Below are a variety of sample hypotheses that would be appropriate for the Sternfels Prize. You may use these as models as you form your own proposal, but remember your submission must be your own novel idea.
Mechanistic Drug-Drug Interactions
Simvastatin is an HMG-CoA reductase inhibitor prescribed,
along with diet changes, to lower high cholesterol and
triglyceride levels in the blood. It is known that increased
plasma concentrations of simvastatin can lead to myopathy
(muscle pain or weakness) and rhabdomyolysis
(rapid breakdown of muscle tissue).
One of the major mechanisms of simvastatin metabolism
is through Cytochrome P-450 (CYP) 3A4. Drugs such as
ketoconazole and ritonavir are strong inhibitors of the
CYP3A4 enzyme. If a patient takes a strong CYP3A4
inhibitor concomitantly with simvastatin, the metabolism
of simvastatin is inhibited and plasma levels of
simvastatin and its active metabolite increase
significantly, putting the patient at high risk for
myopathy and rhabdomyolysis.
Given this danger, the FDA has contraindicated the
concomitant use of simvastatin with any drug known to
be a strong inhibitor of CYP3A4.
Terfenadine is an antihistamine that was used for
treatment of allergies. Soon after administration,
terfenadine is almost completely metabolized to its
active metabolite, fexofenadine, by CYP3A4. It is known
that terfenadine has cardiotoxic properties, while
fexofenadine does not.
While the rapid conversion of terfenadine to fexofenadine
usually resulted in a safe and effective drug, this
conversion was significantly slowed or stopped in
patients taking inhibitors of CYP3A4 or drinking
grapefruit juice. This caused prolongation of the QT
interval and led to cardiac arrhythmias such as Torsades
de Pointe, which can be fatal.
As such, terfenadine has since been withdrawn from the market.
The P-glycoprotein (P-gp) transporter is an efflux pump
that drives drugs and other xenobiotics out of cells
such as the enterocytes lining the lumen of the intestine.
It also facilitates transport of drugs out of the
bloodstream and into the urine and bile in the kidneys
and liver, respectively.
P-gp can be inhibited by drugs such as quinidine, leading
to its inactivation. When P-gp is blocked by quinidine,
the mechanism by which substrates, such as digoxin, move
from the enterocytes back into the lumen of the intestine
is inhibited, allowing more digoxin to cross through the
enterocyte into the bloodstream. Inhibition of P-gp also
leads to reduced clearance of digoxin into the urine.
Together, these phenomena lead to increased concentrations
of digoxin in the plasma.
Digoxin is a narrow therapeutic index drug wherein small
changes in plasma concentration can quickly lead to
toxicity, and the increase of digoxin in the plasma due
to inhibition of P-gp can become dangerous very quickly.
Potential risks include cardiac arrhythmias such as
first-, second-, and third-degree heart block, atrial
tachycardia, ventricular tachycardia, and ventricular
fibrillation. Thus, close monitoring of patients known
to be taking digoxin and an inhibitor of P-gp are
Metformin is a commonly used drug to treat Type 2 diabetes.
Plasma levels of greater than 5 g/mL have been associated
with a rare condition called lactic acidosis, a buildup
of lactic acid in the blood, which is fatal in
approximately 50% of cases. The mechanism of elimination
of metformin is excretion of the unchanged drug via the
Patients with kidney impairment have a reduced ability
to excrete metformin, leading to increased levels of
the drug in the plasma and putting them at higher risk
for side effects such as lactic acidosis. Thus, metformin
administration to patients with certain levels of kidney
impairment is contraindicated.
Abacavir is a nucleoside analog, which inhibits human
immunodeficiency virus (HIV-1) reverse transcriptase
and is used in combination with other drugs to treat
HIV-1 infection. It has been reported that some patients
have severe and sometimes fatal hypersensitivity reactions
As these reactions were being investigated, it was noted
that patients carrying the HLA-B*5701 allele are at a
significantly higher risk for a hypersensitivity reaction.
Though not all patients that have hypersensitivity reactions
carry the HLA-B*5701 allele, the risk is great enough in the
subpopulation of patients with the allele that administration
of abacavir to patients with the HLA-B*5701 allele is
contraindicated, and all patients should be screened for the
presence of the allele prior to administration.