KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study results.

BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin. OBJECTIVE: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults. METHODS: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 × 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals. RESULTS: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC0-24) of 18,600 (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours. CONCLUSION: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated. GOV IDENTIFIER: NCT04349800.

Comparative Bioavailability Study of a New Orodispersible Formulation of Ibuprofen Versus Two Existing Oral Tablet Formulations in Healthy Male and Female Volunteers.

PURPOSE: This study aimed to assess the comparative bioavailability between ibuprofen acid orodispersible tablets (Test product) and ibuprofen acid oral tablets (Reference product). METHODS: This was a randomized, single-dose, 3-way crossover, open-label, pharmacokinetic study in 36 healthy male and female volunteers. Blood samples were taken periodically over a 12-h period after dosing to derive total plasma ibuprofen and S(+)/R(-) ibuprofen enantiomer pharmacokinetic parameters; safety profile and tolerability were evaluated throughout the study. FINDINGS: After a single-dose administration of ibuprofen acid oral tablets (2 × 200 mg), the total ibuprofen Cmax and AUC0-t (geometric least square [LS] mean) for the Test product was 29.4 µg/mL and 100.6 h/µg/mL, respectively, and for the Reference product it was 30.6 µg/mL and 98.7 h/µg/mL. The geometric LS mean Test/Reference ratio 90% CI for both total ibuprofen Cmax (90.71-101.77) and AUC0-t (98.72-105.23) was contained entirely within the predefined 80.00%-125.00% lower and upper limits; in addition, no statistically significant difference was found in Tmax (P = 0.1819) after fasted administration of the Test and Reference products. There were 4 mild treatment emergent adverse events, considered unrelated to the study drug, reported by 2 volunteers during the study; no serious adverse events, no suspected unexpected serious adverse events. and no clinically significant changes in laboratory safety, vital signs, or 12-lead ECG measurements were reported. The enantiomer-specific analysis mirrored that of total ibuprofen, with the Cmax and AUC0-t LS mean Test/Reference ratio 90% CI for both ibuprofen S(+) and R(-) enantiomers contained entirely within the predetermined 80%-125.00% limits. IMPLICATIONS: This study found that ibuprofen acid 200 mg orodispersible tablets and ibuprofen acid 200 mg tablets met the regulatory criteria for bioequivalence for AUC0-t and Cmax. Post hoc analysis of ibuprofen both S(+) and R(-) enantiomers mirrored the findings for total ibuprofen. All investigational products were found to be well tolerated. Clinicaltrials.gov identifier: NCT03180879.

Bioequivalence of 2 Naproxen Sodium Tablet Formulations in Healthy Male and Female Volunteers.

BACKGROUND: Naproxen is an established, effective treatment for pain management in acute musculoskeletal disorders and traumatic sports injuries. Reckitt Benckiser Health Limited have developed a naproxen sodium tablet with the same pharmacokinetic and pharmacodynamic properties as existing marketed naproxen products with the intention of increasing the number of naproxen products available for prescribers and pharmacies. OBJECTIVE: This study aimed to assess comparative bioavailability between a test medicinal product developed by Reckitt Benckiser Health Limited (RB, 103-105 Bath Rd, Slough, SL1 3UH, United Kingdom; RB naproxen sodium 220 mg tablets), and a reference medicinal product, Aleve naproxen sodium 220 mg (Bayer B.V., Energieweg 1, 3641 RT Mijdrecht, Netherlands), in the fasted state. METHODS: This was a randomized, single-dose, 2-way crossover, open-label, comparative bioavailability, pharmacokinetic study in 18 healthy male and female volunteers with a 5- to 8-day washout permitted between doses (based on the anticipated minimum washout period for naproxen determined from the known terminal elimination half-life of up to 17 hours). Blood samples were taken periodically over a 72-hour period following dosing and analyzed for plasma naproxen concentration using a validated LC-MS method. Noncompartmental pharmacokinetic analysis was used to derive pharmacokinetic parameters for naproxen; safety and tolerability were evaluated throughout the study. RESULTS: Following a single-dose administration of naproxen sodium tablets (2 × 220 mg), the Cmax and AUC0-t (geometric least squares mean) for the test product was 65.88 µg/mL and 893.37 h * µg/mL, respectively; and for the reference product was 64.59 µg/mL and 890.60 h * µg/mL. The geometric least squares mean test/reference ratio 90% CI for both Cmax (93.98-110.70) and AUC0-t (98.04-102.63) was contained entirely within the predefined 80.00% to 125.00% lower and upper limits; additionally, there was no statistically significant difference in Tmax (P = 0.9878) following fasted administration of the test and reference product. There was 1 treatment-emergent adverse event reported during the study; there were no serious adverse events, no suspected unexpected serious adverse events, and no clinically significant changes in laboratory safety, vital signs, or 12-lead ECG measurements reported. CONCLUSIONS: This single-dose study found that the test product (RB naproxen sodium tablets) and reference product (Aleve naproxen sodium tablets) met the regulatory criteria for bioequivalence in these fasted male and female volunteers; both test and reference products were found to be safe and well tolerated.

Selectivity in the impact of P-glycoprotein upon pulmonary absorption of airway-dosed substrates: a study in ex vivo lung models using chemical inhibition and genetic knockout.

P-glycoprotein (P-gp) mediated efflux is recognised to alter the absorption and disposition of a diverse range of substrates. Despite evidence showing the presence of P-gp within the lung, relatively little is known about the transporter's effect upon the absorption and distribution of drugs delivered via the pulmonary route. Here, we present data from an intact isolated rat lung model, alongside two isolated mouse lung models using either chemical or genetic inhibition of P-gp. Data from all three models show inhibition of P-gp increases the extent of absorption of a subset of P-gp substrates (e.g. rhodamine 123 and loperamide) whose physico-chemical properties are distinct from those whose pulmonary absorption remained unaffected (e.g. digoxin and saquinavir). This is the first study showing direct evidence of P-gp mediated efflux within an intact lung, a finding that should warrant consideration as part of respiratory drug discovery and development as well as in the understanding of pulmonary pharmacokinetic (PK)-pharmacodynamic (PD) relationships.

Spatial expression and functionality of drug transporters in the intact lung: objectives for further research.

This commentary provides a background appraising evidence in the intact lung on the spatial expression of drug transporters and, where available, evidence in the intact lung of the impact, or otherwise, that such transporters can have upon pulmonary drug absorption and disposition. Ultimately drug discovery and development scientists will wish to identify in a 'pulmonary' context the effect of disease upon transporter function, the potential for drug transporters to contribute to drug-drug interactions and to inter-individual variation in drug handling and response. The rate and extent of lung epithelial permeation of drugs involve an interplay between the dose and the deposition site of drug within the lung and physiological variables operational at the epithelial-luminal interface. Amongst the latter variables is the potential impact of active transporter processes which may well display regio-selective characteristics along the epithelial tract. In pulmonary tissues the spatial pattern of drug transporter expression is generally poorly defined and the functional significance of transporters within the intact lung is explored in only a limited manner. Active transporters in the lung epithelium may affect airway residence times of drug, modulate access of drug to intracellular targets and to submucosal lung tissue, and potentially influence airway to systemic drug absorption profiles. Transporters in the lung tissue may also have the capacity to mediate uptake of drug from the systemic circulation resulting in drug accumulation in the lung. Transporters have physiological roles and new drug candidates while not necessarily serving as transport substrates may modulate transporter activity and hence physiology. The commentary highlights a series of recommendations for further work in pulmonary drug transporter research.

RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models.

OBJECTIVES: Carrier-mediated transport mechanisms play crucial roles in drug absorption and elimination processes, as well as in the transport of endogenous molecules affecting cellular regulation and function. In this study we used RT-PCR analysis to characterise the mRNA transcript expression of a wide range of membrane carrier transporters in several in-vitro lung epithelial cell models. Transporters studied included: 11 ATP-binding cassette (ABC) transporters, 11 solute carrier (SLC) transporters and 9 solute carrier organic anion (SLCO) transporters. METHODS: The cell culture models included both established cell lines (A549, Calu-3, 16HBE14o-, BEAS-2B) and freshly isolated lung epithelial cells in primary culture (human bronchial and alveolar epithelial cells). KEY FINDINGS: The expression profiles of several clinically relevant drug transporters were characterised using RT-PCR analysis. Our results showed differential transporter expression in cell culture models from different regions of the lung and also highlighted disparities when comparing lung cell lines with primary cell culture models. Differences in transporter expression between cell models of pulmonary and gastrointestinal origin were also noted. CONCLUSIONS: The information will guide and validate the use of in-vitro lung epithelial cell lines in the study of pulmonary administered drugs and candidate molecules.