Chrono pharmacokinetics

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  • 1.Chrono-pharmacokinetics Chronobiology Science that studies the biological rythms Chrono-Pharmacokinetics Deals with study of temporal changes in ADME- due to time of administration Chronokinetics Time dependent changes in ADME Chronesthesy Changes in susceptibility or sensitivity of a target system Chrono-therapeutics Application of chrono-biological principles to the treatment of diseases

2. Why study Chrono-Pkinetics?? PK-PD vary with time Gastric motility: is double in day time than in night Plasma protein concentrations are higher in day than in night Hepatic blood flow has been shown to be greatest at 8 am and metabolism to be reduced during the night Symptoms of a disease are circadian phase dependent e.g.asthma, angina pectoris, myocardial infarction, ulcer diseases Drug toxicity can be avoided/ Minimized by administering at aparticular time 3. Body Rythms Cyclic variations over time Ultradian rythms: < 20 hrs Circadian rythms: 20-28 h Infradian rythms: > 28 h Circaseptan: 7 days Circamensual: ~ 30 days Circa-annual rythms: ~ 1 year 4. Circadian Rythm 24 hour cycle Circa meaning around diem meaning day Biological clock Supra-chiasmatic centre SCN inhypothalamus Eyes > Retina (photoreceptors> photoresponsive ganglioncells)> retino hypothalamic tract> SCN) SCN passes the information to Pineal gland >> Melatoninhormone Exposure of light can change endogenous circadian pace Timeof light, duration wavelength, intensity, all determine circadianpatterns of body 5. Examples of circadian rythm Sleep cycle Basal gastric acid secretion WBC count peak at late night Serum cholesterol and triglycerides concentrations are highestearly in the evening Haemoglobin and insulin are highest in the afternoon Intra ocular pressure is highest between 2-4 pm and lowest inlate evening BP increases in morning after night sleep, peaks afternoon anddecreases during sleep Potassium efflux from cells is lowest around 3. pm 6. PK- Absorption Gastric motility, secretions, pH emptying time,blood flow Lipophilic drugs better absorbed in morning Valproic acid, Indomethacin, Ketoprofenbetter absorbed in the morning Skin penetration of lidocaine and prilocaine inevening 7. PK- Distribution Body size, composition, Protien binding,volume of distribution, blood flow to variousorgans Maximum protein binding of antineoplasticslike cisplatin, carbamazepine, diazepam,phenytoin, valproic acid, is found in afternoonand minimum in morning 8. PK- Metabolism Liver enzyme activity, Hepatic blood flow High extraction ratio: metabolism depends on blood flow Low extraction ratio: metabolism depends on enzyme activity Hepatic blood flow high in morning Metabolism reduces in night 9. Asthma Airway resistance increase during nights E. g. Uniphyl a long acting theophylline preparation in theevening improvement in lung function in the morningArthritis Osteo-arthritis: Less pain in morning and more at night Rheumatoid arthritis: pain peaks in morning anddecreases as the day progresses. NSAIDs for RA after evening meal 10. Chrono-therapeutic drug delivery systems Chronotopic DDs Contin Pulsincap system Ceform Time Rx Synchrodose OROS CODAS Diffucaps Pulsatile drug delivery systems Erosion based monolithic tables Multi particulate systems Physicochemical modification of API Chronomodulating infusion pumps Microchip strategies 11. Chronotopic Technology Delayed, time-dependant pulsatile drugdelivery as well as colon specific drug release. HPMC coating undergoes a glassy-rubberytransition when in contact with aqueous fluid. 12. Diffusion and/or erosion mediated release The tablet matrix is prepared by firstly granulatingthe drug with a range of excipients which is thencompressed. A mixture of HPMC and PEG solutions are thenspray-coated onto the core and allowed to dry.Thereafter a coating of Eudragit is applied onto theouter surface of the tablet matrix 13. Contin Technology Molecular co-ordination complexes betweencellulose polymers and non polar solid aliphaticalcohol Drug + hydrophilic polymer-> Hydration andfixation by alcohol Uniform porosity matrices E.g. Uniphyl (Anhydrous Theophylline tablets) forasthma Evening administration 14. Pulsincap 15. A water insoluble drug-loaded capsule The capsule is sealed with a swellable hydrogel plugcomprising polymers such as the poly(methacrylates),HPMC, PVA, PVAc, PEO, Pectin, Saturated polyglycolate d-glycerides An enteric layer that dissolves upon reaching the smallintestine where the polymeric plug begins to swell resultingin a lag-phase prior to drug release. The plug then expands and is pushed outward to affect drugrelease. The variation in dimensions of the plug and its point/depth ofinsertion into the capsule determines the lag-time producedprior to drug release Pulsincaps technology has the versatility of allowing one ormoreminitablets,coated tablets, solutions,ormultiparticulates to be loaded within the capsule for deliveryof drug in a chrono-therapeutic manner 16. CEFORM Technology Uniform size and shaped microspheres 150-180 microns biodegradable polymers Capsules, suspensions, tablets, effervescent tablets and sachets Cardizem LA which is a once-daily Diltiazem formulation 17. Lag-phaseof 5 hrs 18. Oros TechnologyDrug and poly(ethyleneoxide) (PEO) granulated with a solution of poly(vinylpyrolidine) (PVP).The push compartment comprisesPEO, hydroxypropylmethylcellulose (HPMC),sodium chloride Covera-HS (verapamil), antihypertensive Overnight drug release to prevent the surge in blood pressure that occurs inpatients during the early morning Manufacturing the system has proven to be complicated with the need for alaser-drilled hole in the semi-permeable coating. In addition, clogging of the hole may limit drug release. Drying time alsoposesa challenge as the drug delivery system requires a fairly extensivedrying period of four days 19. CODAS technology Verelan PM (verapamil). This formulation is designed to release verapamil 45 hours after ingestion. Chronotherapeutic Oral Drug Absorption System delayed onset of drug release,Both the core and the multilayered membrane comprise water solubleand water insoluble polymers. When the multiparticulates are exposed towater, the water-soluble polymer dissolves and drug diffuses through thepores present in the coating 20. Diffucaps Inert particle such as sugar spheres, crystals or granules. Inert binder is used to bind the drug particles to the inert core The drug-loaded core is then coated with a plasticized enteric coating and thereafter coated with a mixture of water insoluble and enteric polymersSize < 1 mm 21. Egalet A tablet in capsule device Core-in-cup tablet technology A bi-layered tabletPharmaceutical Development and Technology, 2009; 14(6): 602612Drug delivery technologies for chronotherapeutic applicationsZaheeda Khan, Viness Pillay, Yahya E. Choonara, and Lisa C. du Toit 22. Placental Transfer Placental transfer is a concern because certain drugsmay induce congenital abnormalities. If administered immediately prior to delivery, drugs maydirectly adversely affect the infant. Mechanism: typically simple diffusion lipid-soluble,non-ionized drugs are more likely to pass from the maternal blood into the fetal circulation. By contrast, ionized drugs with low lipid-solubility are less likely to pass through the placental "barrier". The fetus is exposed to some extent to all drugs taken by the mother. 23. Physicochemical properties of drugs Lipid solubility: Thiopental: apnea and sedation of fetus, Succinyl choline, and tubocurarine cross placenta very slowly Molecular weight: 250-500 Dalton easily pass through Above 1000 Dalton difficult to pass: eg. Heparin Rate at which drug crosses the placenta and amountreaching fetus Duration of exposure Distribution characteristics in different fetal development Placenta contains drug transporters e.g. Maternalantibodies cross the placenta and provide fetus immunity Eg. Glyburide is pumped out by BCRP transporter andMRP 3 transporter from the placenta >> so no glyburidereaches the fetal circulation 24. Protein binding Drugs show greater proteins binding inplasma than in fetal proteins Drug Metabolism in placenta also preventsseveral drugs from getting in Several aromatic oxidation reactions Drug metabolites can cause toxicity 25. Teratogen Result in malformations Exert its effect in particular stage of fetaldevelopment Dose dependent incidence