Safety data on 19 vehicles for use in 1 month oral rodent pre‐clinical studies: administration of hydroxypropyl‐ß‐cyclodextrin causes renal toxicity

Abstract

Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.

Preformulation study and influence of DMSO and propylene glycol on the antioxidant action of isocoumarin paepalantine isolated from Paepalanthus bromelioides

“…Propylene glycol is a fre-Q5 quently co-administered solvent in formulations used in preclinical and clinical studies. This solvent is generally nontoxic and noncarcinogenic, and commonly used solvent for oral, intravenous, and topical pharmaceutical agents (Kulo et al, 2012;Fiume et al, 2012;Healing et al, 2015).…”

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

“…Shrestha et al, 2014), and the actual comparison between vehicles, including Gelucire, on the pharmacokinetic profiles of drugs has also been reported by several authors (e.g. Green et al, 2011;Healing et al, 2015). Recently, safety data of 19 vehicles after dosing in rats orally for 1 month were described in the literature (Healing et al, 2015).…”

Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension

“…As there were limited data regarding the bioavailability and non‐clinical safety of Miglyol 812, the MCT used in the formulation, a single dose rat PK study was conducted to compare the oral bioavailability of MCTs when compared to SC injection and to bridge the available non‐clinical data for MCTs to provide a comprehensive assessment of non‐clinical safety for Miglyol 812. In addition to this, a 3 month repeat dose toxicity study conducted to support the marketing application for exenatide QWS included a separate group to provide a comprehensive assessment of safety for Miglyol 812 alongside data from a previous study conducted in rats with this MCT (Healing et al, ). In addition to Miglyol 812, tricaprylin, an MCT that was evaluated in a 2 year rat carcinogenicity study previously (NTP, ), was included to compare the oral systemic exposure of the tricaprylin to the current formulation.…”

“…Previous toxicity studies in rats lacked PK data following oral administration of MCTs. Therefore, the rat was selected in this study to bridge the systemic exposure of MCTs following both oral and SC administration to the data from published oral repeat dose toxicity and carcinogenicity studies conducted with MCTs in rats (Healing et al, ; NTP, ; Sellers, Antman, Phillips, Khan, & Furst, ).…”