Search

An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 µg [14C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 µg dose followed by an oral 800 µg dose of [14C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (Fabs), proportion of nemiralisib escaping gut wall metabolism (Fg), hepatic extraction (Eh), fraction of dose absorbed from inhaled dose (Flung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while Flung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (Fabs, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (Fg and Eh being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (Fabs), the proportion of drug escaping first-pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh). Entero-test bile sampling enabled characterization of biliary elimination pathways.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure., Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.)

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [14C]‐radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2‐period, open‐label study, 6 healthy male subjects received a single IV microtracer 1‐hour infusion of 4 μg [14C]‐batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 μg) followed by oral [14C]‐batefenterol (200 μg) in period 2 after a 14‐day washout. The primary end points included: the area under the concentration‐time curve from time zero to last time of quantifiable concentration (AUC0‐t); maximum observed concentration (Cmax); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0‐t of [14C]‐batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC0‐t ratio indicated that [14C]‐batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [14C]‐batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and β2‐agonist) administered in combination (BAT/FF) or as monotherapy. In this open‐label, 6‐period, crossover study of 48 subjects, the treatment sequences were (1) single high‐dose BAT/FF 900/300 μg followed by repeated therapeutic doses of BAT/FF 300/100 μg (once daily for 7 days); (2) single high‐dose BAT 900 μg administered concurrently with FF 300 μg; (3) single high‐dose BAT 900 μg followed by repeated therapeutic‐dose BAT 300 μg; (4) single high‐dose FF 300 μg followed by repeated therapeutic‐dose FF 100 μg; (5) single high‐dose FF 300 μg (magnesium stearate); and (6) single high‐dose FF/vilanterol 300/75 μg. Plasma FF area under the plasma drug concentration‐time curve (AUC) was reduced after single high‐dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75‐0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects.

The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [(14)C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acid-catalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

The Australian Government introduced the National Bowel Cancer Screening Program (NBCSP) in 2006, in which Australian residents are offered a faecal immunochemical test (FIT) for haemoglobin when they turn 50, 55 and 65 years. We describe waiting times, quality of existing colonoscopic services, and quality of documentation of ongoing surveillance activities in those with a positive FIT.A retrospective review of case notes of patients undergoing colonoscopy in public tertiary hospitals in South Australia, identified through the NBCSP (pilot and phase 1 and 2 groups).Records on 433 patients were assessable, representing 65% of public NBCSP cases. Colonoscopy waiting times varied, with only 23% of patients undergoing colonoscopy within the 30 day benchmark. The polyp retrieval rate was 98.4%. Surveillance recommendations after a polyp result were considered appropriate in 55% cases; with inappropriate intervals usually being set too early (59%). Where structured recall systems were utilised, appropriateness of follow up surveillance significantly improved.Overall, quality of colonoscopy was good. Waiting times were delayed with a minority of cases meeting the benchmark 30 day waiting time. Recommended surveillance colonoscopy intervals deviated from the guidelines in nearly half of patients, with a tendency to colonoscope too frequently according to the guidelines. More structured recall systems would be expected to reduce this excessive workload.

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [¹⁴C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.

Purpose: To evaluate the effect of reducing the number of visual acuity measurements made in a defocus curve on the quality of data quantified. Setting: Midland Eye, Solihull, United Kingdom. Design: Evaluation of a technique. Methods: Defocus curves were constructed by measuring visual acuity on a distance logMAR letter chart, randomizing the test letters between lens presentations. The lens powers evaluated ranged between +1.50 diopters (D) and -5.00 D in 0.50 D steps, which were also presented in a randomized order. Defocus curves were measured binocularly with the Tecnis diffractive, Rezoom refractive, Lentis rotationally asymmetric segmented (+3.00 D addition [add]), and Finevision trifocal multifocal intraocular lenses (IOLs) implanted bilaterally, and also for the diffractive IOL and refractive or rotationally asymmetric segmented (+3.00 D and +1.50 D adds) multifocal IOLs implanted contralaterally. Relative and absolute range of clear-focus metrics and area metrics were calculated for curves fitted using 0.50 D, 1.00 D, and 1.50 D steps and a near add-specific profile (ie, distance, half the near add, and the full near-add powers). Results: A significant difference in simulated results was found in at least 1 of the relative or absolute range of clear-focus or area metrics for each of the multifocal designs examined when the defocus-curve step size was increased (P

Background The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy. Methods The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150–1500 mg (NCT01371812). Results Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0–1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%. Conclusion In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

Surveillance following surgery for colorectal cancer aims to detect treatable disease relapse or metachronous neoplasia. Metachronous cancers have been reported within a short duration of follow-up, and may be due to missed lesions, seeding into polypectomy wounds or accelerated tumorigenesis related to genetic instability. The purpose of this study was to establish the timing and method of detection of metachronous cancers in a large population of patients in a surveillance database.This retrospective clinical study used patients with an elevated risk of colorectal neoplasia included in a colonoscopy-based surveillance programme to identify those with two or more colorectal cancers, as well as the timing and method of detection of the tumours. Colonoscopy reports and histopathology results were reviewed to determine quality of bowel preparation, tumour location, and polypectomy data.Fourteen (2.5%) of 569 patients with colorectal cancer developed metachronous malignant tumours, nearly half of which were identified within 3 years of follow-up by surveillance colonoscopy or an interval faecal immunochemical test for globin. None of these had a previous polypectomy at the site of the second tumour, bowel preparation at the original colonoscopy was good in most cases, and no metachronous tumour occurred at a colonic flexure.Metachronous cancers can occur early during follow-up after curative intent resection, and early colonoscopic surveillance may be warranted.

1. The technique of accelerator mass spectrometry (AMS) is outlined. 2. The use of AMS in an initial validation study in animals is outlined. As part of the validation of the technique, samples from the animal study were analysed by both liquid scintillation counting (LSC) and, following dilution, by AMS. The results were similar. 3. The use of AMS in support of a clinical study is described. Six healthy male human volunteers were administered 2.7 mg [14C]-GI1817771 (121 Bq; 3.3nCi) to produce an exposure to ionizing radiation of 0.06 microSv. Mass balance in recovery of administered radioactivity was achieved and information about the presence of systemically circulating metabolites was gained. 4. The future potential of the technique of AMS is discussed.

The purpose of this study was to assess the clinical performance of hydrogel contact lenses manufactured from a novel, biomimetic, 59% water content, hydrogel material (Omafilcon A) as compared with a representative range of control materials (Polymacon, Etafilcon A, Atlafilcon A, and Welcon CE).Thirty subjects were enrolled in a 2-month, double-masked, randomized, comparative, daily wear study. Subjects wore two sets of lenses; each pair was worn for 1 month. In each part of the study, subjects wore a Proclear (Biocompatibles Ltd.) test lens (Omafilcon A) in one eye and a control lens in the other eye. In vivo lens dehydration was measured after 1 week of lens wear. Lenses were collected at the end of the study and subjected to in vitro spectrofluorimetric analysis to measure protein and lipid deposits.Omafilcon A showed significantly less lipid spoilation than all the controls and significantly less protein than the Etafilcon A and Atlafilcon A lenses. High levels of protein were found on the Group 4 lenses (Etafilcon A) and high levels of lipid were found on the Group 2 lenses (Weicon CE). The Omafilcon A lenses exhibited significantly less on-eye dehydration than the Etafilcon A lenses (P0.0001) and the Weicon CE lenses (P0.005). The majority of subjects expressed a preference for the Proclear lens, generally for reasons of comfort. Some minor differences in aspects of lens fit were noted between the test and control lenses, however, none of these were felt to be great enough to affect comfort.We hypothesize that the reduced spoliation seen with the Omafilcon A lens relates to the biomimetic nature of the material which incorporates phosphorylcholine.