thereafter had higher Cmax and greater fluctuation in peak to trough tramadol concentration. The primary metabolite M1 (a potent µ agonist) had lower area under the plasma concentration-time curve and Cmax for both IV regimens than for the oral regimen. IV tramadol at both doses was well tolerated, with adverse event profiles consistent with the known pharmacological effects of tramadol. IV tramadol 50 mg is now in phase 3 development in patients with postsurgical pain.

Effects of aspirin when added to the prostaglandin D2 receptor antagonist laropiprant on niacin-induced flushing symptoms.

Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to prostaglandin D2 (PGD2)-mediated cutaneous vasodilation. Adjunctive treatment with the PGD2 receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P=.180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.

Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus.

SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2 mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2 mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.

First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of an Oral Formulation of DS-1040, an Inhibitor of the Activated Form of Thrombin-Activatable Fibrinolysis Inhibitor, in Healthy Subjects.

DS-1040, a low-molecular-weight imidazole derivative, inhibits the enzymatic activity of thrombin-activatable fibrinolysis inhibitor (TAFIa), enhancing endogenous tissue plasminogen activator-triggered fibrinolysis. This first-in-human, randomized, placebo-controlled, phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation of DS-1040. Healthy adults (aged 20-45 years; N = 56) were randomized 3:1 to receive DS-1040 orally administered as single ascending doses (50, 100, 200, or 400 mg) or placebo, or DS-1040 multiple ascending doses (100 mg once daily, 200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and PD parameters were assessed. All doses of DS-1040 were well tolerated; no serious/severe adverse events (AEs) or discontinuations due to AEs occurred. DS-1040 had no effect on coagulation parameters, and no treatment-related trends in the bleeding time were observed. DS-1040 exposure (peak concentration and area under the concentration-time curve) increased in a dose-proportional manner across the single-dose range. With multiple doses, steady state was achieved by day 7 with minimal accumulation (mean accumulation ratio 1.15-1.25), and the PK was time-independent. After 72 hours, approximately 10% of the DS-1040 400-mg single dose was recovered in urine as intact parent drug. The mean terminal half-life ranged from 17.2 to 24.9 hours, which was similar to previous intravenous administration data. Dose-dependent inhibition of total TAFIa activity was observed following single and multiple doses of oral DS-1040. The safety and PK/PD profiles of oral DS-1040 in healthy subjects support further clinical development.

Lack of Impact by SCY-078, a First-in-Class Oral Fungicidal Glucan Synthase Inhibitor, on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports the Low Risk for Clinically Relevant Metabolic Drug-Drug Interactions.

SCY-078, the first in a new class of ß 1,3-glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY-078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of the potential interaction with SCY-078, this phase 1, open-label, 2-period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY-078 dosed to therapeutically relevant SCY-078 concentration exposure after repeat dosing. Healthy adult subjects were randomized to 2 treatment sequences: a single oral 4-mg rosiglitazone dose alone on day 1 or a 1250-mg SCY-078 loading dose on day 1 followed by a once-daily 750-mg SCY-078 dose for an additional 7 days (reflecting the clinical regimen evaluated during phase 2 studies for infections by Candida species) and concurrent administration of a single oral 4-mg rosiglitazone dose on day 3, before alternating following a ≥10-day washout. The exposure to SCY-078 observed in this study was in line with the intended exposure for treatment of invasive fungal infections. The 90% confidence intervals for rosiglitazone exposure geometric mean ratios were within the prespecified no effect interval of 0.70-1.43. Additionally, maximum concentration values for rosiglitazone and its metabolite, N-desmethylrosiglitazone, were not significantly affected by co-administration with SCY-078. Overall, rosiglitazone exposure was not impacted to a clinically meaningful extent with co-administration of therapeutically relevant SCY-078 concentration exposure after repeat dosing. The results are indicative of low risk for interaction of SCY-078 with drugs metabolized via the CYP family of enzymes.

An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults.

BACKGROUND: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism. OBJECTIVES: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree. METHODS: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences. RESULTS: Total edoxaban exposure was similar between the intact and crushed tablet regimens (mean area under the plasma concentration-time curve from time zero to infinity: whole tablet, 2132 ng·h/mL; nasogastric tube, 2021 ng·h/mL; apple puree, 2076 ng·h/mL). Mean maximum plasma concentration, area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, terminal half-life, and apparent total body clearance values were also similar. Time to maximum plasma concentration was significantly shorter for the nasogastric tube suspension and apple puree vs. the whole tablet [Hodges-Lehmann estimate of median difference (90% confidence interval): -0.75 (-1.25, -0.28); p = 0.0003 and -0.62 (-0.99, -0.26); p = 0.0024, respectively]. The maximum plasma concentation, area under the plasma concentration-time curve from time zero to infinity, and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80-125% bioequivalence criterion. The safety and tolerability of edoxaban did not differ between treatment regimens. CONCLUSION: The results support the use of edoxaban tablets crushed and administered either via a nasogastric tube or orally mixed in apple puree in patients who are unable to swallow solid oral dose formulations.

A Prospective Multicenter Evaluation of the Accuracy of a Novel Implanted Continuous Glucose Sensor: PRECISE II.

BACKGROUND: Persistent use of real-time continuous glucose monitoring (CGM) improves diabetes control in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS: PRECISE II was a nonrandomized, blinded, prospective, single-arm, multicenter study that evaluated the accuracy and safety of the implantable Eversense CGM system among adult participants with T1D and T2D (NCT02647905). The primary endpoint was the mean absolute relative difference (MARD) between paired Eversense and Yellow Springs Instrument (YSI) reference measurements through 90 days postinsertion for reference glucose values from 40 to 400 mg/dL. Additional endpoints included Clarke Error Grid analysis and sensor longevity. The primary safety endpoint was the incidence of device-related or sensor insertion/removal procedure-related serious adverse events (SAEs) through 90 days postinsertion. RESULTS: Ninety participants received the CGM system. The overall MARD value against reference glucose values was 8.8% (95% confidence interval: 8.1%-9.3%), which was significantly lower than the prespecified 20% performance goal for accuracy (P < 0.0001). Ninety-three percent of CGM values were within 20/20% of reference values over the total glucose range of 40-400 mg/dL. Clarke Error Grid analysis showed 99.3% of samples in the clinically acceptable error zones A (92.8%) and B (6.5%). Ninety-one percent of sensors were functional through day 90. One related SAE (1.1%) occurred during the study for removal of a sensor. CONCLUSIONS: The PRECISE II trial demonstrated that the Eversense CGM system provided accurate glucose readings through the intended 90-day sensor life with a favorable safety profile.

A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of DS-3801b, a Motilin Receptor Agonist, in Healthy Subjects.

DS-3801b is an orally active, nonmacrolide, selective motilin receptor agonist. The aim of this 2-part first-in-human study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects on proximal and distal gastrointestinal (GI) motility of single oral doses of DS-3801b in healthy subjects. The 13 C-octanoate breath test was used to assess gastric emptying (GE), a measure of proximal GI motility. The time to first bowel movement (TTFBM) and the consistency of the first bowel movement according to the Bristol Stool Scale (BSS) were recorded to assess distal GI motility. In part A, 48 subjects received single oral doses of DS-3801b from 1 to 100 mg or placebo (6 DS-3801b, 2 placebo per cohort). In part B, 12 subjects received 50 mg of DS-3801b or placebo to assess GE. DS-3801b is safe and generally well tolerated after doses up to 50 mg, resulting in mild, predominantly GI adverse events. DS-3801a plasma concentrations increase with increasing doses; however, Cmax increases greater than dose-proportionally, whereas AUC increases less than dose-proportionally. The double peaks observed are consistent with multiple absorption sites. Results of the 13 C-octanoate breath test indicate that DS-3801b accelerates GE. Fifty milligrams of DS-3801b resulted in a 20.8% median reduction in GE T1/2 and a 20.6% median reduction in GE Tlag compared with placebo. However, this increase in proximal GI motility was not accompanied by an effect on distal GI motility, as indicated by no significant differences in TTFBM and BSS values across DS-3801b dose levels or compared with placebo.

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.

UNLABELLED: GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. TRIAL REGISTRATION: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Absence of pharmacokinetic interaction between intravenous peramivir and oral oseltamivir or rimantadine in humans.

Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.