Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility

Abstract

Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this author's 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection.

Intestinal Toxicity in Rats Following Administration of CDK4/6 Inhibitors Is Independent of Primary Pharmacology

“…The vehicle for abemaciclib and ribociclib was 0.5% hydroxypropyl methylcellulose, 0.25% tween 80 in 10 mmol/L citrate buffer, pH 3; and the vehicle for palbociclib was 0.5% methylcellulose. These vehicles are considered well tolerated by the GI tract based on concurrent vehicle results, our previous use of these and similar vehicles, and on reported literature (21,22); therefore, we used only one vehicle as control. Plasma exposure was measured in samples obtained on Day 10 at 1, 4, 7, and 24 hours after dosing.…”

Pharmacokinetics of Intravenous and Oral Metformin and R,S-Verapamil in Sinclair, Hanford, Yucatan and Göttingen Minipigs

“…The animals were dosed orally with MET.HCL formulated in 1% hydroxyethylcellulose (w/v), 0.25% polysorbate 80 (v/v), 0.05% antifoam (v/v), purified water q.s. at a dose of 5 mg/kg in a 5 ml/kg dose volume [21]. After a 7-day washout period, the animals were intravenously administered 0.5 mg/kg of MET.…”

“…After a 7-day washout period, the animals were intravenously administered 0.5 mg/kg of MET. HCL or R,S-VER formulated in 25 mM NaPO 4 buffer, pH6 [21]. Blood samples were collected in K 2 EDTA tubes prior to dosing and at selected time points up to 48 h after dose administration.…”

Effects of 0.5% and 2.0% Sodium Lauryl Sulfate in Male CD-1 Mice From a 3-Month Oral Gavage Toxicity Study

“…Sodium lauryl sulfate, also referred to as sodium dodecyl sulfate (SDS), is an anionic surfactant used in cosmetics, other consumer products, laboratory applications, and pharmaceutical formulations. [4][5][6] The chemical properties of surfactants such as SLS aid the dissolution of substances in pharmaceutical formulations. 7 Sodium lauryl sulfate is an irritant to various tissues, including the respiratory mucosa.…”

“…6 The oral toxicity and tolerability of SLS, with or without other excipients, have been evaluated in dogs and rats via gavage, feed, or water. 4,8,9 However, limited information exists regarding the oral tolerability or toxicity in mice when administered by gavage. Dogs and rats tolerate daily oral dosing of formulations containing 0.5% SLS for at least 26 weeks by gavage.…”