• Multiple IV doses

• Some drugs may be used clinically

on a single-dose basis, but most
drugs are administered continually
over a period of time.
• When a drug is administered at a
regular dosing interval (orally or
IV), the drug accumulates in the
body and the serum concentration
will rise until steady-state
conditions are attained, assuming
the drug is administered again
before all of the previous dose has
been eliminated (see Fig. below).
• Steady state
• Steady state occurs when (in a
given time period) the amount of
drug administered is equal to the
amount eliminated.
•
• At steady state the plasma
concentrations of the drug (C p ) at
ss

any time during any dosing

interval, as well as the peak and
trough, are similar.
• The time to reach steady-state
concentration is dependent on the
half-life of the drug under
consideration.
• Effect of dose
• The higher the dose, the higher
the steady-state levels, but the
time to achieve steady-state levels
is independent of dose (see fig.
below).
• Note that the fluctuations in Cp max
and Cp min are greatest with higher
• Effect of dosing interval
• Consider a drug having a half-life of
3 h. When the dosing interval,τ , is
less than the t1/2, steady-state levels
are higher and there is less
fluctuation in Cpmax and Cpmin.
• When, τ > t1/2, then a lower
accumulation occurs with greater
fluctuation in C and C
• If the dosing interval is much
greater than the half-life of the
drug, then Cp min approaches
zero. Under these conditions no
accumulation will occur and the
plasma concentration–time profile
will be the result of administration
of a series of single doses.
• Accumulation
• Let’s consider a situation where a
drug is given iv bolus dose every
dosing interval (T).
• NB: after each dose, the fraction
remaining after time t is (e-kt). The
fraction remaining after T is then
(e ), and that remaining after 2T
-kT

is (e-2kT).
• The amount of drug remaining
after multiple doses is the sum of
the amounts from each of the
previous doses.
• See the table below for the
calculation of the amount of drug
remaining just after the next dose,
for four successive equal doses
given every (T).
• From the table above, the maximum
amount of drug in the body just after the
fourth dose (A4max) is the fourth dose plus
sum of the amounts remaining from the
previous doses
• That is: (if r = e-kT)
• A4,max = Dose(1+r+r2+r3) (1)
• Just after the Nth dose the amount in the
body is:
• AN,max = Dose(1+r+r2+r3 … rN-2+rN-1)(2)
•
• Multiplying by r:
A
• N,max .r = Dose(r+r +r +r
2 3 4
….. r +r )
N-1 N

(3)
• Subtracting (3) from (2)
• AN,max .(1-r) = Dose(1-rN ) (4)
• Therefore:
• AN,max = Dose(1-rN )/(1-r) (5)
• Hence the amount of drug remaining at any time (t)
during a dosing interval after the Nth dose (AN,(t)) is
given by:
• AN,(t) = AN,max . e-kt (6)
• At the end of the dosing interval when (t = T). The
minimum amount of the drug in the body after Nth
dose (AN,min ) is given by:
• AN,min = AN,max .r = Dose(1-rN ).r/(1-r) (7)
• Steady-state:
• As the number of doses, N, increases, the value rN
approaches to zero, since r is always less than (1)
• The amount lost at steady-state equals the amount
gained and hence the values Ass,max , Ass,min and Ass,(t)
are obtained by letting (rN = 0) i.e.:
• Ass,max = Dose/(1-r)
(8)
• Ass,min = Dose.r/(1-r) = Ass,max – Dose (9)
• Ass,(t) = Dose . e-kt /(1-r) (10)
• Time to Reach Steady-State
• The time to approach plateau,
whether defined with respect to
the maximum or minimum
amount of drug in the body,
depends solely on the half-life of
the drug.
• This is proved by dividing the
equations that define the
respective amounts after the Nth
dose by the equations that define
the respective amounts at plateau.
• AN,max / Ass,max = AN,min / Ass,min = 1-r N
• CASE STUDY (Multiple IV bolus)
• Patient D receives Drug Code XR2,
100 mg every 8h.
• At steady state, two plasma
concentrations are measured:
• Sample 1 is taken at 1 h post dose:
Conc 9.6 mg/L
• Sample 2 is taken pre dose: Conc
2.9 mg/L (see fig. below)
• 1. Calculate the elimination rate
constant (k ), and t1/2
• K = (lnCp1-lnCp2)/t2-t1
• Cp1 = 9.6 mg/L and Cp2 = 2.9
mg/L, and sample times are 1 h
and 8 h.
• Thus: t2 - t1 = 7h
• Then:
• K = (ln9.6 – ln2.9)/7 = 1.197/7 =
0.171H -1

• and the half-life (t1/2) is:

• t1/2 = 0.693/0.171 = 4.1h
• 2. Calculate the volume of
distribution (Vd)
• The volume can be calculated
from either the 1 h post- or pre-
dose samples.
• From the 1h post-dose sample:
• The following equation describes
the plasma concentration 1h post
dose at steady state:
• Cp1 = Dose. e-kt/Vd(1-e-kT)
• Then Vd = Dose . e-kt /Cp1(1-e-kT)
• Vd = 100. e-0.171 /9.6(1-e-(0.171x8)) =
11.8L
• From the pre-dose sample
• The following equation describes
Cp,min at steady state:
C
• p,min = Dose . e -kT
/Vd(1-e -kT
)
• Thus
• Vd = Dose . e /Cp,min(1-e )
-kT -kT

• Vd = 100. e-0.171x8/ 2.9(1-e-0.171x8) =

11.8L
• 3. Calculate clearance
• CL = k . Vd
• = 0.171 x 11.8 = 2.02L/H