Question 1 (25 points)
The pharmacokinetics, metabolism, and excretion of Compound A, a MEK inhibitor, were characterized in healthy male
subjects (n = 6) following a single 20 mg (200 PCi) oral dose. Unchanged Compound A and metabolites were identified by
LC-MS. Compound A accounted for 21% of the drug-related material in plasma up to 48 hours postdose; it had a
terminal plasma half-life of 75.5 h. Multiple hydroxylated and glucuronidated metabolites were identified in plasma,
urine and feces, with only 2% and 6% unchanged Compound A in urine and feces, respectively (Fig 1).
Fig 1: Structures of Compound A and its metabolites
Fig 2A shows the concentration-time profiles of total radioactivity (solid squares) and Compound A (open diamonds) in
plasma following a single oral dose of [14C]Compound A (20 mg, 200 PCi). Fig 2B shows the recoveries of radioactivity in
urine (open diamonds), feces (open squares) and total recovery (black squares).
The fraction of administrated 14C absorbed was 88%, while the absolute bioavailability of Compound A was determined
to be 28%. Notably, a PK modeling program gave a good fit for the plasma concentrations of Compound A after IV
administration but did not adequately model the oral data (Fig 3).
Fig 3: Panel A illustrates the observed PK profile of Compound A in plasma (data points) after IV administration of 2 mg
and the computed fit (red line). Panel B shows the plasma concentrations after 20 mg oral dose (data points) and the
computed fit (black line).
QUESTIONS:
A. How would you account for the effective absorbance of radioactivity in this oral administration study, compared
with the relatively low bioavailability (28%) of Compound A. Specify what may be happening and what may be
causing it (8 points)
B. How would you account for the extensive metabolism of Compound A in comparison to its long plasma half-life?
Based on the data provided, provide a quantitative estimate of the clearance from plasma. (8 points)
C. Design in vitro experiments to further the understanding (mechanistic basis) of Compound A pharmacokinetics in
vivo. (9 points)