1. Introduction Excipients are crucial assets in pharmaceutical formulations. Whilst not responsible for the therapeutic effect, many are used to enhance the active ingredient (AI) efficacy, by altering the ADME properties of the drug [1]. These so-called "inactive ingredients" are not inert, they can produce intended positive effects [2] by interacting with the AI (efficacy optimisation); however, sometimes unintentional effects can lead to toxicity [3]. A number of toxicity tests are therefore required for excipients safety assessment, mainly governed by the route and duration of administration [4]. Use of entirely new excipients is limited as the ones not previously registered with regulatory authorities have to undergo a full safety evaluation, which is very expensive in terms of expense, time and number of animals. Thus, most formulations will be developed using excipients already authorised and registered in the pharmacopeia for a specific functionality [5]. Adverse effects from excipients can emerge late in drug development, during clinical trials or even after marketing authorisation. Therefore, information on previous safety assessment of excipients is critical to both the pharmaceutical and regulatory organisations. Guidelines are currently being revised (EMA guideline on Excipients in the Label and Package Leaflet of Medicinal Products for Human Use (CPMP/463/00); FDA Guidance for Industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical). After giving a brief overview of the type of information within the database, a use-case analysis will be presented. Emphasis will be placed on how such in silico tools provide suitable answers within the context of REACH, which requires data sharing between companies in order to avoid duplication of animal experiments.

3. Record count in the current database

2. A consortia approach to database generation

5. Conclusion

Excipients data sharing initiative: a step towards 3-R principle implementation Anne-Laure Werner, Monika Kister and David Wilkinson

Figure 1: Evolution of the number of Excipients (A) and Study records (B) in the 5 successive releases (2009 to 2013)

The Excipients data sharing initiative was derived from the Dog project and initially involved 10 pharmaceutical companies, 2 charities (FRAME and RSPCA) and Lhasa Limited. Lhasa's role is to design and populate the database with proprietary data along with some additional data extracted from the literature, host confidential data and liaise between the different members. The Excipients pilot version was initially released to members in 2008 and the database has subsequently been released annually (figure 1). A large amount of archives toxicity data donated by the members along with more recent ones have already been captured and peer-reviewed (to a high quality standard) in the fit-for-purpose Vitic Nexus schema, making them easily searchable and retrievable. 11 pharmaceutical companies are currently involved in expanding the data coverage. Members are required to donate 50 to 60 excipients study data over the first 3 years. Thereafter, donation will be focused more on a quality rather than quantity basis, emphasizing new excipients and/or data that fits with the identified knowledge gaps such as reprotoxicity, juvenile toxicity or carcinogenicity.

The Excipients database addresses REACH requirements by encouraging data sharing between companies thus reducing unnecessary animal testing. Members use the database to choose an appropriate vehicle and dosage for a specific study design (species, treatment route and duration). It has been used to optimise drug efficacy whilst ensuring excipients safety. The data coverage is still expanding, focusing on filling the actual knowledge gaps both through data donation and literature research. Together, with feedback from our members, we are aiming to diversify the database applications to help in early drug development stages and to quantify the impact of the Excipients database on reducing the number of animals tested.

4. Use case of the Excipients database Due to member confidentiality issues, a literature case study [6] is described to illustrate a potential use case of the Excipients database. The aim of the study was to define an appropriate vehicle and dosage for poorly water soluble drugs to be used for non-clinical safety assessment in Wistar rat toxicity studies by oral route (figure 2).

Figure 2: Excipient database screenshot displaying: • Single and repeat-dose study table : A/ Study design information such as dose, route, duration and frequency of administration, species and strain, number of animals per group, sex, age B/ Study outcome such as tolerability, mortality, effects on bodyweight, food and water consumption and ophthalmology findings. • Supplementary tables: C/Components : exact vehicle composition D/ Citation: full literature reference E/ Clinical signs F/ Clinical chemistry G/ Haematology H/ Urinalysis I/ Organ weight J/ Macropathology K/ Histopathology L/ Free text for any additional findings and study information.

• No information was available on the vehicle ADME and its effect on the bone marrow, gastrointestinal tract, cardiovascular, respiratory and reproductive systems.

• The toxicity findings of the tested vehicle selected as a bioavailability enhancer and solubiliser were dose and sex-dependant.

• It was concluded that a daily dose of 5 mL/kg was an acceptable volume to be used in Wistar rat oral toxicity studies.

236

441537

676764

0

100

200

300

400

500

600

700

800

900

2009 2010 2011 2012 2013

Num

ber o

f rec

ords

Year

Cumulative Number of Vehicle Records

Number of vehicles 432

840

1291

18272026

53 53 61254 254

0

500

1000

1500

2000

2500

2009 2010 2011 2012 2013

Num

ber o

f rec

ords

Year

Cumulative Number of Study Records

Single and repeat dose study recordsBlood compatibility records

Last Excipients Vitic Nexus release 2013.1 (see table 1) was gathering information regarding 764 vehicles with a total of 2286 study records (including 296 single excipients and 412 water + single excipient study records) split into types of studies such as single or repeat dose toxicity, carcinogenicity, reprotoxicity, juvenile toxicity, blood compatibility and genotoxicity in vivo studies.

Table 1: Data coverage for different routes of administration (A), treatment durations (B), test species (C) and tolerabilities (D)

Acknowledgments to the Excipients Consortium

D E F

G I H

L

B A

C

J

K

6. References • [1] Buggins TR et al, Adv Drug Deliv Rev (2007), 59(15), 1482-1503 • [2] Kalinkova GN, Int J Pharm (1999), 187(1), 1-15 • [3] Pifferi G et al, Farmaco (2003), 58(8), 541-550 • [4] Steinberg M et al, Regul Toxicol Pharmacol (1996), 24(2 Pt 1), 149-154 • [5] Osterberg RE et al, Int J Toxicol (2003), 22(5), 377-380 • [6] Delongeas JL et al, Regul Toxicol Pharmacol (2010), 57(2-3), 284-290

A B

A B C D

Route of Admin. No. of Vehicles

No. of Records

Oral (gavage, capsule or dietary admixture)

448 1336 (66%)

Intravenous (bolus or infusion) 249 545 (27%)

Subcutaneous 47 69 (3%) Dermal 21 31 (2%)

Intraperitoneal 22 29 (1%) Others ( intraarterial,

intramuscular, intranasal, nasogastric, ocular, perivenous)

10 16 (1%)

Length of Study

No. of Vehicles

No. of Records

1 day 300 663 (33%)

2 – 7 days 190 311 (15%)

8 – 14 days 223 389 (19%)

15 – 31 days 232 423 (21%)

32 – 93 days 85 156 (8%)

94 – 273 days 38 47 (2%)

>= 274 days 10 22 (1%)

Species No. of Vehicles No. of Records

Dog 228 379 (19%) Guinea Pig 35 80 (4%)

Minipig 29 36 (2%) Monkey 89 148 (7%) Mouse 83 149 (7%) Primate 6 11 (1%) Rabbit 76 112 (6%)

Rat 467 1111 (55%)

Tolerability No. of Vehicles

No. of Records

Tolerated without findings

551 1562 (77%)

Tolerated with findings 181 346 (17%)

Not tolerated 52 67 (3%)

Inconclusive 48 51 (3%)