Dataset Information

Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters.

ABSTRACT: In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC₉₀ levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide's limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.

SUBMITTER: Jara MO

PROVIDER: S-EPMC8112893 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters.

Jara Miguel O MO Warnken Zachary N ZN Sahakijpijarn Sawittree S Moon Chaeho C Maier Esther Y EY Christensen Dale J DJ Koleng John J JJ Peters Jay I JI Hackman Maier Sarah D SD Williams Iii Robert O RO

International journal of pharmaceutics 20210512

In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 ...[more]

PMID: 33989748

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Project description:Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration "as needed", to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). Results: RT234 was generally safe and well tolerated at single doses of 0.2-2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The tmax occurred at the time that the first blood sample following completion of dosing. After Cmax was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t1/2 values were comparable after single- and repeated-dose administration. Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

Project description:IntroductionTreprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers.MethodsHealthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4).ResultsOverall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured.ConclusionTPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.

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Dataset Information

Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters.

Publications

Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters.

Similar Datasets

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