Chronopharmacokinetics..

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

1. CHRONOPHARMACOKINETICS by, Syed Baseeruddin Alvi (09)

2. Introduction Definition Aim Examples Types Dosage forms Merits & Demerits content

3. Drug A bsorption, D istribution, M etabolism and E limination 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

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. 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…….

6. 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:

7. Apart from that it has an effect on toxicity of certain drugs which may decrease at different time of day eg: Aminoglycosides: P eak 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( CL T & AUC) than light period.

8. 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:

9. 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:

10. 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

11. 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

12. CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

13. 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,

14. 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

15. 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

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