Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?

Pharmaceutical Research, May 2016

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 Drugs continue to be withdrawn from the market due to unforeseen toxicity, side effects, and drug interactions.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.

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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)


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Timothy Hammond, Patricia Allen, Holly Birdsall. Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?, Pharmaceutical Research, 2016, pp. 1545-1551, Volume 33, Issue 7, DOI: 10.1007/s11095-016-1942-0