Safety and Antiviral Effects of Nebulized PC786 in a Respiratory Syncytial Virus Challenge Study.

BACKGROUND: PC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways. METHODS: Fifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics, and safety were assessed until discharge. RSV infection was confirmed by reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples. RESULTS: In the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated. CONCLUSIONS: Nebulized PC786 demonstrated a significant antiviral effect against RSV, warranting further clinical study. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18.

Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial.

AIM: To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity. METHODS: Y14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg. Part B was double-blinded and tested multiple ascending doses between 9 and 36 mg, given at 7- to 14-day intervals, over the course of 28 days, with up to five doses given per participant. The primary outcome was safety and tolerability; the secondary outcome was assessment of pharmacokinetic (PK) characteristics. Exploratory outcomes included food intake, body weight change and glucose tolerance after multiple doses. RESULTS: Between April 11, 2017 and December 24, 2018, 53 participants were enrolled into Part A and 24 into Part B of the trial. The PK characteristics were compatible with administration every 7 to 14 days. The most common adverse events (AEs) were nausea, vomiting or administration site reactions, which were mild in most cases and settled with time. No serious AE occurred. Participants given multiple doses of Y14 lost between -2.87 and -3.58 kg body weight compared with placebo (P <0.0001) at 31 days from the first dose, with profound reductions in food intake of 38% to 55% (P <0.0001, compared to placebo) and there was no evidence of tachyphylaxis. CONCLUSIONS: Our results support the continued development of Y14 as a novel treatment for obesity.

Safety and nonclinical and clinical pharmacokinetics of PC945, a novel inhaled triazole antifungal agent.

PC945 is a novel antifungal triazole formulated for nebulized delivery to treat lung Aspergillus infections. Pharmacokinetic and safety profiles from nonclinical studies and clinical trials in healthy subjects, and subjects with mild asthma were characterized. Toxicokinetics were assessed following daily 2-hour inhalation for 14 days. Potential for drug-drug interactions was evaluated using pooled human liver microsomes. Clinical safety and pharmacokinetics were assessed following (a) single inhaled doses (0.5-10 mg), (b) 7-day repeat doses (5 mg daily) in healthy subjects; (c) a single dose (5 mg) in subjects with mild asthma. Cmax occurred 4 hours (rats) or immediately (dogs) after a single dose. PC945 lung concentrations were substantially higher (>2000-fold) than those in plasma. PC945 only inhibited CYP3A4/5 substrate metabolism (IC50 : 1.33 µM [testosterone] and 0.085 µM [midazolam]). Geometric mean Cmax was 322 pg/mL (healthy subjects) and 335 pg/mL (subjects with mild asthma) 4-5 hours (median tmax ) after a single inhalation (5 mg). Following repeat, once daily inhalation (5 mg), Day 7 Cmax was 951 pg/mL (0.0016 µM) 45 minutes after dosing. Increases in Cmax and AUC0-24h were approximately dose-proportional (0.5-10 mg). PC945 administration was well tolerated in both healthy subjects and subjects with mild asthma. Treatment-emergent adverse events were mild/moderate and resolved before the study ended. No clinically significant lung function changes were observed. PC945 pharmacokinetics translated from nonclinical species to humans showed slow absorption from lungs and low systemic exposure, thereby limiting the potential for adverse side effects and drug interactions commonly seen with systemically delivered azoles.

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation.

Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and in vivo models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in vivo in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420.

AIMS: The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality. METHODS: This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS: PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS: Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.

Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion.

This article reviews currently used approaches for establishing dose proportionality in Phase I dose escalation studies. A review of relevant literature between 2002 and 2006 found that the power model was the preferred choice for assessing dose proportionality in about one-third of the articles. This article promotes the use of the power model and a conceptually appealing extension, i.e. a criterion based on comparing the 90% confidence interval for the ratio of predicted mean values from the extremes of the dose range (R(dnm)) to pre-defined equivalence criterion (theta(L),theta(U)). The choice of bioequivalence default values of theta(L)=0.8 and theta(U)=1.25 seems reasonable for dose levels only a doubling apart but are impractically strict when applied over the complete dose range. Power calculations are used to show that this prescribed criterion lacks power to conclude dose proportionality in typical Phase I dose-escalation studies. A more lenient criterion with values theta(L)=0.5 and theta(U)=2 is proposed for exploratory dose proportionality assessments across the complete dose range.

Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers.

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated. OBJECTIVES: The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. METHODS: This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a > or =7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastatin 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing. RESULTS: Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21-51 years), their mean height was 177 cm (range, 169-182 cm), and their mean body weight was 77.6 kg (range, 68-85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%,and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for approximately 28% of total plasma clearance (48.9 L/h). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers. CONCLUSIONS: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was approximately 20%, and absorption was estimated to be 50%. The volume of distribution at steady state was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was cleared by both renal and nonrenal routes; tubular secretion was the predominant renal process.