The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products.

HFO-1234ze (E) is proposed as a near zero global warming propellant for use in metered dose inhaled (MDI) products. This paper describes the non-clinical safety assessment in mice, rats, and dogs and supplements previously reported data (genetic toxicology, short-term toxicology, and reproductive toxicology). In all species, HFO-1234ze (E) was only detectable in blood for a short period after dosing with no evidence of accumulation. HFO-1234ze (E) was without any toxicological effects at very high doses in subchronic (13-week mouse) and chronic (39-week dog) studies. Chronic (26-week) administration to rats at very high doses was associated with an exacerbation of rodent progressive cardiomyopathy, a well-documented background finding in rodents. In a 2-generation study, extremely high doses were associated with the early euthanasia of some lactating female rats. This finding was considered to be significantly influenced by a state of negative energy balance, reflecting the specific vulnerability of rats during lactation. These findings are considered to not pose a risk to humans with typical MDI use given they occurred at doses which far exceed those expected in patients. Overall, the nonclinical safety data for HFO-1234ze (E) support its further development as an MDI propellant.

Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group.

Excipients are essential components within drug products that contribute significantly to their overall quality, effectiveness, and safety. There is a lack of global, harmonized guidance relating to the non-clinical testing of novel excipients which is perceived to create uncertainty and strategic risk, potentially hindering innovation and disincentivizing their use. To test these perceptions, the IQ Novel Excipient Working Group surveyed member companies regarding their main concerns and prior experience regarding the non-clinical evaluation of excipients. Of the 19 respondents, 13 provided, collectively, 33 non-clinical program examples supporting the development of novel excipients. Programs were distributed across a range of therapeutic areas and included a variety of drug modalities and administration routes. Package designs were variable, but where possible, employed the use of existing data, supplemented with new toxicology studies as appropriate. Of the programs which had submitted data to regional health authorities, only three received feedback requesting additional studies or that demonstrated differences in regional opinion. In addition, companies provided recommendations on how the current (or new) guidance related to non-clinical excipient evaluation (and other areas, such as Chemistry, Manufacturing, and Controls and databases) may be improved.

Controlled Delivery of Dutasteride Using Dissolvable Microarrays: Initial Formulation and In Vivo Evaluation.

Dutasteride is prescribed as a once-daily oral capsule for the treatment of symptomatic benign prostatic hyperplasia. As an alternative and patient-focused drug product, this laboratory evaluated the potential to deliver dutasteride in a controlled/sustained manner when formulated as a microarray. The low oral dose, low aqueous solubility, and slow rate of elimination of dutasteride were considered ideal properties which may enable a once-weekly microarray option for patients. The concept of sustained release was initially proven in mini-pigs whereby simple intradermal administration of a nanomilled dutasteride suspension (0.12 mg/kg) was associated with an exposure period of at least 1 month. Dissolvable microarrays were successfully manufactured using a nanomilled suspension and were administered to rats at doses up to 0.32 mg/kg. In these studies, serum dutasteride was quantifiable for approximately 2 weeks after a single application. In silico modeling of the rat data using a two-compartment intradermal model was conducted and predicted that, in humans, a once-weekly dose of 2 mg, given as a microarray, could deliver cumulative and therapeutically relevant levels of dutasteride in a manner which is comparable to that observed with the current oral regimen.

Alpha-glutathione S-transferase in the assessment of hepatotoxicity--its diagnostic utility in comparison with other recognized markers in the Wistar Han rat.

The diagnostic utility of alpha-glutathione S-transferase (alphaGST) in the assessment of acute hepatotoxicity was compared with a range of markers including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Rats were given a single oral dose of either alpha-naphthylisothiocynate (AN IT), bromobenzene (BrB). or thioacetamide (TAM) at concentrations previously shown to induce marked hepatotoxicity. The progression of each hepatic lesion was monitored by the measurement of a battery of markers, including alphaGST, in plasma collected at time points ranging from 3 h to 7 days after dosing. alphaGST was seen to increase significantly at 24 h (ANIT/BrB) and 3 h (TAM) postdosing, corresponding with histopathological findings. For each compound, when the degree of insult was most severe, fold increases in alphaGST were greater than those seen with ALT and AST, yet lower than those seen with glutamate dehydrogenase (BrB and ANIT). sorbitol dehydrogenase (TAM), or total bilirubin and bile acids (ANIT). Elevations in alphaGST were also detected no earlier than any other marker. AlphaGST in the rat was shown to be a valid marker of hepatotoxicity; however, its measurement offered no additional information in detecting either the time of onset/recovery or the severity of each type of hepatic injury induced.