Multiple intravena

bolus administration
IKA NURZIJAH
 Multiple intravena
bolus administration
A d r u g h a s a n ar ro w t h er a p e ut i c r a ng e, a n d p la s m a
concentrations are outside the range are associated with serious
clinical consequences

E.g : aminoglycosides, phenytoin, lithium, immunosuppressants,

and digoxin

A d r u g d i s p l a y s w i d e i nt e r p at i e nt var i a b i l i t y in its
pharmacokinetic parameters.

A patient possesses a characteristic that is frequently associated

with altered pharmacokinetics. This may include renal disease,
hepatic disease, altered activity of the drug metabolizing
enzymes or transporters as a result of genetic polymorphism or
concomitant medications.
 The typical plasma
concentration vs time
profile
 Multiple dose
pharmacokinetics
 Assumptions involving
multiple iv bolus
administration
With the possible exception of the first dose
(loading dose), the dose and the dosing
i nter val are co n s ta nt t h ro u g h o ut t h e
duration of therapy. The dose may be
referred to as the maintenance dose

The drug’s phar macokinetic parameters

remain constant throug hout the entire
duration of therapy. This assumes that the
drug displays linear pharmacokinetics
 BASIC EQUATION BEFORE
STEADY STATE
peak concentration

Through concentration Dose interval

 BASIC EQUATION DURING
STEADY STATE

Average Steady State Concentration

 Factors influence
steady state

1. Directly proportional to the effective rate

of drug administration, S ⋅ F ⋅ Ra (this is a
characteristic of linear pharmacokinetics)

2. Inversely proportional to clearance

3. Independent of the volume of distribution

Time to reach
steady state
 Principle of
Superposition
Fluctuation

the difference between the

p e ak and the tro ug h
p la s m a co n ce nt r at i o n s
within a dosing interval.
 Principle of
Accumulation
Accumulation is the increase in drug concentrations
that occur with each additional dose
 Principle of
Accumulation
Accumulation can also be expressed by comparing the average
amount of drug in the body at steady state (Abav,ss) to the
dose:

Given that t1/2 = 0.693Vd/Cl

 LOADiNG DOSE
The purpose of the loading dose is to provide all the drug that ulti- mately
accumulates at steady state in an initial single dose. At steady state, there is
r times more drug in the body than after a single dose. Thus, the loading
dose will need to be r times greater than the usual maintenance dose.
Pharmacokinetics
consideration
 EXERCISE 1
Assume that a new drug is under development. It has
a very narrow thera- peutic range (12–25 mg/L).
However, since it is being used to treat a serious life-
threatening condition for which few other treatments
are available, development of this drug is being
pursued. The goal is to design a dosing regimen that
will result in a steady-state peak and trough of 20
and 14 mg/L, respectively. The drug’s elimination
rate constant has a popu- lation average value of
0.043 h−1. What dosing interval is needed to provide
the desired steady-state peaks and troughs?
 EXERCISE 2
Multiple intravenous bolus injections (250 mg) of a drug are
administered every 8 h. The drug has the following
parameters: S = 1, Vd = 30 L, k = 0.1 h−1, and τ = 8 h.

A. Calculate The plasma concentration 3 h after the second

dose.

B. The peak and trough plasma concentrations during this

second dosing interval

C. Calculate the maximum and minimum steady-state plasma

concentrations achieved by the regimen

D. What dose should be used?

 EXERCISE 3

D o s e s o f d i g o x i n ar e u s u al ly
administered every 24 h. Calculate
an appro- priate dose of digoxin to
achieve a concentration of 1 μg/L in
a patient whose digoxin clearance is
estimated to be 123 L/day.
 EXERCISE 4

An average s teady-s tate plasma

concentration of 50 μg/L is required
from the administration of multiple
intravenous bolus injections of the
ctitious drug lipoamide. Vd = 420 L
and Cl = 62 L/h. What rate of drug
administration should be used?
 EXERCISE 5
Following a severe blow to the head, an 80-
kg man (L.K.) develo p e d seizu re s.
Recommend a suitable dosing regimen for
phenobarbital sodium. Even though the drug
w i ll b e ad m i n i s tere d o r ally, u s e t h e
equations associated with intravenous bolus
injections for your calculations. Would you
recommend a loading dose? If so, calculate
one. TR = 10–30 mg/L, F = 0.9, S = 0.9, Vd =
0.7 L/kg, and Cl = 4.0 mL/h ⋅ kg.
 EXERCISE 6
Deter mine a suitab le dose and
dosing interval for gentamicin to
achieve s teady-s tate peaks and
troughs of 8 and 0.5 mg/L in a
patient who is estimated to have the
fo llo w ing p har macokin et i c
parameters: Vd = 17.5 L and t1/2 =
2.0 h.
 EXERCISE 7
A drug company is developing a new
anticancer drug. Phase I stu d ies have
e s t a b l i s h e d t h e p o p u l at i o n av e r a g e
pharmacokinetic parameters (Cl = 15 L/h
a n d V d = 2 . 3 L /k g ) . A n i m al s t u d i e s
indicated that optimum response is obtained
with a trough and peak of 0.35 and 0.65
mg/L, respectively. Determine a suitable
dosing regimen in an average 70-kg patient.