Transcript Drug Dosage Regimen - Fakultas Farmasi UNAND

Drug Dosage Regimen
Prof. Dr. Henny Lucida, Apt
Goals
• Optimum therapeutic response with
minimum adverse effects
• Individualization of drug dosage regimen,
esp drugs with a narrow therapeutic
window
Drugs w/ narrow ther window
Drug
Amikacin
Carbamazepine
Digoxin
Gentamicin
Lidocaine
Lithium
Phenytoin
Procainamide
Theophylline
Tobramycin
Valproic acid
Vancomycin
Disease/condition
Gram-negative infection
Epilepsy
Cardiac dysfunction
Gram-negative infection
Ventricular arrhythmias
Manic & recurrent depression
Epilepsy
Ventricular arrhythmias
Asthma
Gram-negative infection
Epilepsy
Penicillin-resistant infection
Therapeutic window
20-30 mcg/mL
4-12 mcg/mL
1-2 ng/mL
5-10 mcg/mL
1-5 mcg/mL
0.6-1.2 mEq/L
10-20 mcg/mL
4-10 mcg/mL
10-20 mcg/mL
5-10 mcg/mL
50-100 mcg/mL
20-40 mcg/mL
Dosage regimen design
Activity-toxicity
-Therapeutic window
-Side effects
-Toxicity
-conc-response rel
Pharmacokinetics:
ADME
Dosage
Regimen
Clinical Factors
-Patients (age, weight, patophysiologic cond
-Management of ther (multiple drug ther,
convenience of regimen, compliance of
patient)
Other factors:
-Route of adm
-Dosage form
-Tolerance-dependence
-Drug interaction
-Cost
Dosage regimen design
• The most accurate approach to dosage
regimen design is to calculate the dose
based on the pharmacokinetics of the drug
in the individual patient (not for initial dose;
only for readjustment of the dose). The
initial dose was estimated using average
population pharmacokinetic parameters
obtained from literature. Clin pharm
softwares for drugs with narrow ther
window are available (Datakinetics etc)
3 methods
1. Dosage regimens based on population
averages:
(a) the fixed model
(b) the adaptive model
2. Dosage regimens based on partial
pharmacokinetic parameters
3. Empirical dosage regimens
Dosage regimens based on
population averages
• Obtained from clinical studies published in the
drug literature
(a) the fixed model, assumes that population
average pharmacokinetic parameters may be
used directly to calculate a dosage regimen for
the patient without any alteration. Parameters
such as : ka, F, VD apparent, and ke are
assumed to remain constant; follow a onecompartment model. The practitioner may use
the usual dosage suggested by the literature
and/or make small adjustment based on the
patient’s weight and/or age
(b) the adaptive model
dosage regimen was calculated by
using patient variables such as: weight,
age, sex, body surface area, and known
patient patophysiology such as renal
disease as well as the known population
average pharmacokinetic parameters of
the drug. This model assumes that drug
clearance do not change from one dose to
the next.
Dosage regimens based on partial
pharmacokinetic parameters
• For drugs with unknown or unavailable
pharmacokinetic profile, the
pharmacokineticist needs to make some
assumptions to calculate the dosage
regimen. Exp: to let F equal 1 or 100%.
the risk of undermedicated or
overmedicated. Assumptions will depend
on the safety, efficacy and therapeutic
range of the drug.
Empirical dosage regimens
• Not based on pharmacokinetic variables,
but on empirical clinical data, personal
experience and clinical observations.
Constant-rate Regimens
k0
A ss 
k el
k0
Css 
CL
Multiple-dose Regimens
1.44  F  Dose  t1/2
A ss,av 
τ
F Dose
Css,av 

CL τ
 kτ
MD  LD  1  e
MD
LD 
 kτ
1 e




Accumulation Index
1
AI 
 kτ
1 e


Dosage regimens for continuous
maintenance of therapeutic conc
• Half-lives < 30 minutes
low TI drugs : must be infused
ex: heparin
high TI : may be given less frequently
(than t1/2) but with higher MD
ex: Penicillin, 4 – 6 hr interval (t1/2 = 30
min)
Dosage regimens for continuous
maintenance of therapeutic conc
• 30 min < t1/2 < 8 hr
- low TI drugs: must be given every
half- life or more frequently or by
infusion
ex: lidocain (90min) infusion,
theophylline (3-6 doses/day)
- high TI drugs: once every 1 – 3 t1/2
ex: cephalosporins (30min-3hr) 3 – 6
halflives
Dosage regimens for continuous
maintenance of therapeutic conc
• 8 < t1/2 < 24 hr
- the most convenience
- a dose is given every half life, LD
must be twice MD to achieve Css
immediately
ex: sulfamethoxazole (high TI) and
clonidine (low TI)
Dosage regimens for continuous
maintenance of therapeutic conc
• T1/2 > 24 hr
administration once daily is convenient
and promotes patient compliance
Ex: Chloroquine (high TI), Digitoxin (low TI)
Design of dosage regimens
from plasma conc
Clower  C upper  e
τ max 
 max
 kτ max
ln C upper  Clower 
k
 Cupper

 1.44  t1/ 2  ln 

C
lower 

Design of dosage regimens
from plasma conc
MD max
MD max
τ max
Css,av 
V
 C upper  C lower 
F
CL

 Css,av
F
C
upper
 C lower 
 C upper

ln 

C lower 

Maintenance of a peak conc
MD max


MD  
τ

τ
max 

MD
LD 
- k
1- e


F  MD
C av 
CL  τ
AUC singleDose
Css,av 
τ
F  MD
Css,max 
 kτ
V 1 e


 kτ
Css,min
F  MD  e

 kτ
V 1 e



Case Study 1
Case Study 2
Case Study 3
the cumulation factor (CF):
CF = 1 / 1 − e−kt
Case Study 4
Case Study 5
Study case 6
An antibiotic drug is to be given to an adult
male patient (75 kg, 58 years old) by IV
infusion. The drug is supplied in sterile vials
containing 30 mL of the antibiotic solution at
a concentration of 125 mg/mL. What rate
(mL/min) would you infuse this patient to
obtain a Css of 20 mg/mL? What loading
dose would you suggest? Assume: onecompartment model, Vd = 0.5L/kg and t1/2
elimination = 3 hours
Study case 7
For prolonged surgical procedures,
succinylcholine chloride is given by iv
infusion for sustained muscle relaxation.A
typical initial dose is 20 mg followed by
continuous infusion of 4 mg/min. The
infusion must be individualized because of
variation in the kinetics of metabolism of
succinylcholine. Estimate the elimination
half-lives of succinylcholine in patients
requiring 0.4 mg/min and 4 mg/min,
respectively, to maintain 20 mg in the body.
Study case 8
. A patient with renal dysfunction received a
dose of vancomycin. Cp were 22 and 15
mg/L at 24 and 48 hours after infusion
respectively. Determine when the
concentration would reach 10 mg/L!
a. 54 hours
b. 72 hours
c. 96 hours
d. 128 hours
Study case 9
Mr. J, a non smoking 60 kg patient with chronic
obstructive pulmonary disease, is to be started on
an oral regimen of aminophylline (85% of which is
theophylline). The pharmacokinetic s parameter
values for a typical patient population with this
disease are: F = 1 (for theophylline), V=0.5 L/kg
and CL= 40 mL/hr/kg. Design an oral dosage
regimen of aminophylline (100 and 200 mg tablets
are marketed) for this patient to attain and
maintain a plasma conc within ther window 10 – 20
mg/L. The absorption of theophylline is complete
and rapid