PKPD analysis of furosemide data
Background: The drug furosemide was administered as a single dose to 8
human healthy subjects on three different occasions in a cross-over design. On
one occasion the drug was given intravenously, on another occasion orally on a
fasting stomach and on the third occasion orally together with a meal. The
sequences of administration for the 8 individuals were randomised. There was a
one-week wash-out period between occasions.
Furosemide is a loop-diuretic used against high blood pressure, heart failure and
oedema. It elicits its effects by inhibiting the urine-to-blood reabsorption of
chloride ions in the proximal and distal tubuli as well as in loop of Henle.
The plasma protein binding of furosemide is approx. 96%.
Analyse the data as thoroughly as you can using both Excel and WinNonlin.
Following points are only a suggestion in order to help you in your analysis
PK data analysis: Open the Excel dataset Furosemidedata. Import this data to a
new workbook in WinNonlin. Note the organisation of the data (ID, route
(occasion), independent variable, dependent variable).
As in all data analysis it is always a good practice (i.e. necessary) to first plot the
data graphically in order to get a feeling for the quality of the data and any trends
present. Following parameters are to be calculated by a non-compartmental PK
analysis of the IV data
AUCiv, CL, CLR, CLNR, Vss, Vdβ, t½

Plot renal execration rate against time and cumulative amount of
furosemid excreted against time. Calculate t½

Following parameters are to be calculated by NCA of the po. data.
AUC, Cmax, tmax, t½, F
Describe the results for each parameter with some appropriate measure of
central location and variability, respectively (i.e. basic descriptive statistics).

State the excretion ratio (low, high or intermediate), account for the renal
excretion mechanisms. Is bioavailability mostly dependent on absorption
or first pass effect?

Try to determine with some statistical method of your choice whether
intake of food affects the absorption of furosemide, i.e. whether a fooddrug interaction is evident.
Any difference in relevant parameters is to be accompanied by a p-value
and choice of method.

Plott and assess the relation of furosemid PK and its clinical effect. You
are not required to calculate any parameters; instead you are encouraged
to test different exposure-response relations. Your goal is to find the best
relation. You should be able to discuss and account for the appearance of
your PKPD-relations.
(Hint: you are provided with two effect biomarkers and a surrogate
measure for concentration in the effect compartment (a rate)

Plot renal excretion rate against plasma concentration.
Excel
When using excel templates fill in the dose, sample time and plasma
concentration. IV dose is assumed to be given as short time infution. Fill in a
short value for infusion duration “Inf Dur”.
The results may require some explaining:
lambda z
t1/2
R^2
= Terminal eliminationrate constant (ß)
= Half life (=ln2/ß)
= (r2); Values close to (1) are associated with ”good” log linear
fits.
Lin AUC∞
= Total area under the curve extrapolated to infinity. Calculated by
linear trapezoidal method.
Log AUC∞ = Total area under the curve extrapolated to infinity. Calculated by
log- linear trapezoidal method.
% to ∞
= Extrapolation ratio from last sample time to infinity,
CLP
= plasma clearance
VD Beta
= Vß = CL/ß
VDSS
= distribution volume at steady state = AUMC/AUC2
MRT = Mean Residence Time
3 values are reported for each individual and parameter :
3pt
In estimation of lambda z 3 last measured values were used in the
regression.
4pt
In estimation of lambda z 4 last measured values were used in the
regression.
5pt
In estimation of lambda z 5 last measured values were used in the
regression.
Report: Each student is required to hand in a report. The report should be
organized in the following headlines. Introduction; very brief. Materials and
Methods; describe the conduction of the clinical study, account for the software
used in data handling. Results: briefly summarize your results. Discussion:
discuss and explain your results.
The report should be written in English. No handwritten reports are accepted.
Only relevant plots are to be submitted to the report.