Biopharmaceutics & Pharmacokinetics (Lecture No. 6) (11 files merged).pdf

BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD FACTORS FACTORS AFFECTING ABSORPTION AND BIOAVAILABILITY OF DRUG PHYSIOLOGICAL PHYSICOCHEMICAL DOSAGE FORM FORMULATION...

BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD FACTORS FACTORS AFFECTING ABSORPTION AND BIOAVAILABILITY OF DRUG PHYSIOLOGICAL PHYSICOCHEMICAL DOSAGE FORM FORMULATION PHYSICOCHEMICAL, DOSAGE FORM & FORMULATION BY: SALMAN ASHFAQ AHMAD FACTORS FACTORS PHYSICOCHEMICAL, DOSAGE FORM & FORMULATION FACTORS BY: SALMAN ASHFAQ AHMAD MECHANISM & NOYES-WHITNEY EQUATION  Dissolu on → Transfer of solute in solu on  Difference between solubility and dissolution  Mechanism of dissolu on → Diffusion layer + bulk of solu on  Dissolu on process → Noyes – Whitney equa on → Different parameters are connected mathematically in an equation  Noyes-Whitney equa on → dm / dt = (DAΔC) / h → ΔC = Cs – C  Noyes-Whitney equa on → Rate of diffusion of solute through boundary layers → Surrounding the spherical particle DISSOLUTI BY: SALMAN ASHFAQ AHMAD ON MECHANISM & NOYES-WHITNEY EQUATION MECHANISM OF DISSOLUTION DISSOLUTI BY: SALMAN ASHFAQ AHMAD ON PHYSIOLOGICAL FACTORS DISSOLUTI BY: SALMAN ASHFAQ AHMAD ON DRUG FACTORS SURFACE AREA WETTABILITY DRUG FACTORS SOLUBILITY IN DIFFUSION LAYER EXTENT OF IONIZATION CRYSTAL FORM DISSOLUTI BY: SALMAN ASHFAQ AHMAD ON DRUG FACTORS (SURFACE AREA)  ↑ surface area, ↑ we.ability → ↑ dissolu on  Increased effec ve surface area → Faster dissolu on  ↑ Dissolu on → ↑ Bioavailability (Absorp on → dissolu on rate limited)  ↑ bioavailability → ↑ plasma concentra on  Griseofulvin → Poorly soluble → 10 micron to 2.7 microns → 2x drug absorp on  Hydrophobic drug → Size reduc on → Aggrega on of drug par cles → ↓ Bioavailability → Aspirin, Phenacetin, Phenobarbital, etc.  Milling → Hydrophilic carrier, we>ng agent, or stabilizers DISSOLUTI BY: SALMAN ASHFAQ AHMAD ON DRUG FACTORS (SURFACE AREA)  Several drug delivery systems → Stabilize in nanometers → ↑ Bioavailability  Immunosuppressant Rapamune® (Sirolimus), Antiemetic Emend® (Aprepitant), lipid – regulating agent TriCor® (Fenofibrate), Megace® ES (Megesterol Acetate)  Sirolimus → ↑ bioavailability for Rapamune® tablets → Owing to nanopar cles  Megace® ES → Appe te loss / weight loss → AIDS → nanosuspension vs standard suspension → ↓ viscosity and ¼ of the volume to be dosed FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (WETTABILITY)  We>ng agents are added → Improves bioavailability  Phenace n → 75 µm → Polysorbate 80 added → ↑ rate and extent of drug absorp on  ↓ drug par cle size → No improvement in absorp on → Dissolu on is not rate limi ng factor FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (SOLUBILITY IN THE DIFFUSION LAYER)  Aqueous drug solubility → Cri cal factor for determina on of dissolu on rate  Slow dissolu on → Poor drug bioavailability  Relationship of rate of dissolution with the concentration in diffusion layer  Aqueous solubility of a drug → a) Crystallinity b) Drug molecule – solvent interaction  Solid par cles → Solubility limited due to solid state proper es → Brick dust molecules  ↑ log P values → ↑ lipophilicity → Grease ball molecules FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (EXTENT OF IONIZATION)  Weak electrolytes → Aqueous solubility dependent upon pH of the dissolving medium  Weak electrolyte → Rate of dissolu on dependent upon drug’s solubility and pH of diffusion layer  pH of diffusion layer → pka of drug and its solubility + pka and solubility of the buffers in bulk of GI fluids  PPIs → Increase gastric pH → ~ pH 5.5 → ↓ rate of dissolu on for triazole an fungals, an -cancer drugs  Posaconazole → ↑ dissolu on (~ 40%) → Administra on with acidic beverages  Unionized form of the drug → Absorp on → Replenishment of the unionized form due to equilibrium establishment FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (EXTENT OF IONIZATION)  Changing gastric pH → Pose problem for drugs with poor solubility FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (EXTENT OF IONIZATION) FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG FACTORS (CRYSTAL FORM)  Drugs exist in polymorphic forms → Metastable and stable polymorphic forms  Metastable form → Quicker dissolu on  Chloramphenicol palmitate → Polymorphic form A, B and C → Normal temperature and pressure → Polymorph A is stable, Polymorph B is metastable, and Polymorph C is unstable  Amorphous solids → Quick dissolu on  Hydrates → Anhydrous form dissolves quickly (anhydrous Ampicillin) → Opposite also true (Erythromycin) FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD FACTORS AFFECTING DRUG CONCENTRATION IN BULK OF GI FLUIDS COMPLEXATION DRUG DISSOCIATION AND LIPID SOLUBILITY MICELLAR SOLUBILIZATION FACTORS PRODRUGS ADSORPTION OF DRUGS CHEMICAL STABILITY IN GI FLUIDS FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD COMPLEXATION  Complexa on → Beneficial or detrimental  Streptomycin + Mucin → ↓ bioavailability  Tetracyclines + Calcium → Insoluble complexes  Bisphosphonates + Food → Insoluble complexes  Tetracyclines + Diluent (DCP)→ Insoluble complexes  Amphetamine + CMC  Phenobarbital + PEG 400  Complexa on in liquid formula ons → ↑ stability FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD MICELLAR SOLUBILIZATION  Micellar solubiliza on → Substance or drug incorporated into micelle → ↑ solubility  Bile salts → Ability to solubilize drug → Depends upon lipophilicity of the drug  Food → S mula on of bile → Mechanism of solubility for number of drugs → BCS Class II drugs → E.g., Albendazole, Griseofulvin FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD ADSORPTION OF DRUGS  Concurrent drug administra on → Adsorp on  Extent of adsorp on → Reversibility of drug–adsorbent interaction  Promazine + Ac vated charcoal → Drug–adsorbent interaction  Cyanocobalamin + Glidant → Drug–adsorbent interaction FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD CHEMICAL STABILITY IN GI FLUIDS  Stability of dug in GI fluids → Essen al for absorp on of drug in appropriate quan ty → Therapeutic response  Acidic and enzymatic hydrolysis  Gastro-resistant formula ons → Designed to improve drug bioavailability → E.g., Erythromycin  Prodrugs → Limited solubility → Minimal dissolu on → Drug release at appropriate site → E.g., Erythromycin Stearate FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG DISSOCIATION AND LIPID SOLUBILITY  Drug dissocia on constant & its lipid solubility + pH of absorp on site → Absorp on  Degree of ioniza on + Extent of absorp on → Covered in pH – par on hypothesis → Overton (1899)  GI epithelium → Lipid barrier → Passive diffusion → Lipophilic molecule → Unionized drug penetrates membrane  Extent of ioniza on → Henderson Hasselbalch equa on → log [A-] / [HA] = pH – pKa (acidic drug) → log [BH+] / [B] = pKa – pH  Drug X → pKa = 3.0 → At pH 1.2 (98.4% un – ionized) → At pH 6.8 (99.98% ionized)  Drug Y → pKa = 5.0 → At pH 1.2 (99.98% ionized) → At pH 6.8 (98.4% un – ionized) FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DRUG DISSOCIATION AND LIPID SOLUBILITY  Large surface area, Longer small intes nal residence me, ↓ pH of microclimate → Absorp on of weakly acidic drug  Uns rred water layer → Barrier to drug absorp on for lipophilic drug  Convec ve flow → Increased in jejunum → Water and lipid soluble drugs  Number of drugs → ↑ Unionized form → ↓ Absorp on → Lipid solubility to be determined → Barbiturates → ↓ Barbitone (pka = 7.8) & ↑ Thiopentone (pka = 7.6)  Polar molecules (log P < 0), large molecules → Injectables → Gentamycin, Heparin, CeZriaxone, etc. → Lipid soluble drugs (log P > 3) → Well absorbed orally → ↑ Suscep bility to biliary clearance → Less lipid soluble, smaller molecule absorbed via Paracellular route (e.g., Atenolol) FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PRODRUGS  Prodrugs → ↑ lipid solubility → ↑ absorp on  Ester group is introduced → Prodrug → Re convert into parent co,mpound  Examples: Pivampicillin (Ampicillin + Pivaloyloxymethy), Cefuroxime axetil (Cefuroxime + Acetylethyl), Enalapril (Enalaprilat + 1-carboxylic acid), Ibuterol (Terbutaline + Dibutyl) FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD IMPROVING BIOAVAILABILITY OF POOR AQUEOUS SOLUBLE DRUGS SALT FORMATION METHODS SDDS FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD SALT FORMATION  Drugs are available in salt form → Acidic or basic salt  Tolbutamide + Sodium → Dissolu on 5000x in acidic medium as compared with free acid  Naproxen + Sodium → Faster dissolu on  Chlorpromazine + HCl → Faster dissolu on in gastric and intes nal pH  Other salts form also exist  Some salt forms → Decreased dissolu on as compared with free drug → Sustained release formula on → Aluminum salts of weak acids and Pamoate salts of weak base  Acidic or basic excipients also used → Chemical instability → Sodium salt of Aspirin FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD SDDS SPRING – PARACHUTE MODEL FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD SDDS  SDDS → Improves bioavailability  It follows Spring – Parachute Model.  SDDS → Drug presented at supersaturated concentra on → GI fluids  SDDS → Drug springs into system → Slowly returns (parachute effect)  Polymers included → Prevent precipita on FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD IMPROVING BIOAVAILABILITY OF POORLY SOLUBLE DRUGS DUE TO LIPOPHILICITY COSOLVENTS SEDDs METHODS CYCLODEXTRIN MICELLAR SOLUBILIZATION FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD COSOLVENTS  Co-solvents → Low molecular weight → PEGs, PG, Glycerol → Drugs dissolved → Filled in so: gel capsules  Bexarotene (Targre n®) → An cancer drug + PEG 400  Etoposide (VePesid®) → Anticancer drug + PEG 400 + Glycerol + Citric acid + Water  Ethosuximide (Zarontin®) → Anticonvulsant drug + PEG 400  Drug precipitation → Large variability in bioavailability → E.g., Nifedipine FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD CYCLODEXTRINS  Cyclodextrins (CDs) → Cyclic oligosaccharides → Glucopyranose units  Lipophilic molecules → Trapped inside CDs → Increase aqueous solubility  CDs → Solubility enhancers  Example: Voriconazole → An fungal drug FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD MICELLAR SOLUBILIZATION  Micellar solubiliza on → Improves solubility of drug → ↑ bioavailability  Surfactants used for micellar solubilization.  Used for both liquid and solid formulations. FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD SEDDS  SEDDS → Drug solubilized in oil/surfactant vehicle  Filled in a soft gelatin capsule.  Micro-emulsion or nano-emulsion results.  Drug diffuses into the aqueous medium. FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD IMPROVING THE BIOAVAILABILTY OF DRUGS WITH POOR PERMEABILITY  Drug absorp on → Affected by number of factors  Drug pka, lipid solubility, molecular weight, hydrogen bonding, chemical stability FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD MOLECULAR SIZE & HYDROGEN BONDING  Paracellular absorp on → < 200 Da → Shape is also important  Transcellular passive diffusion → < 500 Da  ↑ Hydrogen bonding → ↓ Absorp on  Pep de drugs → Less well absorbed FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PERMEATION ENHANCERS  Permea on enhancers → Added in formula on → To improve permeability  Improve permeability → Paracellular route by reversibly opening the ght junc ons or transcellular route by altering integrity  Surfactants, bile salts, medium chain fatty acids, chelating agents  FaHy acids and bile salts → Fluidizing the lipid membrane  EDTA chelates calcium FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PERMEATION ENHANCERS  Semaglutide → Polypep de analogue of human glucagon like pep de 1 (GLP-1) → Type 2 diabetes → Use small faHy acid deriva ve → Permea on enhancer to ↑ transcellular transport across gastric mucosa → ↓ TEER (transepithelial electrical resistance) and ↑ membrane fluidity  SNAC + Vitamin B12 → ↑ absorp on of vitamin B12 FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DOSAGE FORM FACTORS  Rate and extent of drug absorp on → Affected by number of physiological and physicochemical factors  The rate and extent of drug absorp on → Affected by dosage form factors → Type of dosage form, manufacturing method, etc.  Oral dosage form → Solu on, suspension or solid dosage form → Affects the number of intervening steps  Generally, aqueous solution > aqueous suspension > solid dosage forms  Other factors beside bioavailability → Influence the type of dosage form prepared for administration FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD DOSAGE FORM FACTORS FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD AQUEOUS SOLUTIONS  Water soluble drug formula on → Eliminates the in vivo drug dissolu on  ↑ Solubility → Using techniques → Precipita on in gastric pH  Salt of weak acidic drug → Precipita on at gastric pH  Experimental drug → 3 formula ons → Bioavailability determined → Polyethylene glycol (19%), Hydroxypropyl β – cyclodextrin (57%) & Hydroxypropyl β – cyclodextrin (89%) → Difference of precipitation  Factors associated with aqueous solu on → Affect bioavailability → Chemical stability, complexation, solubilization & viscosity of the formulation FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD AQUEOUS SUSPENSIONS  Aqueous suspension → Poorly or insoluble drug administra on → Dissolu on rate limited  Administration results in availability of large surface area.  Aqueous suspension → Second to non – precipitating aqueous solution  Drug in hard gela n capsule or tablet → Ul mately achieve condi on of aqueous suspension  Factors associated with aqueous suspension → Affect bioavailability → Par cle size, crystal form, complexation, inclusion of surfactants, viscosity of formulation FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD LIQUID FILLED CAPSULES  Liquid filled capsules → SoA / hard gela n or HPMC  Drug inside capsule → Dissolved or dispersed in non – toxic, non – aqueous vehicles  Water miscible vehicle → Content of capsule released → Vehicle disperse / dissolve → Drug released → Solu on / suspension → Absorp on  Water immiscible vehicle → Content of capsule released → Vehicle dispersion → Facilitated by dispersing agents → Drug released as solu on / suspension / emulsion / nano – emulsion / micro – emulsion → Absorp on  Lipophilic vehicle → Diges ble oil → Drug highly soluble in vehicle → Fat absorp on process FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD LIQUID FILLED CAPSULES  Lipophilic vehicle → Non – diges ble oil → Drug highly soluble in vehicle → Par oning of drug in GI fluids  Drug suspended in oily vehicle → Dissolu on → Diffusion → Par oning  Digoxin → Poorly soluble drug → Mixture of PEG + Ethanol + PG → ↑ Absorp on than tablet  Ciclosporin → SANDIMMUNE®→ Large hydrophobic drug → ↓ Permeability → FaIy diet → Variable bioavailability → Formula on containing mixture of hydrophilic and lipophilic phases, surfactants, cosurfactants, cosolvents → Non – precipita ng microemulsion on dilu on → NEORAL®  Protease inhibitors → Saquinavir → Formulated as soA gela n capsule → ↑ Bioavailability FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD LIQUID FILLED CAPSULES  Factors associated with making of liquid soA gels→ Affect bioavailability → Solubility of drug, particle size, nature of vehicle, inclusion of surfactants, inclusion of suspending agent, complexation FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD POWDER FILLED CAPSULES  Bioavailability from a powder filled hard gela n / HPMC capsule → Similar to compacted tablet → Provided factors are controlled  Rate of drug dissolu on from capsule → Complex func on of different processes  Excipients in capsule dosage form → Influence the rate of dissolu on → Poorly soluble drugs → Hydrophilic excipients → ↑ Penetra on → ↑ Dispersion → Dissolu on of drug  No adsorption of drug by excipients  Formula on & type of process of filling → Affect packing density and liquid penetra on FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD POWDER FILLED CAPSULES  Factors associated with making of powder filled capsules → Affect bioavailability → Surface area & particle size, Use of salt form of drug, crystal form, stability of drug, drug – excipient interaction, nature & quantity of excipients, type and condition of filling process, packing density, composition & properties of capsule shell, interaction between capsule shell and its content FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD TABLETS (UNCOATED)  Tablets → Reduc on in surface area → Excipients added → Bring drug in pre – compacted state  Poorly soluble drug → Rapid disintegra on and release → Fine & well dispersed suspension in GI fluids → Dissolu on and absorp on  Disintegra on → Affected by concentra on and type of drug, excipients & compac on pressure  Dissolu on of poorly soluble drug in tablet → Comparable with dissolu on of drug in fine, well dispersed suspension  Factors associated with making of uncoated tablet → Affect bioavailability → Physico – chemical property of drug, nature & quantity of excipients, drug – excipients interaction, size and method of making granule, compaction pressure and compaction speed, storage condition & age of tablet FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD TABLETS (COATED)  Coa ng applied on tablets → Possess bioavailability related problems (uncoated tablets) + addi onal problems → Physicochemical nature and thickness of coa ng  Sugar coated tablets → Sealing the coat (Shellac & CAP) → Annealing agents (PEGs, CaCO3) added to reduce water impermeability  Film coated tablets → HPMC → Soluble at GI pH  Film coated tablets → Acrylic resins or EC → Hydrophobic → Reduces drug release  Gastro – resistant tablets → CAP, HPMC Phthalate, Co – polymers of methacrylic acid and their esters & Polyvinyl acetate Phthalate → Dissolve at pH 5  Gastro – resistant coa ngs → Offer ↓ onset of ac on FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD TABLETS (COATED)  Gastro – resistant formula ons → Pellets or intact tablet → Affect the release pa8ern of drug and hence onset of action  Gastro – resistant pellets → < 1 mm FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD INFLUENCE OF EXCIPIENTS  Excipients added in formula ons → To facilitate prepara on, pa ent acceptability and func oning of dosage form as DDS.  Excipients → Interact with the ac ve → Have poten al to influence the release, absorp on and other characteris cs of drug → Tetracycline + DCP, Amphetamine + Sodium CMC, Phenobarbital + PEG 4000, etc.  Excipients → Large variety → Example: Diluents, Surfactants, Lubricants, Disintegrants, Viscosity enhancers, Binders, Lubricants, Colorants, Stabilizers, Flavoring agents, Suspending agents, Emulsifiers, etc. FACTORS AFFECTING BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTICAL CHARACTERISTICS  Biopharmaceu cs → Factors affec ng rate and extent of drug absorp on  Factors → Release of drug, dissolu on, stability, ability to cross & pre – systemic metabolism → Influence absorption  Key biopharmaceu cal proper es → Quan fied → Give insight about absorp on  Bioavailability → Overall measurement of availability of drug in systemic circula on → Need to be assessed RELEASE FROM STABILITY OF TRANSPORT PRE – SYSTEMIC DOSAGE FORM DRUG OF DRUG METABOLISM ASSESSMENT BY: SALMAN ASHFAQ AHMAD RELEASE OF DRUG  Dosage form design → Controls the release of the drug  Solubility of the drug at GI pH → First indicator → Dissolu on is rate limi ng process  Rate of dissolu on determined → Intrinsic + dosage form  In vitro dissolu on tes ng → Reflects in vivo dissolu on performance  Scientists nowadays focus on in vitro – in vivo correla ons → Useful in number of ways  In vitro – in vivo correla ons → Useful for drugs where dissolu on is rate limi ng → Dissolu on profile of drug studied in various physiological media  Dilute HCl based solu on of pH 1.2 → Simulate gastric pH ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD RELEASE OF DRUG  Phosphate buffer pH 6.8 → Simulate intes nal pH  For in vitro – in vivo correla ons → To mimic gastric fed state → Homogenize the meal to be used and dilute with water → Milk also used for fed state  Dura on of dissolu on test → Depends upon site of absorp on of drug + ming of administra on  Volume of dissolu on media + Degree of agita on → Difficult to decide  Immediate release → 500, 900 or 1000 ml → Gentle agita on ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD STABILITY IN PHYSIOLOGICAL FLUIDS  Stability of drugs in physiological fluids → Chemical stability across GI pH range & suscep bility to enzymatic breakdown  Stability of drug in GI fluids → Simulated GI fluids or real GI fluids → Incuba on at 37°C for 3 hours → Loss of > 5% drug indicates poten al instability  Drugs when reach to colonic region → Resistance to the bacterial enzymes → Needed to be considered ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD PERMEABILITY  Number of methods to es mate permeability → Assessment of oral absorp on in humans  Methods → In silico to physicochemical and biological methods  Biological methods → In vitro, in situ, and in vivo methods ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD PARTITION COEFFICIENT  Par on coefficient of the molecule → Determined between oil and water phase (log P) → Lipophilicity of the molecule  n – octanol → Commonly used solvent → Oil phase  Shake flask method → Commonly used method  Aqueous phase saturated with oily phase & vice versa  Constant temperature is maintained → Drug is added and system is allowed to reach equilibrium (24 hours) → Concentra on is measured  Distribu on coefficient (log D) is determined → Weakly acidic or basic drug → BeJer predic on of drug’s ability to permeate ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) PARTITION COEFFICIENT SHAKE FLASK METHOD ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) PARTITION COEFFICIENT  Par on coefficient of the molecule → Computa onal methods → Correla on between calculated and measured values  Molecule fragmented and analyzed for lipophilicity → clog P  Moriguchi method → 13 parameters → mlog P  HPLC method → Used for es ma ng how well drug par ons into lipophilic phase ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) CELL CULTURE TECHNIQUES  Cell culture techniques → Widely used → Predict intes nal absorp on → Cell line widely used is Caco – 2  Caco – 2 → Human colon carcinoma cell line → First proposed model for absorp on by Hidalgo  In culture of Caco – 2 → Cells differen ate to form monolayer of polarized enterocytes → Resemble cells those in small intestine ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) CELL CULTURE TECHNIQUES Caco – 2 CELL CULTURE SYSTEM ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) TISSUE TECHNIQUES  Range of ssue techniques → Used as absorp on models  Two popular models → Isolated sheets of intes nal mucosa & use of everted intes nal rings ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) PERFUSION STUDIES  Rat model is preferred for perfusion studies → Ease of use and similarity to the permeability to human intestine  In situ intes nal model is used → Whole animal is used → Nerve , blood and lympha c supply intact ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) PERFUSION STUDIES  Rat model is preferred for perfusion studies → Ease of use and similarity to the permeability to human intestine  In situ intes nal model is used → Whole animal is used → Nerve , blood and lympha c supply intact ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD (PERMEABILITY) PRE – SYSTEMIC METABOLISM  Intes nal cell frac ons (brush border membrane prepara ons) → Homogenized prepara ons of rat intes nal segments → Used for pre – systemic metabolism  Incubation at 37°C.  Various liver prepara ons → Phase I and Phase II metabolism reac ons ASSESSMENT – KEY BIOPHARMACEUTICAL PROPERTIES BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD INTRODUCTION RELEASE OF DRUG CONCENTRATION STABILITY OF DRUG TIME PROFILE PERMEABILITY MEASUREMENT PRE – SYSTEMIC OF METABOLISM BIOAVAILABILITY ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PLASMA CONCENTRATION – TIME CURVE PERORAL ADMINISTRATION (BLOOD SAMPLE) ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PLASMA CONCENTRATION – TIME CURVE TERMINOLOGIES ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PLASMA CONCENTRATION – TIME CURVE PLASMA CONCENTRATION TIME CURVE (3 FORMULATIONS) ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD PLASMA CONCENTRATION – TIME CURVE  Three different formula ons A, B, & C → Administered to same person at different mes → Same route of administration  Assump ons: Sufficient me elapsed between administra on of each formula on → No residual concentra on and residual effects → Kine cs & pa"ern of distribu on, binding phenomenon, the kinetics of elimination and experimental conditions are all same  Differences exist → Rate and / or extent of absorp on of the drug from each formula on  Differences in bioavailability → Due to different formula ons → Pa ent can be over, under or correctly medicated  Plasma concentra on me curve → Beside biopharmaceu cal factors → Affected by other factors ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOPHARMACEUTIC S: DRUG BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD URINARY DRUG EXCRETION CURVE  Urine method of analysis → Intact drug and / or metabolites  Drug assay method not available for urine → Drug assay method not sensi ve → Assay of metabolites done in urine  Assumptions: No drug metabolism before reaching systemic circulation  Assumption: The appearance of drug and / or metabolite in the urine is the function of the rate and extent of absorption  Urinary excre on studies → Cumula ve amount of intact drug and / or metabolite & rate of excre on → Urine samples are collected → Construct cumula ve urinary excre on curve → Urine samples collected till all drug and / or metabolites excreted ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD URINARY DRUG EXCRETION CURVE PLASMA CONCENTRATION TIME CURVE & URINARY EXCRETION CURVE ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD URINARY DRUG EXCRETION CURVE  Comparison of bioavailability → Three formula ons A, B, & C → Administered to same pa ent → Same dose → Oral route → Same plasma concentra on – time curve in previous example  Slope of curve → A > B > C → Rate of oral absorp on of drug → A > B > C  Plasma and urine concentration – me profile → Same drug → Indicate Tmax A < B < C  Tmax ∝ 1 / drug absorption rate ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD URINARY DRUG EXCRETION CURVE URINARY EXCRETION CURVE (3 FORMULATIONS) ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD ABSOLUTE BIOAVAILABILITY  Absolute bioavailability → Frac on / percentage of administered dose → Reaches systemic circulation  Comparison of total amount of intact drug from a particular route of administration to the amount that reaches via IV route (bolus administra on) → Same or different dose but different dosage forms  AUC of both routes are compared  Absolute bioavailability = (AUCT)abs / (AUCT)iv → Equivalent doses  Absolute bioavailability = [(AUCT)abs / (AUCT)iv] x (Div / Dabs) → Different doses ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD ABSOLUTE BIOAVAILABILITY  Absolute bioavailability = (XU)abs / (XU)iv → Equivalent doses  Absolute bioavailability = [(XU)abs / (XU)iv ] x (Div / Dabs) → Different doses  Calculated value of absolute bioavailability → Valid if: Kine cs of distribu on and elimina on → Independent of route & time of administration and size of the dose administered ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD ABSOLUTE BIOAVAILABILITY ABSOLUTE BIOAVAILABILITY OF A DRUG ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD RELATIVE BIOAVAILABILITY  Rela ve bioavailability → Drug cannot be administered IV bolus dose  Comparison of total amount of intact drug from a test dosage form to the amount that reaches via standard dosage form → Same or different dose but different dosage forms  Standard → Orally administered solu on or commercial formula on of proven efficacy  AUC of both routes are compared  Relative bioavailability = (AUCT)test / (AUCT)standard → Equivalent doses  Relative bioavailability = (AUCT)test / (AUCT)standard ] x (Div / Dabs) → Different doses ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD RELATIVE BIOAVAILABILITY  Relative bioavailability = (XU)test / (XU)standard → Equivalent doses  Relative bioavailability = [(XU)test / (XU)standard ] x (Div / Dabs) → Different doses  Numerous dosage form factors → Affect the bioavailability of drug ASSESSMENT OF BIOAVAILABILITY BY: SALMAN ASHFAQ AHMAD BIOEQUIVALENCE STUDIES BY: SALMAN ASHFAQ AHMAD NAMING OF DRUGS  There are three ways of equal frequency → To name drugs  Several names of a same drug might be confusing → Health care professional should have the knowledge → To prevent the incorrect dispensing of drug, not to mix one drug with another & proper substitution  Classifica"on of drug → Depends upon prevailing circumstances → Classified according to convenience of whoever is discussing it  Classification: Body system, Therapeutic use, Mode / site of action (molecular interaction & cellular site), Molecular structure, etc. DRUG NOMENCLATURE BY: SALMAN ASHFAQ AHMAD NAMING OF DRUGS MODE OF ACTION VS THERAPEUTIC USE ADDICTIVE DRUGS CLONIDINE MIGRAINE BLOOD PRESSURE DRUG NOMENCLATURE BY: SALMAN ASHFAQ AHMAD NAMING OF DRUGS TRICYCLIC ANTIDEPRESSANTS DRUG NOMENCLATURE BY: SALMAN ASHFAQ AHMAD NAMING OF DRUGS  3 names → Chemical name, generic name & trade name  Chemical names → Describe about chemical composi"on of the molecule → Usually long names → Example: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Diazepam)  Generic names → Given by WHO (rINNs), APA, AMA & US Adopted Names Council → Official and approved name → Excep"ons in UK: Adrenaline (rINN: epinephrine) & Noradrenaline (rINN: norepinephrine) → Wri>en with lowercase alphabets  Trade name → Brand name → Owned by manufacturer → Trademark → First le>er and sometimes all letters are capitalized  Pharmacist → Can do generic subs"tu"on → Cannot do therapeu"c subs"tu"on DRUG NOMENCLATURE BY: SALMAN ASHFAQ AHMAD INTRODUCTION  Drug approval process → Vary from country to country  USA → FDA → Manufacturer files an applica"on for new molecule → NDA → Manufacturer gets permission → Innovator product → Patent period  Expiry of patent license → Generic drug product development by other manufacturers  Generic drug product approval → ANDA → No evidence of safety and efficacy → Evidence of bioequivalence  Approval of ANDA → Manufacturing of safe, effec"ve and a low-cost drug alternative  Supplemental applica"ons needed → In case of some changes  Objec"ve of ANDA → Safe and effec"ve alternate for patient BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD INTRODUCTION INTENDED USE DOSAGE FORM GENERIC DRUG ROUTE OF PERFORMANCE PRODUCT ADMINISTRATION QUALITY STRENGTH OF PARAMETERS PRODUCT BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD INTRODUCTION  Drug product performance → In vivo → Release of drug → Bioavailability  Assessment of drug product performance → Bioavailability leads to pharmacodynamics and adverse drug events  Drug product performance test → Relate quality to clinical safety and efficacy  Bioavailability studies → Drug product performance studies → Define effect of changes  Drug product performance studies → Used for new and generic drug product development  Bioavailability → One aspect of quality → Links in vivo performance of new product with original product  Bioavailability & bioequivalence → Drug product performance in vivo BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD INTRODUCTION PHARMACEUTICAL EQUIVALENT ABSENCE OF RATE & EXTENT → API BECOMES BIOEQUIVALENCE AVAILABLE AT SITE OF ACTION PHARMACEUTICAL ALTERNATIVE SAME MOLAR DOSE & SIMILAR CONDITIONS APPROPRIATELY DESIGNED STUDY BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD INTRODUCTION  Pharmaceu"cal equivalents → Same (API + dosage form + route of administra"on + strength + compendial requirements)  Compendial requirements → Strength, quality, purity, & iden"ty  Pharmaceu"cal alterna"ves → Same API with different salts / ester / complexes or different dosage form or strength  Bioequivalence studies → Evaluate therapeu"c equivalence → API absorbed at the same rate and extent as the corresponding reference product  Two pharmaceutically equivalent products are bioequivalent = Therapeutically equivalent BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD INTRODUCTION  Therapeu"cally equivalent products → Same efficacy and safety profile → Administered under same conditions mentioned in product labeling  For generic products → BE studies → Clinical equivalence between the generic and reference product  For new drugs → BE studies → Clinical equivalence between different formula"ons and between different strengths  BE studies → Integral part of development and regula"ons → Generic and new drugs BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD HISTORY  Evolu"on of bioequivalence → 3 "me periods: 1970 – 1980s, 1990s, and 2000s  1970 – 1980s → Bioequivalence was first established with an important role in drug development and regulations.  1990s → Intense discussion of the individual bioequivalence concept, development of the BCS and its subsequent applications to regulatory guidance, and development of the predictive CAT model  2000s → Development of BDDCS, evolu"on of BE standards for highly variable drugs, implementation of pAUC, creation of novel approaches for NTI drugs, and the development of several BE approaches for locally acting drugs. BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD DRUG APPLICATIONS A request to the FDA to begin clinical trials of a new drug in humans. The IND must include information about the drug's IND chemistry, manufacturing, and controls, as well as preclinical (animal) testing data. The FDA reviews the IND to ensure that the drug is safe enough to be tested in humans. BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD DRUG APPLICATIONS A request to the FDA to approve a new drug for marketing. The NDA must include all the information in the IND, as well as NDA data from clinical trials in humans. The FDA reviews the NDA to determine whether the drug is safe and effective for its intended use. BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD DRUG APPLICATIONS A request to the FDA to approve a generic drug for marketing. An ANDA can be submitted if the generic drug is bioequivalent to a brand-name drug that is already approved by the FDA. The ANDA FDA reviews the ANDA to determine whether the generic drug is safe and effective, and whether it is manufactured and labeled in accordance with FDA regulations. BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD APPLICATION OF BA / BE STUDIES  BA / BE studies → Important for drug development and regulatory approval  BA and / or BE studies → Needed for INDs, NDAs, ANDAs, and their amendments and supplements  IND & NDA period → BA studies → Assess performance of the drug product(s) used in clinical trials → Evidence of safety and efficacy  BA studies → Pharmacokine"c informa"on related to drug ADME in vivo → Es"mate frac"on of dose absorbed from an orally administered drug product → Provide informa"on on dose propor"onality and linearity in pharmacokine"cs → Effect of various intrinsic/extrinsic factors on the pharmacokinetics of the drug under examination BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD APPLICATION OF BA / BE STUDIES  Orally administered NME → Absolute and rela"ve BA can be determined  BE studies → Bridging tool to support evidence for safety and efficacy between two drug products  BE studies → For ANDA → Test drug is bioequivalent with drug listed in RLD  Documenta"on of BE → Essen"al to ensure product quality throughout the shelf life of a drug product whenever changes occur in the manufacturing or formulation, which applies to both new and generic drug products  Depending on the level of changes → BE established → Compara"ve in vivo or in vitro studies → Between products before and after change. BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD BIOEQUIVALENCE STUDIES BY: SALMAN ASHFAQ AHMAD APPROACHES  Accurate, sensitive and reproducible.  Approaches recommended include: 1. Comparative pharmacokinetic studies DECREASING ORDER 2. Comparative pharmacodynamic studies 3. Comparative clinical trials 4. Comparative in vitro tests, and 5. Any other approach deemed adequate by FDA. EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD APPROACHES  In vivo BE → Performed by number of methods → Direct or indirect → Depends upon purpose of study, analytical method available and the nature of the drug  BE studies → Blood level study method, Pharmacological endpoint study, clinical endpoint study & In vitro methods  Drug absorp*on sufficient to measure concentra*on in blood or other biological fluid or *ssues → Systemic absorp*on is relevant to the drug ac*on → Blood (or other biological fluid or *ssue) level BE study should be conducted → Generally preferred above all others → Need jus*fica*on for choosing either a pharmacological or clinical endpoint study over a blood level (or other biological fluids or tissues) study EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD APPROACHES  Measurement of the rate and extent of absorption of the drug in biological fluids cannot be achieved /unrelated to drug ac*on → Pharmacological endpoint study may be conducted  In order of preference → If drug concentra*ons in blood (or fluids or *ssues) are not measurable or no pharmacological endpoint study could be conducted → Clinical endpoint study may be conducted → Comparing the test (generic) product to the reference (pioneer) product and a placebo (or negative) control  Tradi*onally compara*ve in vitro techniques were rarely used → With development in pharmaceu*cal science and technology in vitro tests have gained more success → With the development of BCS in vitro determination of BE has gained more success EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD APPROACHES Refer to official document of 21 CFR 320.24 Adobe Acrobat Document EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD REGULATORY REQUIREMENTS  All ANDA requesting approval of a generic drug product shall include evidence demonstrating that the drug product that is the subject of the ANDA is bioequivalent to the reference listed drug. A complete study report must be submitted for the in vivo BE study upon which the applicant relies for approval.  All supplemental applications should include evidence demonstrating that the approved generic drug product that is the subject of the supplemental application is bioequivalent to the reference listed drug. This is required if the supplemental application proposes changes in: manufacturing site, manufacturing process, product formulation, dosage strength, labeling to provide for a new indication if clinical studies are required, labeling to provide for a new dosage regimen, or an additional dosage regimen for a special patient population. EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD REGULATORY REQUIREMENTS  Pharmaceutical companies holding approved ANDA should submit supplemental application containing new evidence demonstrating the in vivo BE of the drug product that is the subject of the application if notified by the drug regulatory authorities that: a) There are data demonstrating that the dosage regimen in the labeling is based on incorrect assumptions or facts regarding the pharmacokinetics of the drug product and that following this dosage regimen could potentially result in sub-therapeutic or toxic levels. b) There are data showing significant intra-batch and batch-to-batch variability, for example, ±25%, in the bioavailability (BA) of the drug product. EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD REGULATORY REQUIREMENTS Refer to official document of 21 CFR 320.21 Adobe Acrobat Document EVIDENCE TO MEASURE BIOEQUIVALENCE BY: SALMAN ASHFAQ AHMAD CONSIDERATIONS  Under certain circumstances → CFR 320.22 → Requirements for determining the in vivo BA and BE → Waived off a) For certain drug products → In vivo BA or BE → May be self-evident → Example: solu*ons b) Based on evidence obtained in vitro → One can rely on the evidences c) BCS based biowaivers  Refer to official document of 21 CFR 320.22 Adobe Acrobat Document BIOWAIVERS BY: SALMAN ASHFAQ AHMAD SELF – EVIDENT BA  The drug product is a parenteral solution administered by injection or an ophthalmic or otic solution and contains the same active and inactive ingredients in the same concentration as another approved drug product.  The drug product is administered by inhalation as a gas and contains the active ingredient in the same dosage form as another approved product.  The drug product is a solution (for application to skin, oral solution, elixir, syrup, tincture, solution for aerosolization or nebulization, nasal solution, etc.) and: BIOWAIVERS BY: SALMAN ASHFAQ AHMAD SELF – EVIDENT BA a) Contains an active drug ingredient in the same concentration and dosage form as another approved drug product and b) Contains no inactive ingredient that may significantly affect absorption of the active drug ingredient (systemic or local depending on the intended site of action). BIOWAIVERS BY: SALMAN ASHFAQ AHMAD EFFECT OF EXCIPIENTS  Xylitol, Mannitol and Sorbitol → Not well absorbed → ↑ Osmo*c pressure in intes*ne → Changes flux of water inside intestine  Osmo*c stress → Influences gastric emptying and intes*nal transit *me (upper and lower)  Osmo*c agents → ↓ Residence *me → Upper intes*nal part (minor) and lower intes*nal part (major)  Osmo*c pressure changes → Transport of drug across membrane → Affects major low permeability drugs  Sucrose and Sorbitol → Rani*dine (low permeability) & Metoprolol (High permeability) → Cmax, AUC and Tmax affected BIOWAIVERS BY: SALMAN ASHFAQ AHMAD EFFECT OF EXCIPIENTS SUCROSE VS SORBITOL BIOWAIVERS BY: SALMAN ASHFAQ AHMAD BIOWAIVER BASED ON IN VITRO DATA  Waiver of in vivo studies for different strengths of a drug product can be granted when a) The drug product is in the same dosage form but in a different strength b) This different strength is proportionally similar in its active and inactive ingredients to the strength of the product for which the same manufacturer has conducted an appropriate in vivo study c) The new strength meets an appropriate in vitro dissolution test. BIOWAIVERS BY: SALMAN ASHFAQ AHMAD PROPORTIONALLY SIMILAR  All active and inactive are in same proportion between different strengths  Active and inactive ingredients are not in the same proportion between different strengths but the ratios of inactive ingredients to total weight of the dosage form are within the limits defined by the SUPAC-IR (1995) and SUPAC-MR (1997) guidance  For high-potency drug substances→ The total weight of the dosage form remains nearly the same for all strengths (within 10 % of the total weight of the strength on which a bio-study was performed), the same inactive ingredients are used for all strengths, and the change in any strength is obtained by altering the amount of the active ingredients and one or more of the inactive ingredients. The changes in the inactive ingredients are within the limits defined by the SUPAC-IR (1995) and SUPAC-MR (1997) guidance BIOWAIVERS BY: SALMAN ASHFAQ AHMAD DISSOLUTION PROFILE COMPARISON  Comparison to assess the similarity of dissolu*on characteris*cs → Two formula*ons or different strengths of the same formulation  To decide about performance of in vivo BE studies  FDA guidance SUPAC – IR and SUPAC – MR → Recommenda*ons to firms who want post approval changes for components or compositions, site of manufacture, scale-up or scale down of manufacture, manufacturing process or equipment → Various documents depending upon complexity of the proposed change  For some minor & major changes → Dissolu*on profile comparison → Profile considered similar if overall or every dissolution sample time point show similarity BIOWAIVERS BY: SALMAN ASHFAQ AHMAD DISSOLUTION PROFILE COMPARISON  Two approaches → Model independent & model dependent  Model independent → Difference factor (f1) & Similarity factor (f2)  Difference factor → % difference between the two curves at each *me point and is measurement of rela*ve error between the two curves → 0 – 15  Similarity factor → Logarithmic reciprocal square root transforma*on of the sum of squared error and is a measurement of the similarity in the percent (%) dissolu*on between the two curves → 50 – 100 → Above 50: less than 10% difference BIOWAIVERS BY: SALMAN ASHFAQ AHMAD DISSOLUTION PROFILE COMPARISON BIOWAIVERS BY: SALMAN ASHFAQ AHMAD DISSOLUTION PROFILE COMPARISON DISSOLUTION OF REFERENCE AND TEST ER TABLET BIOWAIVERS BY: SALMAN ASHFAQ AHMAD BIOEQUIVALENCE STUDIES BY: SALMAN ASHFAQ AHMAD INTRODUCTION  Oral route → Most preferred route  Drug development of oral dosage form → How much drug becomes bioavailable and how quickly it occurs  Orally administered drug molecule → Stable to chemical degrada on, traverse the intes nal barrier & sufficient intact amount after hepatic metabolism for therapeutic response  Oral bioavailability (F) = fa x fg x fh → Each value ranges from 0 – 1  Oral absorp on of drug → Controlled by 1) dissolu on rate and solubility and 2) intes nal permeability  Determina on of dissolu on, solubility and permeability → Informa on about drug absorp on BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD INTRODUCTION  BCS → Biopharmaceu cal Classifica on System → Scien fic network → Classifica on of drug based on their solubility and permeability  BCS → Class I (High solubility – high permeability), Class II (Low Solubility – High Permeability), Class III (High Solubility – Low Permeability) & Class IV (Low Solubility – Low Permeability)  BCS combined with in vitro dissolu on → Three major characteris cs → Dissolu on rate, solubility, and permeability → Governs rate and extent of oral drug absorp on from an immediate release dosage forms BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD INTRODUCTION BCS BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD DESCRIPTION AND HISTORY OF BCS  BCS system → Originated in 1990s → Described in a seminal paper by Amidon et al.  BCS system → Solubility & intes nal permeability → Governs drug absorp on  BCS system → Main objec ve → Predict in vivo pharmacokine c behavior → Solubility & permeability  Principles of BCS → Applied to pre – clinical, clinal drug development, NDA, ANDA submissions, post approval changes for marketed products BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD REGULATORY DEVELOPMENT  Since the introduc on of BCS → Some changes in criteria defini ons within the BCS and its applica on to biowaivers → Regulatory agencies  FDA guidance in 2000 → Other global regulatory agencies published guidelines on BCS → EMA, Health Canada & WHO  Guidelines → BCS principles → Subtle differences → Acceptance criteria, required tes ng, and supportive data required for biowaiver application  2016 → Interna onal Council for Harmonisa on → Endorsed development of a BCS – Based Biowaivers (ICH M9) → Experts: global regulatory and pharmaceu cal industry BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD REGULATORY DEVELOPMENT  2019 → Final harmonized guideline → US FDA, EMA, MHLW / PMDA Japan, Health Canada, Swissmedic, ANVISA Brazil, HSA Singapore, MFDS Republic of Korea, NMPA China, and TFDA Chinese Taipei BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD APPLICATION OF BCS – BASED BIOWAIVERS  For an application to grant BCS – based biowaiver following things are needed to be checked: 1. Solubility & permeability 2. Drug product type 3. Composition 4. Dissolution similarity BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD GUIDELINES Refer to official document of ICH M9 Adobe Acrobat Document BCS (BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) BY: SALMAN ASHFAQ AHMAD DRUG METABOLISM BY: SALMAN ASHFAQ AHMAD INTRODUCTION Human body → Number of mechanisms to dispose metabolic waste → Protect itself from poten al toxic chemicals → Poten al to differen ate between substances → Physiologic role and non – physiologic role Xenobio cs → Can be poten ally toxic → Found within a living organism → Most drugs, natural, and industrial contaminants, other industrial compounds used for technical purposes, cosmetics, food additives, food components with no physiologic function, and recreational and social drugs Xenobio cs → Above men oned along with their bio-transformed products of physiological importance Xenobio cs → Endogenously produced compounds → Taken in high doses DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD INTRODUCTION NON – PHYSIOLOGICAL MECHAMISMS OF THERAPEUTIC DRUGS COMPOUNDS DISPOSAL VARIOUS MEANS 1. PREVENTING ENTERING 2. PHYSICAL REMOVAL 3. METABOLISM DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD INTRODUCTION Drug metabolism + Drug excre on → Highly integrated phenomenon Ul mate objec ve of elimina on systems → promote excre on of xenobio cs → Changed or unchanged drug molecules → Majorly via bile and urine Biotransforma on → Polar biochemical product → Enhance excre on → Increased t1/2 for non-polar drugs if not converted Drug metabolites → Tend to have pharmacological effect Drug metabolism & Excre on → DOA and clinical effect Drug metabolites → Disposi on studies & analy cal method development Drug metabolizing enzymes → Selec on of animal species DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD METABOLISM Biotransforma on reac ons → Enzyme mediated → Drug metabolites forma on Drug metabolism → Sequen al manner → Primary metabolite → Sequen al metabolite Biotransforma on reac ons → Phase I and Phase II reac ons Phase I → Redox reac ons, hydrolyses/hydra on reac ons, etc. Phase II → Glucuronic acid, glutathione, sulfate, phosphate, amino acids, acetyl, etc. Drug metabolism → Physico – chemical changes + Inactivation Occasionally metabolites → Pharmacologically ac ve or excessively reac ve DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD METABOLISM PHASES OF METABOLISM IN LIVER DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD METABOLISM EXAMPLE OF METABOLISM IN LIVER DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER Governs body energy metabolism → Maintains metabolism homeostasis Metabolism & storage → Carbohydrates, lipids, and fats Hepatocytes → Uptake of excessive glucose → Glycogen → Maintain glucose concentra on Production of glucose from fatty acids and amino acids Synthesis of proteins → Produc on of circula ng proteins Excess glucose → Glycogen + Fa:y acids Liver alternates between sources of energy Hepatocytes → Uptake of fa:y acids → Esterifica on with glycerol-3-phosphate or cholesterol → TAG or cholesterol esters, respec vely → Stored as lipid droplets or secreted into blood DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER Amino acids → Not stored in liver → Deamina on in liver → Energy produc on or glucose produc on or non – essential amino acids Ammonia → Conversion into less toxic compound 1st line of defense → Immunological organ → Drug and alcohol detoxifica on Hepa c metabolism → Controlled → Nutrients + Hormonal + Neuronal Dysfunc on in signaling → Hepa c disorders → NAFLD or Type II DM, etc. DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER Oxygen and nutrient → Hepa c vessels (red) in the corners toward a central vein in the middle (blue) Periportal hepatocytes (zone 1) are at the periphery of the lobule → Followed by mid-lobular cells → Finally pericentral hepatocytes surround the central vein (zone 3) Variable microenvironment along the periportal-pericentral axis → Graded gene expression and the spatial separation of certain metabolic processes to periportal (red) and pericentral (blue) regions Certain liver disease → zone specific Metabolic compartmentaliza on → Opposing metabolic func ons → Operate simultaneously Glutamine synthesis → Two layers of hepatocytes → Around central vein → Ureagenesis exclusively restricted to periportal area DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER Enzymes for lipid synthesis → Pericentral region → Expression decreases towards periportal region → β-oxidation enzymes predominant in periportal region NAFLD / NASH → Pericentral → Progress outwards → Same for parasite infec on Autoimmune hepa s, iron overload induced injury, etc. → Restricted to periportal area Enzymes → Not evenly distributed Some important drug metabolizing P450 enzymes → Expressed in pericentral zone 3 → E.g., CYP3A4 Drug metabolism → Highly reac ve intermediates → Ac va on and detoxifica on (double edged sword) DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER LIVER ANATOMY & HEPATIC GLOBULE DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD LIVER LIVER DISORDERS DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD DRUG METABOLISM IN LIVER Plasma (hydrolysis, mainly of esters); nerve terminals; mucosal cells; kidney, lung, and muscles; brain (glucuronidation of morphine), intestinal bacteria (several drugs + hydrolysis of glucuronide metabolites) Liver → Most important site of drug metabolism Drug metabolism → Altera on of drug molecules Metabolism → ↓ Drug therapeu c effect → ↑ Water solubility Metabolism → Produc on of ac ve compounds and inac ve compounds Produc on of ac ve compounds → Diamorphine, codeine, enalapril, levodopa, etc. → Prodrugs DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD DRUG METABOLISM IN LIVER SER of hepatocytes → Principal site of metabolism → Mul ple drug metabolizing enzymes in the microsomes Largest family of membrane bound, non – specific, mul func onal enzymes → P450 system → Name derived from certain properties Most drugs → Metabolized by more than one enzyme Enzyme → Oxygen splits → Substrate is oxidized → Oxygen is reduced → Mono – oxygenase system → Mixed function oxidases Non – cytochrome P450 enzymes → Esterases and flavin containing mono – oxygenases DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD PHASES OF METABOLISM Phases of metabolism → 2, 3 or 4 phases Phase 1 and 2 → Xenobio c metabolizing enzymes Phase 0 → Passage across plasma membrane → Influx transporters Phase 1 → Introduc on of a reac ve group Phase 2 → Transfer of polar groups → Mainly by glucuronic acid, sulfate, acetate, and amino acids Phase 3 → Transport outside → Efflux transporters DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD PHASE I REACTIONS Phase I reac ons → Expose (hydrolysis) or introduce (oxida on) → Func onal groups (-OH, -NH2, -SH, etc.) Enzymes: Oxygenases/oxidases → CYP450 isozymes, flavin containing monooxygenases, monoamine oxidases, peroxidases, xanthine oxidases, alcohol oxidases, etc. Enzymes: → Reductases → Aldo – keto reductases Enzymes: Hydroly c → Estrases, amidases Phase I reac ons → Redox reac ons → 60% Endoplasmic re culum → Oxidizing environment Mitochondria → Monoamine oxidases Cytosol → Xanthine oxidases and alcohol dehydrogenases DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD PHASE 1 REACTIONS Phase 1 → P450 enzymes → Predominant catalyst Phase 1 → Oxida on, reduc on, and hydrolysis → Oxida on is the most common mechanism Oxida on → Inser on of oxygen atom → Hydroxyla on, epoxida on, dealkyla on, deamina on, and dehalogena on reac ons → Examples: Paracetamol, codeine, ropivacaine, omeprazole, etc. Reduc on → Under anaerobic condi ons → Example: Reduc on of prednisone (prodrug) to prednisolone, warfarin inactivation (ketone group to hydroxyl group), halothane inactivation (oxidation and reduction) Hydrolysis → Not catalyzed by P450 system → Esterases and amidases → Amide local anesthe cs → Example: Prilocaine DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD PHASE 1 REACTIONS REACTION EXAMPLES Hydroxylation Aromatic hydrocarbons (R-Ar) Sulfo – oxidation Disulfides (R-S-R) Dehydrogenation Alcohols (R-OH) Reduction Nitro compounds (R-NO2) Hydrolysis Esters (R-COO-R’) DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD PHASE 2 REACTIONS Phase 2 → Conjuga on → Hydrophilic moiety + drug molecule → ↑ Water solubility → Excre on in bile and urine → Inac vate drug and ac ve metabolites Phase 2 → Transferases → Glucuronida on, sulfa on, acetyla on, and methyla on Glucuronida on → Important pathway for anesthe c drugs → Propofol metabolism Glucuronida on → UDP – glucuronosyltransferase (UGT) → Transfer of sugar α – glucuronic acid (from uridine – α – glucuronide) to the drug molecule Morphine → Glucuronida on → 3 – O – glucuronide & 6 – O – glucuronide metabolites Paracetamol → Glucuronida on + sulfa on + N – hydroxylation (forms N-acetyl-p- aminobenzoquinoneimine by CYP2E1) DRUG METABOLISM AND EXCRETION BY: SALMAN ASHFAQ AHMAD