IMPORTANCE OF PHARMACOKINETIC PARAMETERS IN

ESTABLISHING A RATIONALE THERAPEUTIC SCHEDULE

I. THEORETICAL PART

1. Pharmacokinetic parameters

Pharmacokinetics is the part of pharmacology that studies the drug circulation into the
body, from administration to elimination. In order to establish the optimal dose of a drug, direct
measurements or calculations of the pharmacokinetic parameters are necessary. The main
parameters are:
a. Primary pharmacokinetic parameters, which are established by direct measurement:
- The plasma concentration (Cp)
b. Secondary pharmacokinetic parameters, which are established through calculation:
- The volume of distribution (Vd)
- Bioavailability (Bd)
- The halflife (T1/2)
- The clearance (Cl)
There are certain categories of drugs in which pharmacokinetic monitoring is necessary:
- Antiepileptics: Fenitoin, Carbamazepin, Valproic acid, Lamotrigin, Etosuximid,
Fenobarbital, Primidone
- Cardioactive : Digoxin, Lidocaine
- Bronhodilating agents : Theophyline
- Antibiotics : Gentamycin, Tobramycin, Amykacin, Vancomycin
- Antivirals : Efavirenz, Tenofovir, Ritonavir
- Citostatics : Metotrexat, 5-Fluorouracil
- Imunosupressants : Ciclosporin, Tacrolimus, Sirolimus, Micofenolat

The plasma concentration

3
medium plasma concentration (mg/ml)

2.5

1.5

0.5

0
0 1 2 3 4 5 6 7
time (hours)
 AD = Vd x Cp
AD = attack dose, Vd = volume of distribution, Cp = plasma concentration

The volume of distribution

D
Vd = ----------
Cp max
D = dose of drug administered IV, Cp max = maximum plasma concentration

Bioavailability (after IV administration, the Bd = 100%)

Cp oral (other route with abs)

Bd% = ----------------------------------------- x 100
Cp after IV
or

AUC oral (other route with abs)

Bd% = ------------------------------------------ x 100
AUC after IV
Cp – plasma concentration, AUC – area under the curve

In the medical practice, by calculating the Bd, we can compare 2 doses after different routes of
administration. An example: if a drug has a Bd of 25 % after oral administration, than the oral
dose will be four times higher compared to IV.

The half-life can be determined from the concentration/time graphic or through calculation,
beeing directly proportional with the volume of distribution and inversely proportional with the
clearance of the specific drug. In general, the half life is not related to the dose.

ln 2 x Vd 0,693 x Vd
T1/2 = ---------------- = ------------------
Cl Cl
Vd = volume of distribution, Cl = clearance of the drug

The plasmatic clearance

0,693
Cl = Ke x Vd = ---------- x Vd
T1/2
or
D
Cl = --------
AUC
Ke = elimination constant, Vd = volume of distribution, T1/2 = half-life, D = dose of administered
drug, AUC – area under the curve

The value of clearance is important for the calculation of the maintainning dose.

MD = Cp const. x Cl x t
MD – maintaining dose, Cp – plasma concentration which has to be maintained at a steady level,
Cl = clearance of the drug, t = time between administrations, in minutes

The main organs of drug elimination are the kidney and the liver. The clearance of an
organ depends on the capacity of elimination, called intrinsic clearance and on the blood
perfusion of this specific organ. Liver, renal or heart diseases can influence the clearance of an
organ.

Qs x Cl int.
Cl organ = ------------------
Qs + Cl int.
Qs = blood flow through an organ, Cl int. = intrinsic clearance

The total systemic clearance :

Cltotal = Clrenal + Clhepatic + Clother organs

Pharmacokinetic parameters of some drugs for a 70 kg patient

Drug Oral bioavailability (%) Total clearance Vol. of distribution

(ml/min) (l)
Acetaminophen 63 350 67
Valproic acid 100 8,4 9,1
Amikacin - 77 15
Amoxicillin 93 370 29
Ampicillin 25-70 270 20
Aspirin 68 650 11
Carbamazepin > 70 89 98
Cephalexin 90 300 18
Cephalotin - 470 18
Chloramphenicol 75-90 250 64
Chlordiazepoxide 100 26 21
Cimetidin 62 840 150
Clonidine 74 210 150
Diazepam 100 27 77
Digitoxin > 90 3,2 36
Digoxin 60-70 130 640
Disoyramide 83 90 55
Erythromycin 18-45 420 50
Ethambutol 77 600 110
Furosemid 40-60 140 7,7
Gentamycin - 90 18
Hydralazine 20-60 420 110
Imipramine 47 1400 1050
Indometacin 98 110 65
Lidocaine 35 640 77
Meperidine 52 1200 290
Methotrexate 65 105 28
Morphine 20-30 1100 220
 Nortriptyline 51 500 1300
Phenobarbital > 80 6,5 62
Prazosin 57 210 42
Procainamide 83 350-840 130
Propranolol 36 840 270
Quinidine 70 330 190
Sulphamethoxazo 100 22 15
l
Tetracycline 77 130 91
Theophylline 96 48 35
Tobramycin - 77 18
Tolbutamide 93 21 11
Trimethoprim 100 150 130
Tubocurarine - 160 21
Verapamil 19 830 280

The therapeutic index is a parameter of risk or safety of a drug.

DL50
TI = ----------
DE50
DL50 = medium lethal dose, DE50 = medium efficient dose

TI < 10 => the drug is very active and needs special supervision
TI > 10 => the drug needs no special precautions

II. PRACTICAL PART

1. Calculate the half-life of ……………………., in hours (days), for a patient with 70 kg.

2. A patient, having the bodyweight of 70 kg, is hospitalized with the following diagnosis :
pneumonia with Klebsiella pneumonie, senzitive to Tobramycin. Because of the severity
he will receive immediately Tobramycin IV, in order to obtain a therapeutic plasma
concentration of 4 mg/l. Calculate :
a. The necessary attack dose
b. The dose which has to be administered every 6 hours to maintain this
concentration

3. A drug with sedativ-hypnotic effect is in the process of evaluation, in order to introduce a

new drug on the market. According to the graphic below :
a. Calculate the therapeutic index of the drug
b. State if the drug requires special attention or not
nUMBER OF PATIENTS WHICH RESPONDED TO THE TREATMENT (%)
110

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0
0 100 200 300 400 500 600
doSE OF THE DRUG (mg)

blue line – sleeping, red line - coma