Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug. It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination. It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations. The term circadian coined by Franz Halberg, comes from Latin. “Circa” means around &“diem” means day.

1. CHRONOPHARMACOKINETICS AND TIME
DEPENDENT PHARMACOKINETICS
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
INTRODUCTION,
AIM
NEED, REASONS FOR CHRONOPHARMACOKINETIC STUDIES
TYPES OF BODY RHYTHMS: Circadian rhythms, Ultradian rhythms, Infradian rhythms
PHYSIOLOGICALLY INDUCED TIME DEPENDENCY
 Absorption-elimination parameters
 Distribution and Plasma binding
 Enzymatic metabolic activity
 Systemic clearance
 Renal clearance
 CSF drug concentration
CHEMICALLY INDUCED TIME DEPENDENCY: Auto-induction, Auto inhibition
FACTORS AFFECTING CIRCADIAN RHYTHMS
DRUGS THAT UNDERGO CHRONOKINETICS
APPLICATIONS
CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
IMPORTANCE, MERITS, DEMERITS
CONCLUSION
REFERENCES ANUSHA NADIKATLA

3. INTRODUCTION
• Drug absorption, distribution, metabolism, and elimination are
influenced by many different physiological functions of the body
which may vary with time of the day.
• The PK parameters characterizing these different steps, conventionally
considered to be constant in time, depend on the moment of drug
administration.
• However, the time of day has to be regarded as an additional variable
influencing the kinetics of a drug, since many drugs are affected by
time of administration and the activity or rest period of the human or
animal.
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4. CHRONOPHARMACOKINETICS
• Chronopharmacokinetic studies have been demonstrating that
time of administration is a possible factor of variation in the
kinetics of the drug.
• It entails the study of temporal changes in drug absorption,
distribution, metabolism and elimination.
• It investigates the variation in drug plasma levels as a function of
time of day and the mechanisms responsible for time dependant
variations.
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5. ANUSHA NADIKATLA

6. The main aim of chronopharmacokinetics is to
control the time of administration which can be
responsible for variations of drug kinetics.
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7. Need for chronopharmacokinetic studies:
• When possible daily variations in pharmacokinetics may be
responsible for time dependant variations in drug effects.
• When drugs have a narrow therapeutic range.
• Mechanism responsible for the time dependent variation.
• When symptoms of a disease are clearly circadian phase-dependant
(ex: nocturnal asthma, angina pectoris, ulcer etc.)
• Responsible for variations of drug kinetics but also may explain
chronopharmacological effects observed with certain drugs.
• When drug plasma concentrations are well correlated to the
therapeutic effect in case the latter is circadian-phase dependant.
• When the drug has some serious adverse effects that can be avoided or
minimized because there are related to time of administration ( ex:
amino glycosides nephrotoxicity). ANUSHA NADIKATLA

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9. Reasons for chronopharmacokinetics:
• The time dependant changes are probably due to circadian variation in
GIT.
• It may also be due to variations in levels of various metabolic
enzymes such as cytochrome P450 (CYP 3A).
• Pharmacokinetics of mainly lipophilic drugs can be circadian phase
dependant. The studies show that after oral dosing, peak drug
conc.(Cmax ) is generally higher or time to peak (tmax), shorter after
morning compared with evening administration.
• To summarize, circadian variations in gastric acid secretion and pH,
motility, gastric emptying time, GI blood flow, glomerular filtration,
renal blood flow, urinary pH and tubular reabsorption may play a role
in such kinetic variations.
ANUSHA NADIKATLA

10. BODY RHYTHMS
These are the biological processes that show cyclic variation over
time.
TYPES OF BODY RHYTHMS:
• Circadian rhythms: which lasts for about one day. Ex: sleep
walking, body temperature.
• Ultradian rhythms: which lasts for shorter than a day, like seconds.
Ex: heartbeat.
• Infradian rhythms: which lasts for longer than a day, like monthly
rhythms- menstrual cycle.
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11. CIRCADIAN RHYTHMS
• The term circadian coined by Franz Halberg, comes from Latin.
• “Circa” means around &“diem” means day.
• Pharmacokinetic parameters, which are conventionally considered to
be constant in time, are influenced by various physiological functions
displaying circadian rhythm.
• Circadian changes in gastric acid secretion, gastrointestinal motility,
gastrointestinal blood flow, drug protein binding, liver enzyme
activity, renal blood flow and urinary pH may play a role in time-
dependent variation of drug plasma concentration.
• Exposure of light can change endogenous circadian pace time of light,
duration, wavelength, intensity, which determine circadian patterns of
body.
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12. CIRCADIAN
RHYTHMS
Exogenous
rhythms
Sleep wake
cycles, blood
pressure, pulse
rate, metabolic,
gastro intestinal
Endogenous
rhythms
ACTH output, corticosteroid
output,circulating neutrophils
, circulating eosinophils ,
rapid eye movement
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13. EXAMPLES OF CIRCADIAN RHYTHM:
• WBC count peak at late night.
• Haemoglobin and insulin are highest in the afternoon.
• BP increases in morning after night sleep, peaks afternoon &
decreases during Sleep cycle.
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15. Humans demonstrate a series of changes which lasts about a day
including temperature, respiration and metabolism, sleep-wake cycle
• Lasts for more than
one day.
• Ex: woman's
menstrual cycle which
lasts for 28 days
• Lasts forever.
• Ex: Heart beat
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17. The best-known circadian rhythms:
• Temperature hormone secretion metabolism sleep/wake cycle.
• The circadian system is biphasic.
• Increased sleep tendency and decreased performance capacity during
two periods throughout the 24-hour day, from 2 AM to 6 AM and
from 2 PM to 6 PM.
• These periods are sometimes referred to as circadian lulls.
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21. Disruption of the normal circadian rhythm or incomplete circadian
adaptation leads to:
• Acute and chronic sleep deprivation.
• Decreased alertness.
• Increased subjective fatigue.
• Decreased physical and mental performance.
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22. Clock diagram of the approximate time, in human following the diurnal
activity / nocturnal sleep routine, when symptoms or events of diseases
are worst or most frequent. ANUSHA NADIKATLA

23. CIRCADIAN RHYTHMS AND SEVERITY OF
CLINICAL DISEASE
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24. Physiologically induced time
dependency
Absorption- elimination
parameters
Distribution and Plasma
binding
Enzymatic metabolic activity
Systemic clearance
Renal clearance
CSF drug concentration
Chemically induced time
dependency
Auto-induction
Auto inhibition
CLASSIFICATION
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25. PHYSIOLOGICALLY INDUCED TIME DEPENDENCY
CIRCADIAN CHANGES IN DRUG ABSORPTION
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26. Absorption is altered due to circadian changes in:
• Gastric acid secretion
• pH
• Motility
• Gastric emptying time-longer for evening meal-tmax
• GI blood flow
• Routes of administration
• Absorption is also altered due to physicochemical properties-
lipophilicity or hydrophilicity.
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27. Examples:
• Most lipophilic drugs like phenytoin seems to be absorbed faster
when the drug is taken in morning compared with the evening.
• NSAIDs- indomethacin and ketoprofen has better absorption in the
morning and greater bioavailability.
• Skin penetration of a eutectic mixtures of lidocaine and prilocaine
depend on time of administration with higher penetration rate in
evening.
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28. CIRCADIAN CHANGES IN DRUG DISTRIBUTION
Distribution is altered due to circadian changes in :
• Body size and composition
• Blood flow to organs
• Plasma protein binding
• Membrane permeability to drugs
• Peak plasma concentration of plasma proteins like albumin and
glyco-protein are time dependant and occurs early in the afternoon
when compared during the night.
• Ex: Cis- diamine dichloro platinum (cis DDP) anti- neoplastics
maximum binding to plasma proteins is in afternoon and minimum in
the morning.
• Drug concentration of free fraction of phenytoin and valproic acid
have been found to vary in 24 hrs scale.
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29. CIRCADIAN CHANGES IN DRUG METABOLISM
Metabolism is altered due to circadian changes in: liver
• Cytochrome p-450 monooxygenase ex: ᵝ hydrocortisol.
• Hepatic blood flow.
• First pass elimination of drugs.
• Enzyme activity.
• Temporal variation in oxidase activity of the liver and concentration of
microsomal enzyme at the beginning of activity.
• Temporal variation in conjugation i.e. hepatic glucuronidation and
sulfation ex: paracetamol.
Limitations of metabolism:
• Capacity limited metabolism results in decreased hepatic clearance in
case of phenytoin.
• Enzyme induction causes hepatic clearance of carbamazepine.
• Decreased hepatic blood flow causes hepatic clearance of propranalol.
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30. CIRCADIAN CHANGES IN SYSTEMIC CLEARANCE
• Systemic clearance decreases at night and increases during day time.
• For drugs with low extraction ratios fluctuations in intrinsic metabolic
clearance in plasma protein binding.
Examples:
 Ethosuximide.
 valproic acid.
 Carbamazepine.
 clonazepam.
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31. CIRCADIAN CHANGES IN RENAL CLEARANCE OF DRUG
Excretion is altered due to circadian changes in :
• Glomerular filtration.
• Renal blood flow.
• Urinary pH – change in urinary pH decreases the clearance in case of
salicylic acid.
• Tubular reabsorption- increase in reabsorption increases the clearence
in the case of ascorbic acid.
• Urine output.
• Urinary excretion of electrolytes.
• All these are lowered during the resting period than in activity period
• Acidic drugs are excreted faster after evening administration.
ex: sodium salicylate and sulfasymazine.
ANUSHA NADIKATLA

32. TIME DEPENDENCY IN CEREBROSPINAL FLUID
(CSF) DRUG CONCENTRATION
• The drug concentration will be maximum during the dark period
( 2:00 – 5:00 am)
• It will be minimum during the light period (14:00 – 17:00 pm)
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33. CHEMICALLY INDUCED TIME DEPENDENCY
AUTO INDUCTION
• Induction of enzymes by the drug is responsible for elimination there
by increase the clearence of the drug.
• Ex: repeated doses of carbamazepine, rifampicin induces the enzymes
responsible for their elimination.
AUTO INHIBITION
• The metabolites formed increase in concentration and further inhibit
metabolism of the parent drug.
• Ex: xanthine oxidase inhibitor- allopurinol, verapamil.
ANUSHA NADIKATLA

34. FACTORS AFFECTING CIRCADIAN RHYTHMS
• Food
• Meal timing
• GI pH
• Intestinal motility
• Digestive secretions
• Intestinal blood flow
• Light
• The timing of exposure to light
• The length of exposure
• Intensity and wavelength of light
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35. PHASE RESPONSE CURVE
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36. DRUGS THAT UNDERGO CHRONOKINETICS
CLASS OF DRUGS EXAMPLES
Antibiotics
 Amino glycosides,
 Amikacin
General anesthetics
 Benzodiazepines,
 Halothane
NSAIDs
 Indomethacin,
 ketoprofen
Anticancer drugs
 5-fluoro uracil,
 Cisplatin ANUSHA NADIKATLA

37. DRUGS THAT UNDERGO CHRONOKINETICS
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. Apart from
that it has an effect on toxicity of certain drugs which may decrease at
different time of day
Examples:
 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.
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38. 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.
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.
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39. 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.
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40. APPLICATIONS
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43. CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
 Enteric coatings
 Layered systems
 Time controlled explosion systems(TES)
 Sigmoidal release systems(SRS)
 Press-coated systems
ANUSHA NADIKATLA

44. ENTERIC COATED SYSTEMS
• Enteric coatings have traditionally been used to prevent the release
of a drug in the stomach.
• Enteric coatings are pHsensitive and drug is released when pH is
raised above 5 in the intestinal fluid.
• These formulations can be utilised in time-controlled drug
administration when a lag time is needed.
• Because of the unpredictability of gastric residence, such systems
cannot be the first choice when a time-controlled release is required.
• In the treatment of nocturnal asthma, a salbutamol formulation
containing a barrier coating which is dissolved in intestinal pH level
above about 6, has been successfully used.
• The system contains a core which is film coated with two polymers,
first with HPMC and then with a gastro-resistant polymer
(Eudragit® L30D).
• In this system the duration of the lag phase in absorption can be
controlled by the thickness of the HPMC layer.
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45. LAYERED TABLETS
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46. • These are one or two impermeable or semipermeable polymeric coatings
(films or compressed) applied on both sides of the core.
• To allow biphasic drug release, a three-layer tablet system was developed.
• The two layers both contain a drug dose.
• The outer drug layer contains the immediately available dose of drug.
• An intermediate layer, made of swellable polymers, separates the drug
layers.
• A film of an impermeable polymer coats the layer containing the other dose
of drug.
• The first layer may also incorporate a drug-free hydrophilic polymer barrier
providing delayed (5 h) drug absorption.
• Conte et al has also studied a multi-layer tablet system (Geomatrix®).
• It consists of a hydrophilic matrix core containing the drug dose.
• This kind of threelayer device has been used in the treatment of
Parkinsonian patients using L- dopa / benserazide.
• Night-time problems and early-morning symptoms of Parkinsonism can be
avoided by using a dual-release Geomatrix@ formulation, which allows
daily doses of drug to be reduced and leads to extent of bioavailability 40 %
greater than when a traditional controlled release formulation is employed.
LAYERED SYSTEMS
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47. TIME CONTROLLED EXPLOSION SYSTEMS (TES)
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48. TIME CONTROLLED EXPLOSION SYSTEMS (TES)
• These have been developed for both single and multiple unit dosage
forms.
• In both cases, the core contains the drug, an inert osmotic agent and
suitable disintegrants. Individual units can be coated with a protective
layer and then with a semipermeable layer, which is the rate
controlling membrane for the influx of water into the osmotic core.
• As water reaches the core, osmotic pressure is built up.
• The core ultimately explodes, with immediate release
of the drug.
• The explosion of the formulation can also be achieved through the use
of swelling agents.
• Lag time is controllable by varying the thickness of the outer polymer
coating.
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49. SIGMOIDAL RELEASE SYSTEMS (SRS)
• For the pellet-type multiple unit preparations, SRS containing an
osmotically active organic acid have been coated with insoluble
polymer to achieve different lag-times.
• By aplying different coating thicknesses, lag times in vivo of up to 5
hours can be achieved.
• Release rates from SRS, beyond the lag time, has been found to be
independent of coating thickness.
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50. PRESS-COATED SYSTEMS
• Delayed-release and intermittent-release formulations can be achieved
by press-coating.
• Press-coating, also known as compression coating, is relatively simple
and cheap, and may involve direct compression of both the core and
the coat, obviating the need for a separate coating process and the use
of coating solutions.
• Materials such as hydrophilic cellulose derivatives can be used and
compression is easy on a laboratory scale.
• On the other hand, for large-scale manufacture, special equipment is
needed.
• The major drawbacks of the technique are that relatively large
amounts of coating materials are needed and it is difficult to position
the cores correctly for the coating process.
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51. IMPORTANCE
• These studies are needed in knowing pharmacokinetic data of drugs,
the toxic effects of which can be eliminated or minimized by altering
the time of administration.
• Diseases like angina pectoris, ulcerous conditions, asthma, cardiac
disorders etc. are in such states where symptoms are manifested in
circadian rhythms and chronopharmacokinetic studies, find
themselves as important tool to decide the moment of administration.
• When the drug has some severe adverse effects related to the time of
their administration ex: nephrotoxicity associated with amino
glycosides.
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52. 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
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53. DEMERITS
 Lack of manufacturing reproducibility and efficacy.
 Batch manufacturing process.
 Higher cost of production.
 Trained/skilled personal needed for Manufacturing.
 Large number of process variables.
 Large number of animals are required.
 Harmful to rodents or experimental animals.
 Experimental difference between species rodents and humans
 Very complex during anti cancer drug development.
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54. CONCLUSION
The concept of drug
treatment was earlier “right drug
for the right person” is now
changed to “right dose for the right
person at right time”. Time
dependent pharmacokinetics can
sometimes be responsible for daily
variation drug effects or adverse
effects. Hence time of day should be
considered as an additional variable
that influences the kinetics of the
drug. Drug release pattern if
designed in a time controlled
manner, maximum drug can be
available at peak hours with
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55. REFERENCES
• Applied Biopharmaceuticals & Pharmacokinetecs (5th edition) by Leon
Shargel, page240-242
• Drug disposition & pharmacokinetics – Stephen H. Curry, 122 page.
• Biopharmaceutics and pharmacokinetics by Venkateswarlu
• Time dependent pharmacokinetics by Rene H. Levy, Department of
pharmaceutics BG-20, University of Washington, Seattle, Washington,
U.S.A, pp. 115-127.
• Pharmacology, 6th edition, by H.P. Rang, M.M. Dale, J.M. Ritter and
R.J. Flower, pg no. (98-126).
• Time dependent pharmacokinetics - recent developments by Rene H.
Levy and C.R. Banfield University of Washington, Seattle, Washington.
Pg no. (178-186).
• Clinical Concepts and Applications, 2nd addition, by Rowlend and
Towzer, pp (256-262).
• Bruguerolle B, Lemmer B.1993. Recent advances in
chronopharmacokinetics: methodological problems. Life Sci. 52:1809-
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