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

 Pharmacodynamics
 “what the drug does to the body”  wanted effects - efficacy  unwanted effects - toxicity

disposition

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Pharmacokinetics

Pharmacodynamics

Dose regimen

Exposure

Site of action

Response

Bioavailability & Bioequivalence, June 2, 2004

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 .

June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence. 2004 .

June 2. Bioavailability & Bioequivalence. Population PK. log scale. Simple linear Equations etc  complex math (differential equations. PK-PD etc. statistical concepts etc) for Modeling. 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 Distribution to Tissue and Receptor sites Excretion Metabolism  Need some math background  algebra.

 Following dose administration. This is achieved by analyzing the changes of the drug and/or its metabolite(s) in blood. 2004 . urine etc.. vs time profiles Bioavailability & Bioequivalence. June 2. contd.Bioavailability & Bioequivalence IV administration. we need to follow its drug’s disposition to understand its PK characteristics. A simple approach is to generate Drug Concentration-Time profile Blood withdrawal   Dosing Sampling at Pre-determined Time intervals Bio-analytics Conc. plasma.

2004 . June 2.Bioavailability & Bioequivalence Concentration versus Time Profiles oadly the concentration – time profiles can be viewed as two different ways One-Compartment Model Assumes body as one compartment Dose 1 k Two-Compartment Model Central compartment (drug entry and elimination) Tissue compartment (drug distributes) Dos e 1 2 k Bioavailability & Bioequivalence.

2004 . Bioavailability & Bioequivalence. ♦ This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues.Bioavailability & Bioequivalence ♦ The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment. June 2.

we can use a onecompartment model with a high degree of accuracy Bioavailability & Bioequivalence.Bioavailability & Bioequivalence The distribution phase for aminoglycosides is only 15-30 minutes. 2004 . June 2. therefore.

are best described with a two compartment model Bioavailability & Bioequivalence. 2004 . June 2.Bioavailability & Bioequivalence ♦ Drugs which exhibit a slow equilibration with peripheral tissues.

Therefore.Bioavailability & Bioequivalence Vancomycin is the classic example. June 2. Bioavailability & Bioequivalence. it's distribution phase is 1 to 2 hours. 2004 . the serum level time curve of vancomycin may be more accurately represented by a 2compartment model.

Extracellular water ~16 L. VOLUME (V) Amount (mg) = C (mg/L) * V (L) OR V = Amount / C V is known as Apparent Volume of distribution.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. 2004 . Total body water ~ 42 L Bioavailability & Bioequivalence. June 2. Plasma volume ~ 3 L.

Diovan 17 L. Digoxin: ~500L. the V = 10 L Case -2  Dose = 500 mg  Calculated Concentration at time Zero is 5 mg/L  Then.Bioavailability & Bioequivalence Volume of Distribution Case -1  At Time zero. V = 100 L Examples: Ibuprofen: V is 10 L. Chloroquin: 15000 L Bioavailability & Bioequivalence. June 2. 2004 . the drug amount in the body is the dose (500 mg)  Calculated drug concentration at Time zero is 50 mg/L  Then.

1 Units: Conc*t (mg/L * h)  Proportional to Dose (linear PK) 0 5 10 15 20  Accuracy of the estimate depends on 0. 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  AUC(inf) = AUC(t) + Ct/k 0. June 2.01 frequency of sampling Time (hr) Area Under the Curve (AUC) Bioavailability & Bioequivalence.

and collecting tubule  Drug enters the lumen of the nephron by filtration and secretion  Filtration occurs in the glomerulus. proximal tubule. and reabsorption Bioavailability & Bioequivalence. Active reabsorption usually occurs in the proximal tubule  Appearance of drug in the urine is the net result of filtration. distal tubule. secretion is primarily restricted to the proximal tubules  Reabsorption occurs all along the nephron. secretion.Bioavailability & Bioequivalence How is drug excreted/eliminated?  The Kidneys This is the main excretory organ for drugs The Nephron: Glomerulus. loop of Henle. 2004 . June 2.

intestines. or kidneys) directly by various enzymes at those locations  In any case. June 2. skin. ionized  Some drugs are excreted/eliminated in unmetabolized form.g. via liver enzymes. lungs.Bioavailability & Bioequivalence Drug metabolism/biotransformation  This mainly occurs in the liver. as the original drug molecule (e. 2004 . Lithium) Bioavailability & Bioequivalence. these metabolites are then excreted/eliminated (more easily than would the parent molecule have been) metabolites are often smaller in size.  But it can also occur in the blood plasma or at various other places (stomach.

2004 .more drug eliminated] Bioavailability & Bioequivalence. antibiotics]  In sweat. exhaled breath. esp. excreted in feces) [can excrete from 5 to 95% of drug dose. hair.pulmonary circulation --which then increases amounts of breath exhaled --. saliva. tears. June 2. nails [as heart rate increases --.Bioavailability & Bioequivalence Other Routes of Excretion/Elimination  In bile (which then empties into gut. milk.

to decide when it is safe to put patients on a new drug Bioavailability & Bioequivalence. June 2.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. 2004 .

2004 .Bioavailability & Bioequivalence Concept of “Half Life” 5 4 Conc. [mg/L] 3 2 1 0 0 4 8 12 16 20 24 T e [hours] im Bioavailability & Bioequivalence. June 2.

2004 .Bioavailability & Bioequivalence Bioavailability & Bioequivalence. June 2.

2004 .693 ke = T1/2 Bioavailability & Bioequivalence.Bioavailability & Bioequivalence Elimination ke (lny − ln ) = y 2 T1/2 lny − lny + ln2 ke = T1/2 ln2 ke = T1/2 0. June 2.

2004 .5% 4x ½ life .75% 5x ½ life .96.87.50% of the original drug removed 2x ½ life .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 .93.75% 3x ½ life .875% Bioavailability & Bioequivalence. June 2.

It is also the most useful parameter for the evaluation of an elimination mechanism. 2004 . clearance has the greatest potential for clinical applications.” Rowland & Tozer Bioavailability & Bioequivalence. June 2.Bioavailability & Bioequivalence Clearance “Of the concepts in pharmacokinetics.

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 . June 2.Bioavailability & Bioequivalence Clearance Proportionality factor relating rate of drug elimination to plasma drug concentration Rateof eliminatio = CL × C n Rateof eliminatio n CL = C (dx/dt) CL = C Integrate DoseIV CL = AUC Bioavailability & Bioequivalence.

June 2.life Bioavailability & Bioequivalence. 2004 .Bioavailability & Bioequivalence Clearance Rate of elimination is proportional to the amount (A) of drug present Rateof eliminatio = k * A n Rateof eliminatio = k * V * C n Rateof eliminatio n =k*V C Clearance= k * V 0.693* V Clearance= Half .

Bioavailability & Bioequivalence Dependence of Half-life on Clearance and Volume Bioavailability & Bioequivalence. 2004 . June 2.

June 2. 2004 . Bioavailability & Bioequivalence.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.

the blood drug concentration is inversely proportional to clearance Bioavailability & Bioequivalence. June 2.Bioavailability & Bioequivalence For a given dose rate. 2004 .

June 2. 2004 . accumulation occurs Degree of accumulation is important for safety assessment purposes Bioavailability & Bioequivalence.Bioavailability & Bioequivalence Multiple Dose Administration no t art nec no C i 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 .

reference comparison AUC values (ratio) of different dosage forms / formulations Frel = (AUC a / AUC b) * (Dose b /Dose a) Bioavailability & Bioequivalence. June 2. administration Ratio of the oral:intravenous AUC values normalized for dose Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral) Relative Bioavailability    no I.Bioavailability & Bioequivalence Bioavailability and Its Assessment Bioavailability: The rate and extent to which the parent compound reaches the general circulation. 2004 . Absolute Bioavailability    requires I.V.V.

v.Bioavailability & Bioequivalence 5 5 4 4 Solution Capsule 3 3 2 Conc. 2004 80 mg given as a solution and a capsule (Diovan) . June 2. bolus (Diovan) Bioavailability & Bioequivalence. [mg/L] 0 4 8 12 16 20 24 Conc. [mg/L] 2 1 1 0 0 0 4 8 12 16 20 24 Time [hours] Time [hours] 20 mg administered as an i.

O.4* F=0.O. (80 mg) Capsule P.v. (20 mg) P.adjusted Bioavailability & Bioequivalence.6 F=0. 2004 . (80 mg) Solution *dose . June 2.Bioavailability & Bioequivalence F=0.2* 16 14 12 10 8 C UA 6 4 2 0 I.

2004 . June 2.Bioavailability & Bioequivalence Anatomical Considerations Gut Lumen Portal Vein Liver Gut Wall Systemic Circulation Metabolism Metabolism Release + Dissolution Permeation Absorption Bioavailability Elimination Bioavailability & Bioequivalence.

2004 .Bioavailability & Bioequivalence How Absorption affects Bioavailability? Bioavailability & Bioequivalence. June 2.

Bioavailability & Bioequivalence Absorption  Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement. patches. 2004 .  topical. June 2. Drugs are frequently administered extravascularly  oral. sublingual  intramuscular. 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 Absorption Drug Product  Drug in Blood Distribution to Tissue and Receptor sites  Excretion Metabolism  Bioavailability & Bioequivalence.

2004 . June 2.: dDABS /dt = dDELIM /dt Post-absorption Phase: Bioavailability & Bioequivalence.Bioavailability & Bioequivalence Plasma Concentration-Time Profile for a Drug Following a Single Oral Dose Rate of drug accumulation at any time: dDBO Y /dt= dDABS /dt D dDELIM /dt Absorption Phase: dDABS /dt > dDELIM /dt At time of peak drug conc.

Bioavailability & Bioequivalence Physiological Considerations  Surface area    small intestine = 200 m2 stomach = 1 m2 intestinal membrane>stomach Permeability  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. 2004 . June 2.

Bioavailability & Bioequivalence Physico-Chemical Factors  Partition Theory  Ionization. June 2. pH-pKa Relationship  Polymorphism  Particle Size  Complexation Bioavailability & Bioequivalence. 2004 .

2004 Transcellular . shape and charge)   Paracellular Bioavailability & Bioequivalence. June 2.Bioavailability & Bioequivalence Absorption Involves Movement Through Membranes Influx Efflux    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.

Bioavailability & Bioequivalence

Passive Diffusion of Molecules

Passive diffusion
1 2

Bioavailability & Bioequivalence, June 2, 2004

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
Percent Absorbed (%)
Propanolol Piroxicam L-leucine Naproxen Ketoprofen

 Very low concentration  No saturation effects  Already in solution  No dissolution effects

Phenylalanine Benserazide L-Dopa Metoprolol Terbutaline Furosemide Atenolol Enalaprilate D-glucose

Antipyrine

Human Permeability (104, cm/sec)
Bioavailability & Bioequivalence, June 2, 2004

2004  High resistance to drug movement  movement insensitive to changes in perfusion . June 2.Bioavailability & Bioequivalence Effect of Blood Flow on Absorption blood blood membrane tissue tissue  If the membrane offers no resistance  movement is dependent on blood flow Bioavailability & Bioequivalence.

mostly unionized Phenytoin. unionized in stomach Diazepam.5. June 2. pka : 9. 2004 . pka : 8. mostly ionized in stomach Procainamide. mostly ionized in stomach Bioavailability & Bioequivalence.pH = log [(ionized)/(un-ionized)] Examples: Aspirin.3. pka : 3.3.Bioavailability & Bioequivalence pH – pKa Ionization Weak acid pka .pH = log [(un-ionized)/(ionized)] Weak base pka . pka : 3.5. at pH = 1.

2004 .Bioavailability & Bioequivalence Gastrointestinal pH and Transit Time in the Fasted State Region Bioavailability & Bioequivalence. June 2.

Need to fit the data and it is model dependent A surrogate is Cmx /AUC a Example: Lescol capsule (IR) : 0.19 hr-1  Usually (also) measured as Cmx and Tmx a a Cmx a Lescol IR Lescol XL 438 101 Tmx a 0.37 hr-1 Lescol XL: 0.5-1 h 1. and Extent (AUC) For Rate .Bioavailability & Bioequivalence Assessment of Drug Absorption     Absorption is measured as Rate of Absorption. ka.5-4 h Bioavailability & Bioequivalence. 2004 . June 2.

Bioavailability & Bioequivalence Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve 0.2/hr Bioavailability & Bioequivalence. 2004 . June 2.5/hr 0.

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 (Cmx ) a  time to Cmx (tmx ) a a Extent of Absorption:  area under the concentration-time curve (AUC) Bioavailability & Bioequivalence. June 2.

June 2. 2004 .Bioavailability & Bioequivalence Effect of Absorption Interactions on Drug Plasma Concentration Profiles Bioavailability & Bioequivalence.

 FDA Guidance gives type of food High Fat Meal (breakfast) – total of 800 – 1000 calories of which 150 cal from Proteins. 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.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. June 2. 250 cal from carbohydrates and 500 – 600 cal from fat. 2004 .

June 2.Bioavailability & Bioequivalence Effect of Food on Rivastigmine Absorption MEAN RIVASTIGMINE PLASMA LEVELS (ng/mL) 7 6 5 4 3 2 1 0 -1 0 2 4 6 8 10 12 14 3 m (fasted) N g =20 3 m (fed) N g =19 TIM (hrs) E Bioavailability & Bioequivalence. 2004 .

2004 Fasted Fed 18 24 .Bioavailability & Bioequivalence Effect of Food on Lescol XL Concentration (ng/mL) 150 120 90 60 30 0 0 6 12 Time (h) Bioavailability & Bioequivalence. June 2.

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. June 2. 2004 . Cases when time to peak concentration is important (analgesic) Bioavailability & Bioequivalence.

formulation factors. and the anatomy and physiologic functions at the site of drug absorption.Bioavailability & Bioequivalence Summary  Absorption is influenced by physico-chemical properties of the drug. 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. Drug absorption process may be zero order (active transport) or first order (passive diffusion) process. 2004 .

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 . June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence.

2004 . June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence.

2004 . smoking)   Drug-Drug interaction   Inhibition (↑AUC and ↑Cmx ) a Induction (↓AUC and ↓Cmx ) a  Age  Disease (hepatic impairment) Bioavailability & Bioequivalence.Bioavailability & Bioequivalence How Drug Metabolism Affects Bioavailability?  Genetic (polymorphism in expression of enzymes in a population)  CYP2D6. CYP2C19. Grapefruit juice (↑AUC and ↑Cmx ) a  Environmental (food. June 2. NAT2. etc.

2004 . June 2.Bioavailability & Bioequivalence St. John’s Wort Bioavailability & Bioequivalence.

2004 .Bioavailability & Bioequivalence How Transporters affect Bioavailability? Bioavailability & Bioequivalence. June 2.

June 2.Bioavailability & Bioequivalence Energy Dependent Efflux Transporters – ATP-binding cassette (ABC) proteins Work against concentration gradient  MDR1 (P-glycoprotein)  MDR3  MRP2 (multidrug resistance associated protein. 2004 . cMOAT)  BSEP (bile salt export pump)  BCRP (breast cancer resistance protein) Bioavailability & Bioequivalence.

June 2.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. 2004 .

   At the same time. 2004 .  Bioavailability & Bioequivalence.  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.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. June 2. 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.” also known as the Waxman-Hatch Act. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.

June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence. 2004 .

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. June 2.Bioavailability & Bioequivalence Bioequivalence Definition . 2004 .CFR 320. BE is not the same as the BA Bioavailability & Bioequivalence.

2004 .Bioavailability & Bioequivalence Bioavailability & Bioequivalence. June 2.

2004 .Bioavailability & Bioequivalence Bioavailability & Bioequivalence. June 2.

2004 . June 2.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.

2004 . June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence.

Bioavailability & Bioequivalence Bioavailability & Bioequivalence. 2004 . June 2.

June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence. 2004 .

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). June 2.  Most of the BE studies are audited by HAs especially for NMEs Bioavailability & Bioequivalence.

June 2. CDER.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. FDA Bioavailability & Bioequivalence.4. 2004 .

June 2. 2004 . sufficient information must be submitted in a BioIND 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.Bioavailability & Bioequivalence Contents of a Bio-IND  OGD's new policy is that in addition to a protocol.

 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. and purity for active ingredient(s) and Certificates of Analysis of excipients. 2004 .  Method and place of manufacturing including the type of equipment. Bioavailability & Bioequivalence. June 2.Bioavailability & Bioequivalence Contents of a Bio-IND  Tests and specifications for identity. quality. strength. batch size and batch records  Tests and specifications for the finished dosage form (Certificates of Analysis).

 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.  If the Bio-IND does not contain the information described in POLICY AND PROCEDURE. Bioavailability & Bioequivalence. a refuse to file letter will be issued and the firm will have to correct the deficiencies and resubmit the Bio-IND.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. Contents of a Bio-IND. June 2.  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. OGD. 2004 .

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.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. 2004 . a medical officer in NDE will be consulted. June 2. Bioavailability & Bioequivalence.  If a protocol raises a medical issue such as proposing to administer a dose not addressed in the labeling.

 A CSO will be assigned the responsibility to track the Bio-IND through the review process. Bioavailability & Bioequivalence. and controls will be reviewed by one of the two Divisions of Chemistry to ensure the safety of the study volunteers. June 2.Bioavailability & Bioequivalence Filing and Review Procedures  Information on chemistry. he or she will inform the firm and may request that the start of the study be deferred until the reviews are completed. including checking periodically with the reviewing divisions on the status of the reviews. A more detailed review will be conducted of the chemistry. manufacturing. manufacturing and controls information that is later submitted in the ANDA. 2004 .  If the CSO determines that the safety reviews will not be completed within thirty days.

No bioequivalence studies should be submitted as amendments to Bio-IND's. Bioavailability & Bioequivalence. That staff will prepare the appropriate action letter for the signature of the Director. 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.  The chemistry and bioequivalence reviews of the Bio-IND.  A bioequivalence study completed under a Bio-IND should be submitted in the ANDA which it supports. when completed.Bioavailability & Bioequivalence Filing and Review Procedures  Upon completion of the safety reviews. will be sent back to the central CSO staff.42. June 2. OGD. 2004 .

June 2.Bioavailability & Bioequivalence Bioavailability & Bioequivalence. 2004 .

Bioavailability & Bioequivalence Bioavailability & Bioequivalence. June 2. 2004 .

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 Waivers of In Vivo Study Requirements  Criteria (21 CFR 320.

2004 .Bioavailability & Bioequivalence The Biopharmaceutics Classification System (BCS) Guidance Bioavailability & Bioequivalence. June 2.

 Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.Bioavailability & Bioequivalence Purpose of the BCS Guidance:   Expands the regulatory application of the BCS and recommends methods for classifying drugs. 2004 . June 2. Bioavailability & Bioequivalence.

High Permeability. June 2.High Permeability. High Solubility Class II . High Solubility Class IV . Low Solubility Bioavailability & Bioequivalence. Low Solubility Class III . 2004 .Low Permeability. drug substances are classified as follows: Class I .Bioavailability & Bioequivalence BCS Classifications According to the BCS.Low Permeability.

 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 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. Bioavailability & Bioequivalence. June 2. based on mass-balance or in comparison to an intravenous reference dose. 2004 .  A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose.

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 stabilityindicating 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

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.  Samples should be collected at a sufficient number of intervals to characterize the dissolution profile of the drug product (e.g. 15.  When comparing the test and reference products. dissolution profiles should be compared using a similarity factor (f2). June 2.Bioavailability & Bioequivalence Dissolution Profile Similarity  A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver request.5 * 100}  Two dissolution profiles are considered similar when the f2 value is 50..Tt)2]-0. 20. 10. and 30 minutes). 2004 . 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. the profile comparison with an f2 test is unnecessary. f2 = 50 * log {[1+(1/n)*t=1n (Rt . Bioavailability & Bioequivalence.

warfarin) drugs Bioavailability & Bioequivalence. phenytoin. 2004 . June 2.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. Lithium. highly permeable drug substance Rapid in vitro dissolution Note: Waivers not applicable for narrow therapeutic range therapeutic range (Digoxin.

8 buffer or SIF USP without enzymes  NLT 85% dissolves within 30 minutes  Similarity factor (f2) for test (T) v.5 buffer pH 6.Bioavailability & Bioequivalence BCS Class I: Dissolution  USP Apparatus I (100 rpm) or II (50 rpm)  Three media 0.5 buffer pH 4.1 N HCl or SGF USP without enzymes pH 4. reference (R) profile comparisons should > 50 Bioavailability & Bioequivalence. 2004 .1 N HCl or SGF USP without enzymes 0. June 2.

a temperature of 370C.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. June 2. and equilibrium conditions Bioavailability & Bioequivalence.5. 2004 .

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.

Bioavailability & Bioequivalence BCS Class I: Permeability  For prodrugs. permeability depends on mechanism. measure permeability of prodrug Bioavailability & Bioequivalence. measure permeability of active moiety  When conversion occurs after intestinal permeation. 2004 . June 2. anatomical site of conversion  When conversion occurs prior to intestinal permeation.

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.

such as studies that do not show that the product meets these criteria. Bioavailability & Bioequivalence. 2004 . such data will increase understanding of how changes in components.  In addition.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. and methods of manufacture may affect formulation performance. composition. June 2.  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.

June 2. 2004 .Bioavailability & Bioequivalence Bioavailability & Bioequivalence.

gov/cder/guidance/index.htm  http://www.3rd Edition By Malcolm Rowland & Thomas N.Bioavailability & Bioequivalence References  Clinical Pharmacokinetics: Concepts and Application .gpo. June 2.fda.gov/nara/cfr/waisidx_03/21 cfr320_03. 2004 . Tozer  http://www.html Bioavailability & Bioequivalence.access.

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