Drug Discovery 301

DRUG DISCOVERY 301

The past two issues, the WEEKLY explored the first two stages of drug discovery. We looked at how pharmaceutical companies identify drug targets, or the molecules (usually proteins) involved in an illness that an ‘as yet undeveloped drug’ will hopefully act on. Next, we examined how researchers develop those pharmaceutical candidates. This week, we turn to what comes next for fledgling drugs on the arduous journey to FDA approval. First, though, a smidgeon of Latin.

Primum Non Nocere

This maxim from Hippocrates means “First, do no harm.” Before testing a drug on people, researchers must make sure it’s safe in two important ways. First, they assess a substance’s safety in vitro. This Latin phrase means “in glass,” that is, lab-grown cells. The cell type varies, but if possible, researchers use one that is relevant to the disease in question. For example, they may use lung cells to test a drug for respiratory syncytial virus (RSV).

In vivo testing (“in a living thing”) comes next. This area of preclinical testing assesses a drug candidate’s toxicity in at least two different species of animals, such as mice and guinea pigs. The animals receive more of the drug for longer than would human volunteers. Meanwhile, lab technicians watch the animals for adverse effects. Preclinical testing must follow the FDA’s Good Laboratory Practice (GLP) guidelines. These regulations help ensure scientific integrity and humane treatment of laboratory animals.

Homing in On the Sweet Spot

Almost any substance (even water!) can be toxic in very high amounts. Consequently, drug developers aim for just the right dose—one that gives the desired effect with minimal unwanted consequences. Finding the sweet spot is the domain of pharmacokinetic (PK) and pharmacodynamic (PD) analyses. Think of pharmacokinetics as “what a body does to a drug” and pharmacodynamics as “what a drug does to a body.”

PK analyses typically measure:

• The time it takes to absorb a drug into the body
• Maximum concentration (Cmax) of a drug in plasma and target tissues
• Bioavailability (where in the body and at what concentration the drug ends up)
• Half-life, or how long a drug takes to reach half its maximum concentration in the body
• Clearance, or the time for a drug to reach undetectable levels through excretion

Pharmacodynamic analyses involve observing the biological repercussions of increasing amounts of a drug. Negative side effects include nausea, loss of appetite, fatigue, skin sensitivity, and changes in blood pressure or heart rate. Animal PK and PD studies give scientists an idea of what a safe and effective dose of a drug might be in people.

Hunting for Mutants

Most drug candidates also undergo mutagenicity testing, which determines their likelihood of triggering mutations. Causing mutations indicates that a fledgling drug may be carcinogenic, hence often consigning it to the graveyard of pharmaceutical failure. One common screening for mutagenicity is the Ames test, which identifies chemicals that cause increased rates of mutations in bacteria.

Researchers can also assess a drug’s carcinogenic potential by examining test animals for tumors. (Article continues below)

Q/T Testing

Heart problems aren’t just bad for people, they’re bad for baby drugs too. So, companies try to rule out anything with potential cardiac side effects as early as possible. To find drugs that may be heart-unhealthy, researchers look at the “QT interval.” This is the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. A lengthened QT interval suggests improper activity in a person’s ventricles and is a risk factor for sudden death. If an experimental drug binds to proteins on heart cells that enable the flow of calcium ions into the heart, they may extend a QT interval. Longer intervals generally seal a drug’s doom.

Alternatives to animal testing

Currently, drug development necessitates in vivo testing to best understand how drugs act in a human body. In vitro testing simply can’t replicate Homo sapiens’ complex physiology. However, two innovations may help reduce the animal testing involved in the search for new treatments:

• 3D tissue arrays: Companies such as Organovo (San Diego, CA) create tissue arrays that better mimic human physiology than flat layers of cells in tissue culture flasks
• Computer modeling: Researchers at the University of California, San Francisco, and SeaChange Pharmaceuticals (San Francisco, CA) have developed software that reliably predicts small molecule drugs’ interaction with “off-target” molecules. These are cellular proteins other than the intended drug target. More off-target interactions mean a greater chance of undesirable side-effects

The Paper Chase

Once researchers amass enough safety data to ensure that a drug candidate will be safe for people, they submit an Investigational New Drug (IND) application to the FDA. The IND application contains short-term safety data, information on manufacturing the drug, and details about the methodology and design of clinical testing. If the FDA blesses the application, the drug candidate may enter Phase 1 clinical testing. Animal testing often continues in parallel with clinical (human) studies to collect long-term safety data, especially for medicines that treat chronic diseases.

Cocktail Fodder

For every 5,000 drugs tested preclinically, only about five show enough promise to justify submitting an IND application to the FDA. Once a drug clears the preclinical testing hurdle, it can move on to human testing. Tune in next week to learn more about this crucial process.