Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?
Pharm Res
I s T h e r e a S p a c e - B a s e d Te c h n o l o g y S o l u t i o n t o Pr o b l e m s with Preclinical Drug Toxicity Testing?
Timothy Hammond 0 1 2 4 5 6 7
Patricia Allen 0 1 2 4 5 6 7
Holly Birdsall 0 1 2 4 5 6 7
0 Space Policy Institute, Elliott School of International Affairs , Washington, District of Columbia 20052 , USA
1 Nephrology Division, Department of Internal Medicine, Duke University School of Medicine , Durham, North Carolina 27705 , USA
2 Medicine Service Line/Nephrology Section, Durham VA Medical Center , Building 15, Room 109, 508 Fulton Street, Durham, North Carolina 27705 , USA
3 Timothy Hammond
4 Department of Psychiatry, Baylor College of Medicine , Houston, Texas 77030 , USA
5 Department of Immunology, Baylor College of Medicine , Houston, Texas 77030 , USA
6 Department of Otorhinolaryngology, Baylor College of Medicine , Houston, Texas 77030 , USA
7 Office of Research & Development, Department of Veterans Affairs , Washington, District of Columbia 20420 , USA
Even the finest state-of-the art preclinical drug testing, usually in primary hepatocytes, remains an imperfect science. Drugs continue to be withdrawn from the market due to unforeseen toxicity, side effects, and drug interactions. The space program may be able to provide a lifeline. Best known for rockets, space shuttles, astronauts and engineering, the space program has also delivered some serious medical science. Optimized suspension culture in NASA's specialized suspension culture devices, known as rotating wall vessels, uniquely maintains Phase I and Phase II drug metabolizing pathways in hepatocytes for weeks in cell culture. Previously prohibitively expensive, new materials and 3D printing techniques have the potential to make the NASA rotating wall vessel available inexpensively on an industrial scale. Here we address the tradeoffs inherent in the rotating wall vessel, limitations of alternative approaches for drug metabolism studies, and the market to be addressed. Better pre-clinical drug testing has the potential to significantly reduce the morbidity and mortality of one of the most common problems in modern medicine: adverse events related to pharmaceuticals.
drug metabolism; hepatocyte; space; suspension culture
THE PROBLEM WITH PRE-CLINICAL DRUG
TESTING
To develop and market a new drug, companies must prove
both efficacy and safety. It is clearly more cost effective to
identify and disqualify toxic alternatives as early in the
development process as possible. In vitro models for ADME/Tox
(absorption, distribution, metabolism and excretion &
toxicology) screening have been the holy grail of drug development
(
1
). Not only are in vitro systems more cost effective than in vivo
testing, but they support the guidelines of the National
Research Council and the EPA calling for refinement,
reduction and replacement to minimize the use of in vivo testing in
animals (
2
).
The liver is the major site of drug metabolism and
degradation in vivo. 5–10% of adverse drug reactions are the result
of liver toxicity and a third of all post-market drug withdrawals
are because of liver toxicity (
3
). The central role of the liver has
led to the use of liver cells (hepatocytes) as a major choice for
in vitro testing systems (
1,4
). The FDA has already found drug
testing with hepatocyte cell culture to be an acceptable
preclinical tool (5).
Despite extensive screening, a surprising number of drug
failures are still not recognized until late stage clinical trials,
after there has been significant investment in the development
of the drug candidate (
6–9
). A recent study found that about
19% of the drugs that failed in Phase II clinical trials and 21%
of the drugs that failed in Phase III clinical trials were failures
due to safety issues (
6,7
). One company estimates that clinical
failures due to liver toxicity cost them more than $2 billion
over the last decade (
10
). Thus there is a renewed emphasis on
earlier and more accurate toxicology evaluation as one way to
increase future success and avoid adverse clinical reactions
(
11
)
An ideal in vitro hepatocyte model would include cells with
prolonged robust biosynthetic capacity (e.g. production of
albumin) and normal basal and inducible levels of
biotransforming enzymes. Key hepatic biotransforming
enzymes include those that metabolize drugs through Phase I
(oxidation, reduction and hydrolysis) and/or Phase II (by
conjugation of functional groups) processes. An ideal in vitro liver
model would also recapitulate the organoid structure of the
intact organ in vivo where hepatocytes cluster to form channels
called bile canaliculi into which they secrete their products.
Current in vitro liver models fall short of these ideals in many
ways. Liver slices lose key metabolic enzymes within hours
(
2,12
). Immortalized hepatocytes remain viable over longer
periods of time, but have lower liver specific enzymes than
primary cells. Furthermore, cell (...truncated)