CHRONOPHARMACOKINETICSby,

Syed Baseeruddin Alvi (09)

• Introduction• Definition• Aim• Examples• Types• Dosage forms• Merits & Demerits

CONTENT

• Drug Absorption, Distribution, Metabolism and

Elimination are influenced by many different

physiological functions of the body which may

vary with time.

• Hence the time of day has to be regarded as an

additional variable influencing the kinetics of a

drug

• The time of administration is a possible factor of

variation in the k i n e t i c s o f a d r u g

INTRODUCTION

• Chronopharmacokinetics deals with the study

of the temporal changes in absorption,

distribution, metabolism and elimination and

thus takes into account the influence of time on

these different steps.

i.e

DEFINITION

variations

in drug absorption

•plasma protein binding

•enzyme activity, hepatic blood flow

Distribution &

metabolis

m

•circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow

renal drug excretion

•glomerular filtration, renal blood flow, urinary pH and tubular re absorption

• The main aim of chronokinetic studies is to

control the time of administration which

among others, can be responsible for

variations of drug kinetics

Aim of chronokinetic studies…….

Antibiotics

• Experimental has shown that for Antibiotics

such as beta-lactams that have concentration-

independent killing effects in vitro, the time

that the antibiotic concentration remains

greater than the MIC(T> MIC) is the most

important factor for determining the in vivo

efficacy.

D r u g s t h a t u n d e r g o c h r o n o k i n e t i c s:

• Apart from that it has an effect on toxicity of certain

drugs which may decrease at different time of day

eg:

Aminoglycosides:

• Peak renal toxicity was observed when

aminoglycosides were injected in the middle of the

rest period of the experimental animals & vice

versa

• Gentamicin

• Tobramycin: dark period( CLT & AUC) than light

period.

• Nearly all physiological functions as well as

pathophysiological events display reproducible

rhythmic changes within 24 hours of a day,

including the cardiovascular system.

• Chronopharmacokinetic studies with propranolol,

oxprenolol, nifedipine, verapamil, etc. also

revealed daily variations in the drugs' kinetics.

• Cmax was higher and/or tmax shorter after

morning than evening dosing

Antihypertensive drugs:

• After oral administration, VPA concentrations

in plasma were significantly higher in the

morning than in the evening during the

absorption phase. Cmax tended to be higher,

tmax was shorter and absorption rate constant

(ka) tended to be larger for VPA in the morning

Valporic acid:

Sumatriptan:

• (sumatriptan is a drug of choice in migraine

treatment) The mean area under the serum

concentration time curve from time zero to

the last time-point (AUC0-t), the area under

the serum concentration-time curve from

zero to infinity (AUC0-infinity), and the area

under the first moment curve (AUMC) were

significantly higher following the 07:00hr

• NSAID: ketoprofen: The rate of absorption of

Ketoprofen was also found to be higher when it

was administered in the morning

Scope

• New tools, such as new formulation procedures or

pumps with constant or programmable delivery

rates, now make it possible to deliver a drug at a

definite time, or during a definite span of time

Time controlled chronotropic

systems

Stimuli induced pulsatile DDS

Externally regulated

pulsatile DDS

CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

Time controlled chronotropic

systems

Based on capsule

Time controlled explosion

system

Time controlled reservoir systems with

soluble or eroding polymer coating

Stimuli induced pulsatile drug delivery system

Chemical stimuli induced pulsatile

DDS

pH sensitive pulsatile release

Enzyme catalyzed pulsatile

chronotropic systems

Temperature induced pulsatile

DDS

pH sensitive hydrogel containing glucose-oxidase enzyme immobilized in hydrogel

utilize pH dependentpolymers, targeting at specific site of gastrointestinal tractis possible as well as a desired lag time can be achieved

These systems are generally developed for colonic delivery of drug as release rate of drug is dependent upon the catalysis of polymeric membrane by enzymes secretedby colonic microflora

These are system which uses temperature of thesite as stimuli for drug release. Certain cells posses different temperature with respect to other cells like tumorcells,

Externally Regulated Pulsatile Drug Delivery Systems

Ultrasound Based drug

delivery systems

Magnetic Based drug

delivery systems

Electric Based drug delivery

systems system

Radiation Based drug

delivery systems.

Dosage forms used for chronotherapy

• Core in cup tablets

• Compression coated/press coated tablets

• Double coated hard gelatin capsules and

double coated tablets

• Pulsincap systems

• Layered systems

MERITS:

·Predictable, and short gastric

residence time

·Less inter- and intra-subject

variability

·Improve bioavailability

·Limited risk of local irritation

·No risk of dose dumping

·Flexibility in design

·Improve stability

DEMERITS

· Lack of manufacturing

reproducibility and efficacy

· Large number of process

variables

·Batch manufacturing process

·Higher cost of production

·Trained/skilled personal needed

for Manufacturing

Slide Title

Product A• Feature 1• Feature 2• Feature 3

Product B• Feature 1• Feature 2• Feature 3

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