PHARMACOKINETICS

VARIABILITY

Kelompok 4
Arwinadiva Azwardi
M. Iqbal
Anngun Kemala Putri
Veny Wahyu Saputri
Yolanda Mayestika Wati
PHARMACOKINETICS VARIABILITY

 Definition : Due to differences in drug

concentration at the site of action because of
inter-individual differences in drug absorption,
distribution, metabolism and excretion.

 Also known as inter-individual variations of a

drugs pharmacokinetic parameters, resulting in
different pharmacokinetic profiles after
administration of the same dose to different
patients.
TYPES OF VARIABILITY

 Variability in adsorption, distribution,

metabolism and excretion will affects the
plasma drug level/concentration.
 Intra-individual
 Difference within the same individual.
 eg. Difference in drug plasma level between day
and night.
 Inter-individual
 Difference between individual to other individual.
 CONTRIBUTING FACTORS
 Drug or Product
 Active Metabolite
 Primidone ---- phenobarbitone
 Procainamide --- N-acetyl procainamide
 Tolerance and Resistance; antibiotics
 Formulation; generic differences
 Route of Administration; oral vs intravenous
 Drug Interaction; Theophylline with Rifampicin
 Foods; Potassium rich foods with Digoxin
 Pollutants; Smoking with Theophylline
 Time and Season; Day vs Night for Theophylline
 Location; Humidity for oral tablets
 FACTORS AFFECTING THE PHARMACOKINETIC
VARIABILITY IN DISEASES STATES
Body weight

• Same drug dose administration with different body weight

individuals may results into different plasma profile
• The dose adjustment according to the body weigh individual (obese
and thin) can reduce the pharmacokinetic variability.
• In the obese patients, it is difficult to reduce the pharmacokinetic
variability of drug because the recommended dose of the drugs are
normally based on the body weight of the normal individuals. This
pharmacokinetic variability is due to the function of organs such as
kidney and liver is different from the normal individuals.
 Age
 Age can affect the distribution and elimination
of drugs
 Drug protein binding, drug metabolism and
drug excretion may change according to age
 There are 5 groups :
 Sex
 The body size are different for both men and women which
led to different volume of distribution and different drug
clearance.
 Higher body fat in female may enhance the volume of
distribution for the lipophilic therapeutic agents.
 The oral bioavailability in somewhat higher in female in
comparison to male.
 Bioavailability after transdermal drug administration does not
appear to be significantly affected by gender; nor does protein
binding.
 The transdermal drug administration are not affected by sex.
 Nomenclature

 Substrates
Undergo metabolism or transport
 Inhibitors
Decrease the ability of the isozyme(s) or transporter
to metabolize or transport substrates
May also be substrates
 Inducers
Increase the amount or ability of the isozyme(s) or
transporter to metabolize or transport substrates
May also be substrates
 Drug Interactions

 Occur when either the pharmacokinetics or the

pharmacodynamics of one drug is altered by
another
- are a source of variability in drug response
- are graded responses, that are dependent upon
the concentration of the interacting species, and
on dose and time
- pharmacokinetic interactions may affect
absorption rate, availability, distribution, and
hepatic or renal clearance
- pharmacodynamic interactions may be
antagonistic, synergistic, or additive
PK Variability and Drug
Interactions
What Do We Need to Know ?
 How muchvariability is expected?
Intrapatient
Interpatient
 What is the magnitude of the effect of the drug interaction
on concentrations --how does it exaggerate variability?
 How much is too much?
Exposure-response relationships
 Can we controlfor, or accommodate the effects of
pharmacokinetic variability?
Pharmacokinetic strategies
Pharmacodynamic strategies
Clinical Significance of Drug-
Drug Interactions
 The clinical significance of a drug-drug
interaction can only be determined or confirmed
through a clinical study.
 In the absence of (or pending) clinical trial data,
well defined exposure-response data provide a
basis to predict the significance of a drug-drug
interaction; however, there will be settings
where the existing data are not informative as to
PK and PD of the interaction.
Exercise a measure of caution in managing drug
interactions where no confirmatory clinical data
exist
POPULATION PHARMACOKINETICS
 Analysis of population pharmacokinetic data:
 Pooled data of plasma drug concentration from
large group of subjects.
 Considered kinetic and non-kinetic related factors.
 Examined in the specific model eg. NONMEM
(Non-linear mixed effect model)/ Bayesian Model
 Estimated basic pharmacokinetics and random
effect parameters.
 Population pharmacokinetic parameters is used to
calculate the initial dose or to adjust the dose.
THE EFFECTS OF DISEASE ON
PHARMACOKINETICS
 Hepatic Diseases
 Alteration of pharmacokinetic principles and
determinants of hepatic elimination.
 Intrinsic clearance, hepatic blood flow and protein
binding.
 Renal Diseases
 Effects on Vd, elimination and protein binding.
 Uremia may decreased protein binding to acidic
drug.
 Cardiac Diseases
 Not directly
 Cardiac failure: decrease in cardiac output leading
to a decrease in blood flow to major tissues and
organs.
 Others: Congestion of vital organs, edema
formation, redistribution of blood flow, increase in
myocardial muscle mass.
 Thyroid Diseases
 Variable effects on hepatic metabolism.
 Gastrointestinal disturbance.
 Pulmonary Diseases
 Gas exchange defects.
 Hemodynamic changes (secondary to increase
pulmonary vascular resistance)
 Burn
 Effects the cardiovascular, renal, dermatologic
and hepatic systems.
 Malnutrition
 Neoplastic Diseases
PHARMACOKINETIC VARIABILITY IN
SPECIAL GROUPS
 Pediatrics (Infant 0 – 2 years old)
 Variation in:
 Body composition
 Maturity of liver

 Maturity of kidney

 Hepatic function
 Attained at third week of life
 Oxidative processes fairly develops.
 Deficiency in conjugating enzymes.
 Renal function
 Newborns show 30 – 50% the renal activity of adults.
 Geriatrics (more than 60 years old)
 Variation in:
 Quantitative: decline number of drug receptors.
 Qualitative: a change in affinity

 Absorption
 Decline splanchnic blood flow
 Reduce gastrointestinal motility
 Reduced gastrointestinal surface
 Distribution
 Decrease albumin concentration
 Decrease muscle mass
 Increase body fat
 Geriatrics (cont’)
 Metabolism
 Decrease enzymes
 Chronic Diseases
 Decline organ function (liver & kidney)
 Decrease blood flow (cardiac failure)
 Multiple drug used
 Obese Patients
 Actual body weight exceeds ideal body weight by
20%
 Distribution
 Smaller total body water (increase in fat)

 Lipophilic drugs vs hydrophobic drugs

 Metabolism
 Fatty infiltration of the liver affects the metabolism
processes
 Excretion
 Cardiovascular changes may affect renal blood flow
 Daftar Pustaka

Khan, Arshad Ali. 2011. Pharmacokinetics

Variability. Malaysia: University Malaysia
Pahang.
Thank You