chronokinetics... "chrono" terms....

1. CHRONOPHARMACOKINETICS
by,
Syed Baseeruddin Alvi (09)

3. INTRODUCTION
• 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

4. • 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

5. variations in
drug
absorption
• circadian variations in gastric acid secretion
and pH, motility, gastric emptying time,
gastrointestinal blood flow
• plasma protein binding
Distribution & • enzyme activity, hepatic blood flow
metabolism
renal drug
excretion
• glomerular filtration, renal blood flow,
urinary pH and tubular re absorption

7. Aim of chronokinetic studies…….
• The main aim of chronokinetic studies is to
control the time of administration which
among others, can be responsible for
variations of drug kinetics

10. 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:
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.

11. • 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.

12. Antihypertensive drugs:
• 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

13. Valporic acid:
• 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

14. 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

15. • 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

16. CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

17. Time controlled
chronotropic
systems
Based on
capsule
Time controlled
explosion
system
Time controlled
reservoir systems with
soluble or eroding
polymer coating

18. 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 dependent
polymers, targeting
at specific site of
gastrointestinal tract
is 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 secreted
by colonic microflora
These are system
which uses
temperature of the
site as stimuli for
drug release.
Certain cells
posses different
temperature with
respect to other
cells like tumor
cells,

19. 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.

20. 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

21.  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

22. Slide Title
Product A
• Feature 1
• Feature 2
• Feature 3
Product B
• Feature 1
• Feature 2
• Feature 3
Thank you