Roy

Bioavailability & Bioequivalence
Bioavailability & Bioequivalence: Pharmacokinetic Principles
Sandip K. Roy, Ph.D. Exploratory Clinical Development PK Novartis Pharmaceutical Corporation
Bioavailability & Bioequivalence, June 2, 2004
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
Pharmacokinetics
Pharmacodynamics
Dose regimen
Exposure
Site of action
Response
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
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)
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, log scale, Simple linear Equations etc complex math (differential equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc.
IV administration, contd.,
Following dose administration, we need to follow its drugs 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
Blood withdrawal
Sampling at Dosing Pre-determined Time intervals

Bio-analytics
Conc. vs time profiles
Concentration versus Time Profiles

Broadly 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)
Dose 1
j The one compartment model linear assumes that the drug in question is evenly distributed throughout the body into a single compartment.
j This model is only appropriate for drugs which rapidly and readily distribute between the plasma and other body tissues.

The distribution phase for aminoglycosides is only 15-30 minutes, therefore, we can use a one-compartment model with a high degree of accuracy
j Drugs which exhibit a slow equilibration with peripheral tissues, are best described with a two compartment model
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.
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
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
Area Under the Concentration Time Curve (AUC)

Concentration (Units/ml) A quantitative measure for exposure from dosing time to time t
10
An important parameter in PK
1
AUC(t) and AUC(inf) Determined by trapezoidal method AUC(inf) = AUC(t) + Ct/k
0.1
0.01 0 5 10 15 20
Units: Conc*t (mg/L * h) Proportional to Dose (linear PK) Accuracy of the estimate depends on frequency of sampling
Time (hr)
Area Under the Curve (AUC)
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
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)
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]
Concept of Half Life

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 life distribution life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in bodys tissue reservoirs elimination life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated It is usually the elimination life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug
Concept of Half Life

5
Conc . [ g L ] m /
42
02
61
]sruoh[ emiT
21
4 3 2 1 0
Elimination
ke
ln lny !
y 2
T1/2
lny lny ln2 ke ! T1/2
ln2 ke ! T1/2
0.693 ke ! T1/2
Rule of Five
5x the elimination life = time at which the drug is completely (97%) eliminated from the body 1x life - 50% of the original drug removed 2x life - 75% 3x life - 87.5% 4x life - 93.75% 5x life - 96.875%
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
Clearance
Quantifies Elimination Is the volume of body fluid cleared per time unit (L/h, mL/min)
Is Usually Constant
Clearance
Proportionality factor relating rate of drug elimination to plasma drug concentration
Rate of eliminatio n ! CL v C
Rate of eliminatio n CL ! C
(dx/dt) CL ! C
Integrate DoseIV CL ! AUC
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
Dependence of Half-life on HalfClearance and Volume
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.
For a given dose rate, the blood drug concentration is inversely proportional to clearance
Multiple Dose Administration

Concentration
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 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)
C onc .m g L ] [ /
C onc .m g L ] [ /
20 mg administered as an i.v. bolus (Diovan)

80 mg given as a solution and a capsule (Diovan)
42
02
eluspaC noituloS
61
]sruoh[ emiT
21
5 4 3 2 1 0
42 02 61
]sruoh[ emiT
21
5 4 3 2 1 0
F=0.6
eluspaC noituloS
% o f f rem a n n g t b e a b so rb e d i i o
AUC
01
]sruoh[ emiT
08
06
04
02
001
F=0.4*
16 14 12 10 8 6 4 2 0 I.v. (20 mg) P.O. (80 mg) P.O. (80 mg) Capsule Solution
F=0.2*
*dose - adjusted
Anatomical Considerations
Gut Lumen Portal Vein Liver Gut Wall Systemic Circulation
Metabolism
Metabolism
Release + Dissolution Permeation Absorption Bioavailability Elimination
How Absorption affects Bioavailability?
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 its 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
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
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
PhysicoPhysico-Chemical Factors
Partition Theory Ionization, pH-pKa Relationship Polymorphism Particle Size Complexation
Absorption Involves Movement Through Membranes

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, shape and charge) Influx
Paracellular
Transcellular
Passive Diffusion of Molecules
Passive diffusion
1 2
Comparison of the Rates of Drug Absorption
A = Passive diffusion B = Active transport/ carrier mediated system
Percent Dose Absorbed vs. Human Permeability

Propanolol Piroxicam L-leucine Naproxen Ketoprofen
Human Permeability (104, cm/sec)
01
57
Already in solution No dissolution effects
05
52
001
Phenylalanine Benserazide L-Dopa Metoprolol Terbutaline Furosemide Atenolol Enalaprilate D-glucose Antipyrine
Very low concentration No saturation effects
Percent Absorbed (%)
Effect of Blood Flow on Absorption
blood
blood membrane
tissue
tissue
If the membrane offers no resistance movement is dependent on blood flow

High resistance to drug movement movement insensitive to changes in perfusion
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
Gastrointestinal pH and Transit Time in the Fasted State

Region
Stomach Duodenum Jejunum Illeum Colon
pH
1.5-2 4.9-6.4 4.4-6.4 6.5-7.4 7.4
Residence time
0-3 hours 3-4 hours 3-4 hours 3-4 hours Up to 18 hours
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) : Lescol XL: 0.37 hr-1 0.19 hr-1
Usually (also) measured as Cmax and Tmax Cmax Lescol IR Lescol XL 438 101 Tmax 0.5-1 h 1.5-4 h
Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug Concentration Versus Time Curve
0.5/hr
0.2/hr
Interactions in Oral Drug Absorption
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)
Effect of Absorption Interactions on Drug Plasma Concentration Profiles
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.
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
Effect of Food on Rivastigmine Absorption

7
ME N R V STG NE PL S A L V L ng / L ) A IA IM I AM E ES ( m
41
21
91=N )def( gm 3 02=N )detsaf( gm 3
01
)srh( EMIT
6 5 4 3 2 1 0 1-
Effect of Food on Lescol XL

Co ncentration (ng/mL) 150 120 90 60 30 0 0 6 12 Tim e (h)
Fasted Fed
18
24
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)
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.
How Drug Metabolism affects Bioavailability?
Drug metabolism/Biotransformation
Liver is the main site of drug metabolism Extrahepatic: Gut wall Intestinal Flora Lung Kidney
Reactions Catalyzed by Drug metabolizing enzymes

Oxidative reactions (Phase I) dealkylation hydroxylation oxidation Deamination Conjugation reactions (Phase II) glucuronidation glutathione conjugation sulfation acetylation
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)
St. Johns Wort
How Transporters affect Bioavailability?
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)
How Transporters Affect Bioavailability?

P-glycoproteins expressed in
Intestine limit absorption kidney t1/2 low BA low BA shorten liver increase bile secretion
increase secretion in urine
Brain protect CNS from penetration of toxic drugs or decrease efficacy of CNS drugs Some lymphocytes drugs drug resistance for HIV
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.
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
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)
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
BioBio-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
Contents of a Bio-IND Bio 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
Contents of a Bio-IND Bio 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.
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.

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.

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.

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.
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
The Biopharmaceutics Classification System (BCS) Guidance
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.
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
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.
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.
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.
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.
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.
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
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
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
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
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
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
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.
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

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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

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

No absorption phase Simple to follow Concepts clear with less assumptions

Distribution to Tissue and Receptor sites

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Sampling at Dosing Pre-determined Time intervals

Conc. vs time profiles

Bioavailability & Bioequivalence

Concentration versus Time Profiles

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, June 2, 2004

Bioavailability & Bioequivalence

Bioavailability & Bioequivalence

Bioavailability & Bioequivalence

Area Under the Concentration Time Curve (AUC)

AUC(t) and AUC(inf) Determined by trapezoidal method AUC(inf) = AUC(t) + Ct/k

Area Under the Curve (AUC)

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

How is drug excreted/eliminated?

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Other Routes of Excretion/Elimination

 In bile (which then empties into gut, excreted in feces)

 In sweat, saliva, tears, exhaled breath, milk, hair, nails

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Concept of Half Life

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Concept of Half Life

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

lny  lny  ln2 ke ! T1/2

Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004

Bioavailability & Bioequivalence

Rowland & Tozer

Bioavailability & Bioequivalence, June 2, 2004

In bile (which then empties into gut, excreted in feces)

In sweat, saliva, tears, exhaled breath, milk, hair, nails

lny lny ln2 ke ! T1/2

Already in solution No dissolution effects

Very low concentration No saturation effects

If the membrane offers no resistance movement is dependent on blood flow

High resistance to drug movement movement insensitive to changes in perfusion