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Bioavailability & Bioequivalence Bioavailability & Bioequivalence: Pharmacokinetic Principles Sandip K. Roy, Ph.D. Exploratory Clinical Development – PK Novartis Pharmaceutical Corporation Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Pharmacokinetics “what the body does to the drug” Absorption Distribution Metabolism Elimination disposition Bioavailability & Bioequivalence, June 2, 2004 Pharmacodynamics “what the drug does to the body” wanted effects - efficacy unwanted effects - toxicity Bioavailability & Bioequivalence Pharmacokinetics Dose regimen Bioavailability & Bioequivalence, June 2, 2004 Exposure Pharmacodynamics Site of action Response Bioavailability & Bioequivalence Pharmacokinetics is either directly or indirectly associated with just about every part of pharmaceutical business: Research and the selection of a promising molecule Dosage formulation development Dose regimen Toxicology and safety assessment Dosing recommendations for age groups & subpopulations (renal/hepatic/race/DDI) Effect of meals and dosing Marketing claims and promotion Generic substitution Manufacturing changes Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence General Outline Basic Pharmacokinetic Concepts Bioavailability Definition How absorption affects bioavailability? Food Effect How drug metabolism affects bioavailability? How transporters affect bioavailability? Bioequivalence Definition Bio-IND Waivers of In Vivo Study Requirements Biopharmaceutics Classification System (BCS) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Basic Concepts Easy to understand using intravenous route Drug Product No absorption phase Simple to follow Concepts clear with less assumptions Drug in Blood Excretion Distribution to Tissue and Receptor sites Metabolism Need some math background algebra, log scale, Simple linear Equations etc complex math (differential equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence IV administration, contd., Following dose administration, we need to follow its drug’s disposition to understand its PK characteristics. This is achieved by analyzing the changes of the drug and/or its metabolite(s) in blood, plasma, urine etc. A simple approach is to generate Drug Concentration-Time profile Dosing Sampling at Pre-determined Time intervals Bioavailability & Bioequivalence, June 2, 2004 Blood withdrawal Bio-analytics Conc. vs time profiles Bioavailability & Bioequivalence Concentration versus Time Profiles Broadly the concentration – time profiles can be viewed as two different ways One-Compartment Model Dose 1 Assumes body as one compartment k Two-Compartment Model Central compartment (drug entry and elimination) Dose 2 1 Tissue compartment (drug distributes) k Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence The distribution phase for aminoglycosides is only 15-30 minutes, therefore, we can use a one-compartment model with a high degree of accuracy Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Vancomycin is the classic example, it's distribution phase is 1 to 2 hours. Therefore, the serum level time curve of vancomycin may be more accurately represented by a 2-compartment model. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Volume of Distribution The concentration in plasma is achieved after distribution is complete is a function of dose and extent of distribution of drug into tissues This extent of distribution can be determined by relating the concentration obtained with a known amount of drug in the body Concentration is related to the amount by a constant, VOLUME (V) Amount (mg) = C (mg/L) * V (L) OR V = Amount / C V is known as Apparent Volume of distribution. Plasma volume ~ 3 L; Extracellular water ~16 L; Total body water ~ 42 L Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Volume of Distribution Case -1 At Time zero, the drug amount in the body is the dose (500 mg) Calculated drug concentration at Time zero is 50 mg/L Then, the V = 10 L Case -2 Dose = 500 mg Calculated Concentration at time Zero is 5 mg/L Then, V = 100 L Examples: Ibuprofen: V is 10 L; Diovan 17 L; Digoxin: ~500L; Chloroquin: 15000 L Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Concentration (Units/ml) Area Under the Concentration – Time Curve (AUC) A quantitative measure for exposure from dosing time to time ‘t’ 10 An important parameter in PK AUC(t) and AUC(inf) 1 Determined by trapezoidal method 0.1 AUC(inf) = AUC(t) + Ct/k Units: Conc*t (mg/L * h) 0.01 0 5 10 15 Time (hr) 20 Proportional to Dose (linear PK) Accuracy of the estimate depends on frequency of sampling Area Under the Curve (AUC) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How is drug excreted/eliminated? The Kidneys This is the main excretory organ for drugs The Nephron: Glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting tubule Drug enters the lumen of the nephron by filtration and secretion Filtration occurs in the glomerulus; secretion is primarily restricted to the proximal tubules Reabsorption occurs all along the nephron; Active reabsorption usually occurs in the proximal tubule Appearance of drug in the urine is the net result of filtration, secretion, and reabsorption Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Drug metabolism/biotransformation This mainly occurs in the liver, via liver enzymes. But it can also occur in the blood plasma or at various other places (stomach, intestines, lungs, skin, or kidneys) directly by various enzymes at those locations In any case, these metabolites are then excreted/eliminated (more easily than would the parent molecule have been) metabolites are often smaller in size, ionized Some drugs are excreted/eliminated in unmetabolized form, as the original drug molecule (e.g. Lithium) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Other Routes of Excretion/Elimination In bile (which then empties into gut, excreted in feces) [can excrete from 5 to 95% of drug dose, esp. antibiotics] In sweat, saliva, tears, exhaled breath, milk, hair, nails [as heart rate increases --- pulmonary circulation --- which then increases amounts of breath exhaled --- more drug eliminated] Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Concept of “Half Life” ½ life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium There are really two kinds of ½ life… “distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs “elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Concept of “Half Life” 5 Conc. [mg/L] 4 3 2 1 0 0 4 8 12 Time [hours] Bioavailability & Bioequivalence, June 2, 2004 16 20 24 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Elimination ke lny ln y 2 T1/2 lny lny ln2 ke T1/2 ln2 ke T1/2 0.693 ke T1/2 Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence “Rule of Five” 5x the elimination ½ life = time at which the drug is “completely” (97%) eliminated from the body 1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875% Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Clearance “Of the concepts in pharmacokinetics, clearance has the greatest potential for clinical applications. It is also the most useful parameter for the evaluation of an elimination mechanism.” Rowland & Tozer Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Clearance Quantifies Elimination Is the volume of body fluid cleared per time unit (L/h, mL/min) Is Usually Constant Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Clearance Proportionality factor relating rate of drug elimination to plasma drug concentration Rate of eliminatio n CL C Rate of eliminatio n CL C (dx/dt) CL C Integrate DoseIV CL AUC Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Clearance Rate of elimination is proportional to the amount (A) of drug present Rate of eliminatio n k * A Rate of eliminatio n k * V * C Rate of eliminatio n k * V C Clearance k * V 0.693 * V Clearance Half - life Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Dependence of Half-life on Clearance and Volume Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Why is Clearance Important? Clearance is the one parameter that determines the maintenance dose rate required to achieve a desired plasma conc. Dosing rate = clearance X desired plasma conc. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence For a given dose rate, the blood drug concentration is inversely proportional to clearance Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Concentration Multiple Dose Administration Time (hr) Minimum and maximum conc should be within therapeutic window – depends on dose, frequency and t1/2 Depending on dosing frequency and t1/2, accumulation occurs Degree of accumulation is important for safety assessment purposes Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability and Its Assessment Bioavailability: The rate and extent to which the parent compound reaches the general circulation. Absolute Bioavailability requires I.V. administration Ratio of the oral:intravenous AUC values normalized for dose Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral) Relative Bioavailability no I.V. reference comparison AUC values (ratio) of different dosage forms / formulations Frel = (AUC a / AUC b) * (Dose b /Dose a) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence 5 5 4 4 Conc. [mg/L] Conc. [mg/L] Solution Capsule 3 2 1 3 2 1 0 0 0 4 8 12 16 20 24 Time [hours] 20 mg administered as an i.v. bolus (Diovan) Bioavailability & Bioequivalence, June 2, 2004 0 4 8 12 16 20 24 Time [hours] 80 mg given as a solution and a capsule (Diovan) Bioavailability & Bioequivalence F=0.6 Solution Capsule 80 F=0.4* 16 14 60 F=0.2* 12 10 40 AUC % of f remaining to be absorbed 100 20 8 6 4 2 0 0 2 4 6 8 Time [hours] 10 0 I.v. (20 mg) P.O. (80 mg) P.O. (80 mg) Capsule Solution *dose - adjusted Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Anatomical Considerations Gut Lumen Portal Vein Liver Gut Wall Systemic Circulation Metabolism Metabolism Release + Dissolution Permeation Elimination Absorption Bioavailability Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How Absorption affects Bioavailability? Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Absorption Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement. Drugs are frequently administered extravascularly oral, sublingual intramuscular, topical, patches, inhalation Absorption is a prerequisite for a drug to exert it’s pharmacologic effect (other than local effect) Several possible sites contribute to the loss Bioavailability & Bioequivalence, June 2, 2004 Absorption Drug Product Drug in Blood Excretion Distribution to Tissue and Receptor sites Metabolism Bioavailability & Bioequivalence Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose Rate of drug accumulation at any time: dDBODY/dt= dDABS/dt - dDELIM/dt Absorption Phase: dDABS/dt > dDELIM/dt At time of peak drug conc.: dDABS/dt = dDELIM/dt Post-absorption Phase: dDABS/dt < dDELIM/dt Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Physiological Considerations Surface area small intestine = 200 m2 stomach = 1 m2 Permeability intestinal membrane>stomach Blood flow (for perfusion rate-limited absorption) small intestine = 1000 mL/min through intestinal capillaries stomach = 150 mL/min Gastric emptying and pH GI transit Rate of gastric emptying is a controlling step for rapid absorption Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Physico-Chemical Factors Partition Theory Ionization, pH-pKa Relationship Polymorphism Particle Size Complexation Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Absorption Involves Movement Through Membranes Efflux Influx Passive diffusion Active transport Rate of diffusion = P *(C1-C2) where P is permeability coefficient Lipophilicity (partition between oil and water) Hydrophilicity (paracellular movement depends on size, shape and charge) Paracellular Bioavailability & Bioequivalence, June 2, 2004 Transcellular Bioavailability & Bioequivalence Passive Diffusion of Molecules Passive diffusion 1 Bioavailability & Bioequivalence, June 2, 2004 2 Bioavailability & Bioequivalence Comparison of the Rates of Drug Absorption A = Passive diffusion B = Active transport/ carrier mediated system Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Percent Dose Absorbed vs. Human Permeability Very low concentration No saturation effects Already in solution No dissolution effects Percent Absorbed (%) Propanolol Piroxicam Naproxen Ketoprofen L-leucine 100 Phenylalanine 75 Benserazide L-Dopa Metoprolol 50 D-glucose Antipyrine Terbutaline Furosemide 25 Atenolol Enalaprilate 0 0 2 4 6 8 Human Permeability (104, cm/sec) Bioavailability & Bioequivalence, June 2, 2004 10 Bioavailability & Bioequivalence Effect of Blood Flow on Absorption blood blood membrane tissue If the membrane offers no resistance movement is dependent on blood flow Bioavailability & Bioequivalence, June 2, 2004 tissue High resistance to drug movement movement insensitive to changes in perfusion Bioavailability & Bioequivalence pH – pKa Ionization Weak acid pka - pH = log [(un-ionized)/(ionized)] Weak base pka - pH = log [(ionized)/(un-ionized)] Examples: Aspirin, pka : 3.5, at pH = 1, mostly unionized Phenytoin, pka : 8.3, unionized in stomach Diazepam, pka : 3.3, mostly ionized in stomach Procainamide, pka : 9.5, mostly ionized in stomach Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Gastrointestinal pH and Transit Time in the Fasted State Region pH Residence time Stomach 1.5-2 0-3 hours Duodenum 4.9-6.4 3-4 hours Jejunum 4.4-6.4 3-4 hours Illeum 6.5-7.4 3-4 hours Colon 7.4 Up to 18 hours Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Assessment of Drug Absorption Absorption is measured as Rate of Absorption, ka. and Extent (AUC) For Rate - Need to fit the data and it is model dependent A surrogate is Cmax/AUC Example: Lescol capsule (IR) : 0.37 hr-1 Lescol XL: 0.19 hr-1 Usually (also) measured as Cmax and Tmax Cmax Tmax Lescol IR 438 0.5-1 h Lescol XL 101 1.5-4 h Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve 0.5/hr 0.2/hr Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Interactions in Oral Drug Absorption Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Pharmacokinetic Assessment of Absorption Interactions Clinically significant interactions are typically assessed in terms of: Rate of Absorption: peak plasma drug concentrations (Cmax) time to Cmax (tmax) Extent of Absorption: area under the concentration-time curve (AUC) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Effect of Absorption Interactions on Drug Plasma Concentration Profiles Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Effect of Food A required study – helps for dosage administration in Clinical Trials Measure PK parameters (rate and extent) under Fasted and Fed conditions. Single dose cross over study is recommended. FDA Guidance gives type of food High Fat Meal (breakfast) – total of 800 – 1000 calories of which 150 cal from Proteins, 250 cal from carbohydrates and 500 – 600 cal from fat. Bioavailability & Bioequivalence, June 2, 2004 Test Meal 2 eggs fried in butter 2 strips of bacon 2 slices of toast with butter 4 oz of hash-brown potatoes 8 oz of whole milk Bioavailability & Bioequivalence Effect of Food on Rivastigmine Absorption MEAN RIVASTIGMINE PLASMA LEVELS (ng/mL) 7 6 5 4 3 mg (fasted) N=20 3 mg (fed) N=19 3 2 1 0 -1 0 2 4 6 TIME (hrs) Bioavailability & Bioequivalence, June 2, 2004 8 10 12 14 Bioavailability & Bioequivalence Concentration (ng/mL) Effect of Food on Lescol XL 150 Fasted Fed 120 90 60 30 0 0 6 12 Tim e (h) Bioavailability & Bioequivalence, June 2, 2004 18 24 Bioavailability & Bioequivalence Food Effect Statistical analysis is done for significant difference PK data interpretations are made in conjunction with clinical experience / clinical significance Attention should be paid for the absorption rate and total exposure with and without food. Cases when time to peak concentration is important (analgesic) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Summary Absorption is influenced by physico-chemical properties of the drug, formulation factors, and the anatomy and physiologic functions at the site of drug absorption. Drug absorption process may be zero order (active transport) or first order (passive diffusion) process. Highly soluble and highly permeable drugs are rapidly absorbed. Estimation of drug absorption and bioavailability is critical in early stage drug development. BE studies are required for changing formulations etc. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How Drug Metabolism affects Bioavailability? Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Drug metabolism/Biotransformation Liver is the main site of drug metabolism Extrahepatic: Gut wall Intestinal Flora Lung Kidney Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Reactions Catalyzed by Drug metabolizing enzymes Oxidative reactions (Phase I) dealkylation hydroxylation oxidation Deamination Conjugation reactions (Phase II) glucuronidation glutathione conjugation sulfation acetylation Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How Drug Metabolism Affects Bioavailability? Genetic (polymorphism in expression of enzymes in a population) CYP2D6, CYP2C19, NAT2, etc. Environmental (food, smoking) Grapefruit juice (↑AUC and ↑Cmax) Drug-Drug interaction Inhibition (↑AUC and ↑Cmax) Induction (↓AUC and ↓Cmax) Age Disease (hepatic impairment) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence St. John’s Wort Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How Transporters affect Bioavailability? Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Energy Dependent Efflux Transporters – ATP-binding cassette (ABC) proteins Work against concentration gradient MDR1 (P-glycoprotein) MDR3 MRP2 (multidrug resistance associated protein, cMOAT) BSEP (bile salt export pump) BCRP (breast cancer resistance protein) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence How Transporters Affect Bioavailability? P-glycoproteins expressed in Intestine limit absorption low BA liver increase bile secretion low BA kidney increase secretion in urine shorten t1/2 Brain protect CNS from penetration of toxic drugs or decrease efficacy of CNS drugs Some lymphocytes drug resistance for HIV drugs Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioequivalence: Background Using bioequivalence as the basis for approving generic copies of drug products was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. Brandname drugs are subject to the same bioequivalence tests as generics upon reformulation. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioequivalence Definition - CFR 320.1 It is the absence of significance difference in the rate and extent to which active ingredient or active moiety in pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study Note: BE has a specific definition and regulatory requirements. BE is not the same as the BA Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence When do we do BE studies ? Clinical Service Form to Final Market Form Change of formulations (capsules to tablet) Generic Formulations Change of Process or manufacturing site (some times) Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioequivalence Test Batch Size: 100,000 units or 10% of Production size whichever is greater Retention Samples: Need to retain samples at the study site for further analysis (5 times). Most of the BE studies are audited by HAs especially for NMEs Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bio-IND “The primary purpose of a Bio-IND is to ensure that the proposed product is safe for use in human test subjects and does not expose them to undue risk and untoward effects from the drug product” MAPP 5240.4, CDER, FDA Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Contents of a Bio-IND OGD's new policy is that in addition to a protocol, sufficient information must be submitted in a Bio-IND to enable an OGD bioequivalence reviewer and a review chemist to determine the safety of the formulation to be used in the proposed bioequivalence study. Only one protocol per Bio-IND submission Components and composition of the generic drug to be used in the bioequivalence study including the amounts of the active ingredient(s) and excipients Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Contents of a Bio-IND Tests and specifications for identity, strength, quality, and purity for active ingredient(s) and Certificates of Analysis of excipients; Method and place of manufacturing including the type of equipment, batch size and batch records Tests and specifications for the finished dosage form (Certificates of Analysis); Stability testing data on the drug product stored for three months at 400C and 75% relative humidity including information on the container/closure system(s) used in the stability tests unless other conditions are appropriate for that product. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Filing and Review Procedures A Bio-IND received in the Document Room will be identified by its cover letter and standard form 1571. The Bio-IND will then be routed to the central CSO staff which will review the submission for acceptability and send out an acknowledgment letter under the signature of the Director, OGD. If the Bio-IND does not contain the information described in POLICY AND PROCEDURE, Contents of a Bio-IND, a refuse to file letter will be issued and the firm will have to correct the deficiencies and resubmit the Bio-IND. If a Bio-IND is determined to be acceptable for filing, the thirty-day safety review clock will start on the date of receipt of the submission. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Filing and Review Procedures The central CSO staff will send one copy to the appropriate OGD Chemistry Branch based upon the pharmacological class of the drug to be studied another copy to the Division of Bioequivalence or the appropriate NDE reviewing Division, and a third copy to the Document Room to be filed Normally, the Division of Bioequivalence will review the protocol for the bioequivalence study to ensure that the safety of subjects entering the study will not be compromised. If a protocol raises a medical issue such as proposing to administer a dose not addressed in the labeling, a medical officer in NDE will be consulted. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Filing and Review Procedures Information on chemistry, manufacturing, and controls will be reviewed by one of the two Divisions of Chemistry to ensure the safety of the study volunteers. A more detailed review will be conducted of the chemistry, manufacturing and controls information that is later submitted in the ANDA. A CSO will be assigned the responsibility to track the BioIND through the review process, including checking periodically with the reviewing divisions on the status of the reviews. If the CSO determines that the safety reviews will not be completed within thirty days, he or she will inform the firm and may request that the start of the study be deferred until the reviews are completed. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Filing and Review Procedures Upon completion of the safety reviews, OGD will notify the firm that the study may begin or that the study has been placed under a clinical hold pursuant to 21 CFR § 312.42. The chemistry and bioequivalence reviews of the Bio-IND, when completed, will be sent back to the central CSO staff. That staff will prepare the appropriate action letter for the signature of the Director, OGD. A bioequivalence study completed under a Bio-IND should be submitted in the ANDA which it supports. No bioequivalence studies should be submitted as amendments to Bio-IND's. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Waivers of In Vivo Study Requirements Criteria (21 CFR 320.22) In vivo bioequivalence is self evident Parenteral Solutions Inhalation anesthetics Topical skin solutions Oral solutions Different proportional strength of product with demonstrated BE Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence The Biopharmaceutics Classification System (BCS) Guidance Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Purpose of the BCS Guidance: Expands the regulatory application of the BCS and recommends methods for classifying drugs. Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Classifications According to the BCS, drug substances are classified as follows: Class I - High Permeability, High Solubility Class II - High Permeability, Low Solubility Class III - Low Permeability, High Solubility Class IV - Low Permeability, Low Solubility Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence CLASS BOUNDARIES A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5. A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence SOLUBILITY DETERMINATION pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5. Shake-flask or titration method. Analysis by a validated stability-indicating assay. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence PERMEABILITY DETERMINATION Extent of absorption in humans: Mass-balance pharmacokinetic studies. Absolute bioavailability studies. Intestinal permeability methods: In vivo intestinal perfusions studies in humans. In vivo or in situ intestinal perfusion studies in animals. In vitro permeation experiments with excised human or animal intestinal tissue. In vitro permeation experiments across epithelial cell monolayers. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the following dissolution media: 0.1N HCl or Simulated Gastric Fluid USP without enzymes a pH 4.5 buffer a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes For capsules and tablets with gelatin coating Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Dissolution Profile Similarity A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver request. Samples should be collected at a sufficient number of intervals to characterize the dissolution profile of the drug product (e.g., 10, 15, 20, and 30 minutes). When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. f2 = 50 * log {[1+(1/n)*t=1n (Rt - Tt)2]-0.5 * 100} Two dissolution profiles are considered similar when the f2 value is 50. Note: When both test and reference products dissolve 85% or more of the label amount of the drug in 15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Conditions for BCS Bio-waivers Firms can request waivers of in vivo testing for Class 1 drug substances Drug products must meet these criteria: Immediate-release solid oral dosage forms Highly soluble, highly permeable drug substance Rapid in vitro dissolution Note: Waivers not applicable for narrow therapeutic range therapeutic range (Digoxin, Lithium, phenytoin, warfarin) drugs Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Class I: Dissolution USP Apparatus I (100 rpm) or II (50 rpm) Three media 0.1 N HCl or SGF USP without enzymes 0.1 N HCl or SGF USP without enzymes pH 4.5 buffer pH 4.5 buffer pH 6.8 buffer or SIF USP without enzymes NLT 85% dissolves within 30 minutes Similarity factor (f2) for test (T) v. reference (R) profile comparisons should > 50 Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Class I: Solubility Highest dose strength should be soluble in < 250 mL Volume is derived from BE protocols Doses are generally administered with about 8 oz water Determinations should use a range of pH values over 1 to 7.5, a temperature of 370C, and equilibrium conditions Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Class I: Permeability In vivo methods include determination absolute BA (> 90%) or mass balance In vitro intestinal permeability can be determined by several methods One method is use of cultured epithelial cell monolayers A single method may be sufficient Stability in GI tract should be determined Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Class I: Permeability For prodrugs, permeability depends on mechanism, anatomical site of conversion When conversion occurs prior to intestinal permeation, measure permeability of active moiety When conversion occurs after intestinal permeation, measure permeability of prodrug Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence BCS Class I: Excipients Quantity of excipients should be consistent with intended function Large quantities of some surfactants may be problematic polysorbate 80 Mannitol sorbitol Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Recent Federal Register Notice FDA is proposing to amend its regulations to require an ANDA applicant to submit data from all bioequivalence studies (BE studies) In the past, ANDA applicants have not typically submitted additional BE studies conducted on the same drug product formulation, such as studies that do not show that the product meets these criteria. FDA is proposing this change because the data from additional BE studies may be important in determination of whether the proposed formulation is bioequivalent to the RLD and are relevant to evaluation of ANDAs in general. In addition, such data will increase understanding of how changes in components, composition, and methods of manufacture may affect formulation performance. Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence Bioavailability & Bioequivalence, June 2, 2004 Bioavailability & Bioequivalence References Clinical Pharmacokinetics: Concepts and Application - 3rd Edition By Malcolm Rowland & Thomas N. Tozer http://www.fda.gov/cder/guidance/index.htm http://www.access.gpo.gov/nara/cfr/waisidx_03/21 cfr320_03.html Bioavailability & Bioequivalence, June 2, 2004