Individualization of dosing

In clinical situation, in most cases, the individualization dosage is necessary based on the
patient’s physiological condition and disease state. In other words, the amount of drug (D) or
dosing interval (τ) or both may require specific changes or adjustment, so that the plasma
concentration of the drug remains within the desired level.

The following are the conditions to adjust the dosage.

 Obese patient
 Neonates, infant and children
 Elderly
 Hepatic disease
 Renal disease

About 90% of drugs are excreted through kidney. Therefore renal disease is very important
condition for the dose adjustment. In many cases hepatic disease also plays important
consideration for the dose adjustment. Thus the general approach is based on the total body
clearance.

i.e. Total body clearance = KV = Renal clearance + Non-renal clearance. For drugs mostly
excreted through the kidney, body clearance = renal clearance = GFR of the drug.

GFR = Createnine clearance × fraction of drug excreted in urine.

In patients with renal failure, the half-life of drug is increased and its clearance is reduced.
Hence the dose adjustment is based on the renal function of the patient.

Method for dose adjustment:

The general approach involves:

 Maintaining the same average plasma concentration (C av) as in normal dosing for the
patient with the renal dysfunction also.
 Equation:
The usual relation is Cav = FD/KV Ƭ ………… (i), where Cav is the average plasma
concentration, F bioavailability D usual dose, K is elimination rate constant, V is the
apparent volume of distribution and Ƭ is the frequency of dosing.
Equation (i) can take several forms:
Cav = FD/CL Ƭ …………..(ii), where Cl is the body clearance.

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 Cav = FD/CLcr Ƭ …………..(iii), where Clcr is the creatinine clearance for drugs entirely
excreted through kidney.
Cav = FD ×1.44 t1/2/ V Ƭ ……(iv)

The above equations can be written for the patients with renal insufficiency, e.g.
Equation (ii) can be written as
Cav = F D*/CL* Ƭ* ……. (v), where D*, CL* and Ƭ* represent the values for the renal
patient with failure.

If we examine the above equation, the parameters can be shown as shown below.

Cav = F × 1/CL* × (D*/Ƭ*) (needs adjustment)

(to be kept constant) (constant) (CL decreased due to disease)

Thus comparing the equations for the normal person and a patient with renal disease,
Cav = D/CL Ƭ= D*/CL* Ƭ*
i.e D*/ Ƭ* = D×CL*/CL× Ƭ (if clearance is considered)……. (vi)
or D*/ Ƭ* = D×t1/2/ t1/2*× Ƭ (if t1/2 is considered)……. (vi)

Thus, in dose adjustment the main aim is to find the ration of D* and Ƭ*. Then two
possibilities have to be assessed.
(a) Keep the same value of Ƭ for Ƭ* (Ƭ kept constant) and from the ratio D*/ Ƭ*,
calculate the new dose (D*).
(b) Keep the same value of D for D* (D kept constant) and from the ratio D*/ Ƭ*,
calculate the new dosing frequency (Ƭ*).

Hence, for dose adjustment, we can give the new dose with the usual frequency of
dosing or we can give same normal dose but change the dosing interval based on
the new value of Ƭ.

Problem:

1) Drug A is to be administered to a 70Kg patient at a rate of 2 mg/kg every 12 hrs by

multiple i.m. injection. The drug has a half-life of 2.2 hrs and V of 0.2 L/Kg.
Calculate the new dose or the new dosing interval of the drug in a patient with renal
insufficiency, if the t1/2 increases to 5 hrs.
We have, (D*/ Ƭ*) = D×t1/2/ t1/2*× Ƭ
Or, (D*/ Ƭ*) = 140×2.2/5×12 = 5.13
 If Ƭ* is kept constant as Ƭ i.e 12 hrs,
(D*/ 12) = 5.13

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 i.e D* = 61.6mg with 12 hrs frequency of dosing.
i.e. 0.88 mg /kg with 12 hrs (frequency of dosing i.e. Ƭ not changed)
 If Ƭ is changed (new D remaining same i.e. D = D*)
From above,
(D*/ Ƭ*) = 140/ Ƭ*= 5.13
i.e. Ƭ* = 140/5.13 = 27.3hrs
i.e. same 140 mg dose but the dosing interval will be 27.3 hrs.

2) Problem 2: The normal dose of drug is 200mg. If the fraction excreted unchanged in
urine is 0.75, what would be the dose for a patient whose creatinine clearance is
13ml/min? Calculate the new dosing interval if the dosing frequency (initial) is every two
hrs.

Here, Normal clearance of the drug = GFR of the drug = CrCL = 0.75 ×130l/min = 97.5
ml/min

The Cr Cl of the patient = 13ml/min.

Now we have,

(D*/ Ƭ*) = D×CL*/CL× Ƭ = 200×13/97.5× 2 = 13.3

 Now if Ƭ kept constant i.e 2 hrs,

(D*/2 ) = 13.3

i.e D* = 26.6 hrs.

 If Dose is kept constant,

(D*/ Ƭ*) = 13.3
Or, 200/ Ƭ* = 13.3
i.e. Ƭ* = 200/13.3 = 15hrs.
i.e. 200mg dose (as initial dose) given with 15 hrs of frequency of dosing.