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1 ISSN: (Print) BIOAVAILABILITY: CRITERIA FOR APPROVING A DRUG PRODUCT FOR MARKETING Sandhya Singh 1, Faheem Ajmal Ansari 1, Shravan Paswan 2*, Rnjan Kumar Sharma 2, Alok Ranjan Gaur 3 1 Azad Institute of Pharmacy and Research Lucknow, India 2 Advance Institute of Pharmaceutical Education & Research, Kanpur, India 3 Department of Pharmacy, Pranveer Singh Institute of Technology, Kanpur, India *Corresponding author: paswanshravan@gmail.com ABSTRACT FDA ensure that the drug product for marketing should be safe, effective and meet all applicable standards, for this FDA requires bioavailability/pharmacokinetic studies and, where necessary, bioequivalence studies for all drug products (FDA Guidance for Industry, 2003). The U.S. Food and Drug Administration (FDA) define bioavailability as "the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action". Generally direct and indirect methods use to assess drug bioavailability. For assessing bioavailability or clinical availability of a drug, its rate and extent of absorption and its first-pass metabolism must be evaluated. The clinical response of the patient or the amount of active drug at the target site of action at different time periods should also be assessed. In order to achieve targeted minimum level for therapeutic or clinical effect, the medical practitioner must understand various contributing factors that could affect the bioavailability. For the scientists, they must also be aware of some essential intrinsic factors that influence the formulation. There are basically three factors, which affect bioavailability physiological factors, physicochemical factors and pharmacological factors. Key Words: FDA, Bioavailability, Bioequivalence, Pharmacokinetic, Physicochemical INTRODUCTION In approving a drug product for marketing, the FDA ensures that the drug product is safe and effective for its labeled indications for use. Moreover, the drug product must meet all applicable standards of identity, strength, quality, and purity. To ensure that these standards are met, the FDA requires bioavailability/pharmacokinetic studies and, where necessary, bioequivalence studies for all drug products (FDA Guidance for Industry, 2003). Bioavailability may be considered as one aspect of drug product quality that links in-vivo performance of the drug product used in clinical trials to studies demonstrating evidence of safety and efficacy. For unmarketed drugs that do not have full NDA approval by the FDA, in-vitro and/or in-vivo bioequivalence studies must be performed on the drug formulation proposed for marketing as a generic drug product. Bioavailability: The U.S. Food and Drug Administration (FDA) define bioavailability as "the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action". Because in practice it is rare that drug concentrations can be determined at the site of action (e.g., at a receptor site), bioavailability is more commonly defined as "the rate and extent that the active drug is absorbed from a dosage form and becomes available in the systemic circulation." Objectives of bioavailability studies: Bioavailability studies are important as 1. Primary stages of development of a suitable dosage form for a new drug entity. 2. Determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption. 3. Development of new formulations of the existing drugs. 4. Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption. Relative and absolute bioavailability: The area under the drug concentration time curve (AUC) is used as a measure of the total amount of unaltered drug that reaches the systemic circulation. The AUC is dependent on the total quantity of available drug, FD 0, divided by the elimination rate constant, k, and the apparent volume of distribution, V D. F is the fraction of the dose absorbed. After IV administration, F is equal to unity, because the entire dose enters the systemic circulation. Therefore, the drug is considered to be completely available after IV administration. After oral administration of a drug, F may vary from a value of 0 (no drug absorption) to 1 (complete drug absorption). Volume 1(3) May-June 2013 Page 351

2 Relative availability: Relative (apparent) availability is the availability of the drug from a drug product as compared to a recognized standard. The fraction of dose systemically available from an oral drug product is difficult to ascertain. The availability of drug in the formulation is compared to the availability of drug in a standard dosage formulation, usually a solution of the pure drug evaluated in a crossover study. The relative availability of two drug products given at the same dosage level and by the same route of administration can be obtained using the following equation. Where drug product B is the recognized reference standard. This fraction may be multiplied by 100 to give percent relative availability. When different doses are administered, a correction for the size of the dose is made, as in the following equation: Urinary drug excretion data may also be used to measure relative availability, as long as the total amount of intact drug excreted in the urine is collected. The percent relative availability using urinary excretion data can be determined as follows: Where [D u ] is the total amount of drug excreted in the urine. Absolute Availability The absolute availability of drug is the systemic availability of a drug after extravascular administration (eg, oral, rectal, transdermal, subcutaneous) compared to IV dosing. The absolute availability of a drug is generally measured by comparing the respective AUCs after extravascular and IV administration. This measurement may be performed as long as V D and k are independent of the route of administration. Absolute availability after oral drug administration using plasma data can be determined as follows: Absolute availability, F, may be expressed as a fraction or as a percent by multiplying F x 100. Absolute availability using urinary drug excretion data can be determined by the following: (1.1) (1.2) (1.3) (1.4) (1.5) The absolute bioavailability is also equal to F, the fraction of the dose that is bioavailable. Absolute availability is sometimes expressed as a percent, ie, F = 1, or 100%. For drugs given intravascularly, such as by IV bolus injection, F = 1 because the entire drug is completely absorbed. For all extravascular routes of administration, such as the oral route (PO), the absolute bioavailability F may not exceed 100% (F > 1). F is usually determined by Equation 1.4 or 1.5, where PO is the oral route or any other extravascular route of drug administration. Example: The difference between absolute and relative bioavailability is illustrated by the following hypothetical example. Assume that an intravenous injection (Product A) and two oral dosage forms (Product B and Product C), all containing the same dose of the same drug, are given to a group of subjects in a crossover study. Furthermore, suppose each product gave the values for AUC indicated in Table 1. Table.1. Data for Absolute and Relative Bioavailability Drug Product Are Under the Curve (mcg/ml) x hr A. Intravenous injection 100 B. Oral dosage form, brand or reference standard 50 C. Oral dosage form, generic product 40 Volume 1(3) May-June 2013 Page 352

3 The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respectively. However, when the two oral products are compared, the relative bioavailability of Product C as compared to Product B is 80% [3]. FACTOR AFFECTING BIOAVAILABILITY Drug is absorbed from the gastrointestinal (GI) tract after being dissolved according to its intrinsic absorbability. If the test product shows the same pattern of drug dissolution in the GI tract in vivo as the reference one, that product must be equivalent unless other ingredients do not modulate the absorption of active drug. In other words, physicochemical properties of drugs such as water solubility and membrane permeability do not affect the bioequivalency of oral product. A wide range of factors can influence the bioavailability of a drug. Basically, the availability of the drug or its metabolite to the target organ or receptor is controlled by three principal factors: 1. The rate and extent of drug release from its formulation, and its subsequent absorption. 2. The first-pass effect while passing through the liver after absorption. 3. The conjoint effect of plasma protein binding, drug distribution to various body fluids, metabolism and excretion. For assessing bioavailability or clinical availability of a drug, its rate and extent of absorption and its first-pass metabolism must be evaluated. The clinical response of the patient or the amount of active drug at the target site of action at different time periods should also be assessed. In order to achieve targeted minimum level for therapeutic or clinical effect, the medical practitioner must understand various contributing factors that could affect the bioavailability. For the scientists, they must also be aware of some essential intrinsic factors that influence the formulation. In general, the following factors were discussed. Physiological Factors: High variability in oral drug absorption is caused by several factors. Deviations in physiological conditions in the GI tract of volunteers would affect dissolution and permeation of drugs even in the same individual. For example, bile acid secretion into the small intestine promotes the dissolution of poorly soluble drugs to enhance the bioavailability. On the other hand, it was reported that food intake often reduced the oral absorption of BCS class 3 drugs. These facts indicate that low solubility and low permeability of drugs may cause not only the incomplete oral absorption but also the high variability in it. Metabolism in the intestine and liver affects the oral bioavailability as the first-pass effects after absorption. Also deviations of the metabolic activity in pharmacokinetic parameters due to the change in total body clearance of drugs. High clearance of drugs therefore, might be one of the risk factors for high variability in human bioequivalence study. In short, the following physiological factors are known to affect bioavailability: 1. These include the effect of gastrointestinal fluids such as ph, mucus, bile salts, complexing components. 2. Gastric motility such as gastric emptying, presence of food, rest and exercise. 3. Gastrointestinal transit time which can be affected by a large number of drugs. 4. Metabolism of drugs by the gut wall, liver, skin and bronchial mucosa. 5. The pharmacogenetic factors determining the rate of hepatic metabolism. 6. Various disease states such as malabsorption, achlorhydria, thryrotoxicosis and celiac disease. 7. Other factors include the gut flora, age, sex, weight and physical status of the patients. Physicochemical Factors: There are various physicochemical factors that may influence absorption of drugs into the bloodstream. A dissolution testing is essential to establish a profile of each generic product with specific physicochemical characteristic of the solid dosage form. This testing will ensure the permeability and solubility of drugs. At the drug development stage, these factors are essential to be evaluated and should not be the direct causes of failure in bioequivalence study. The physicochemical factors which point to the need for dissolution testing include: 1. Low drug solubility to establish the evidence that the drug has a low aqueous solubility. 2. Poor product dissolution to establish from the literature that the dissolution of one or more marketed product to develop is, poor when tested by official compendial test procedure. 3. Drug particle size to establish the evidence that the particle size may affect bioavailability. 4. The physical form of drug to establish that certain polymorphs, solvates or complexes have poor dissolution characteristics and hence bioavailability may be affected. Volume 1(3) May-June 2013 Page 353

4 5. Presence of specific excipients to establish evidence that specific excipients may alter dissolution or absorption, hence bioavailability may also be affected. 6. The nature of tablet or capsule coating to establish evidence that coating may interfere with the disintegration or dissolution of the formulation. Biopharmaceutic Classification System (BCS): The biopharmaceutic classification system was developed primarily in the context of immediate release (IR) solid oral dosage forms. It is the scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. It is a drug development tool that allows estimation of the contributions of three major factors namely dissolution, solubility and intestinal permeability that affect oral drug absorption from immediate release solid oral dosage forms. The interest in this classification system is largely because of its application in early drug development and then in the management of product change through its life cycle. Goals of the BCS Guidance: 1. To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests. 2. To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests. 3. To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance. Classification: According to BCS, drug substances are classified as: Class I: High Solubility High Permeability Class II: Low Solubility High Permeability Class III: High Solubility Low Permeability Class IV: Low Solubility Low Permeability Combined with the dissolution, the BCS takes into account the three major factors governing bioavailability parameters namely, dissolution, solubility and permeability. This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers. Absorption number, defined as the ratio of the mean residence time to mean absorption time. Dissolution number, defined as the ratio of mean residence time to mean dissolution time. METHODS FOR ASSESSING BIOAVAILABILITY Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, eg, concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product. Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product. Pharmacokinetic methods: These are indirect methods. Assumption is that pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Advantages include the results are accurate, reliable, reproducible. a) Plasma / blood level time profile: Time for peak plasma (blood) concentration (t max) Peak plasma drug concentration (Cmax) Area under the plasma drug concentration time curve (AUC). b) Urinary excretion studies: Cumulative amount of drug excreted in the urine (Du) Rate of drug excretion in the urine (dd u/dt). Time for maximum urinary excretion (t). Pharmacodynamic methods: Involves direct measurement.(measurement of pharmacologic or therapeutic end point) Disadvantages: High variability, difficult to measure, limited choices, less reliable, more subjective. Drug response influenced by several physiological & environmental factors Maximum pharmacodynamic effect (E max). Time for maximum pharmacodynamic effect. Volume 1(3) May-June 2013 Page 354

5 Area under the pharmacodynamic effect time curve. Onset time for pharmacodynamic effect. They involve determination of bioavailability from: a) Acute pharmacological response. b) Therapeutic response. In-vitro dissolution studies 1. Closed compartment apparatus 2. Open compartment apparatus 3. Dialysis systems. Plasma drug concentration: Measurement of drug concentrations in blood, plasma, or serum after drug administration is the most direct and objective way to determine systemic drug bioavailability. By appropriate blood sampling, an accurate description of the plasma drug concentration time profile of the therapeutically active drug substance(s) can be obtained using a validated drug assay. The time of peak plasma concentration, t max, corresponds to the time required to reach maximum drug concentration after drug administration. At t max, peak drug absorption occurs and the rate of drug absorption exactly equals the rate of drug elimination. Drug absorption still continues after t max is reached, but at a slower rate. When comparing drug products, t max can be used as an approximate indication of drug absorption rate. The value for t max will become smaller (indicating less time required to reach peak plasma concentration) as the absorption rate for the drug becomes more rapid. Units for t max are units of time (eg, hours, minutes). The peak plasma drug concentration, C max, represents the maximum plasma drug concentration obtained after oral administration of drug. For many drugs, a relationship is found between the pharmacodynamic drug effect and the plasma drug concentration. C max provides indications that the drug is sufficiently systemically absorbed to provide a therapeutic response. In addition, C max provides warning of possibly toxic levels of drug. The units of C max are concentration units (eg, mg/ml, ng/ml). Although not a unit for rate, C max is often used in bioequivalence studies as a surrogate measure for the rate of drug bioavailability. The area under the plasma level time curve, AUC, is a measurement of the extent of drug bioavailability. The AUC reflects the total amount of active drug that reaches the systemic circulation. The AUC is the area under the drug plasma level time curve from t = 0 to t =, and is equal to the amount of unchanged drug reaching the general circulation divided by the clearance. where F = fraction of dose absorbed, D 0 = dose, k = elimination rate constant, and V D = volume of distribution. The AUC is independent of the route of administration and processes of drug elimination as long as the elimination processes do not change. The AUC can be determined by a numerical integration procedure, such as the trapezoidal rule method. The units for AUC are concentration time (eg, μg hr/ml). For many drugs, the AUC is directly proportional to dose. For example, if a single dose of a drug is increased from 250 to 1000 mg, the AUC will also show a four fold increase. In some cases, the AUC is not directly proportional to the administered dose for all dosage levels. For example, as the dosage of drug is increased, one of the pathways for drug elimination may become saturated. Drug elimination includes the processes of metabolism and excretion. Drug metabolism is an enzyme-dependent process. For drugs such as salicylate and phenytoin, continued increase of the dose causes saturation of one of the enzyme pathways for drug metabolism and consequent prolongation of the elimination half-life. The AUC thus increases disproportionally to the increase in dose, because a smaller amount of drug is being eliminated (ie, more drug is retained). When the AUC is not directly proportional to the dose, bioavailability of the drug is difficult to evaluate because drug kinetics may be dose dependent. Volume 1(3) May-June 2013 Page 355

6 ISSN: (Print) Plasma drug concentration time curve Urinary drug excretion data: Urinary drug excretion data is an indirect method for estimating bioavailability. The drug must be excreted in significant quantities as unchanged drug in the urine. In addition, timely urine samples must be collected and the total amount of urinary drug excretion must be obtained. The cumulative amount of drug excreted in the urine, D u is related directly to the total amount of drug absorbed. Experimentally, urine samples are collected periodically after administration of a drug product. Each urine specimen is analyzed for free drug using a specific assay. The relationship between the cumulative amounts of drug excreted in the urine and the plasma level time curve shows when the drug is almost completely eliminated, the plasma concentration approaches zero and the maximum amount of drug excreted in the urine, D u is obtained. The rate of drug excretion, because most drugs are eliminated by a first-order rate process, the rate of drug excretion is dependent on the first-order elimination rate constant k and the concentration of drug in the plasma Cp. In the maximum rate of drug excretion, (dd u/dt) max, is at point B, whereas the minimum rate of drug excretion is at points A and C. Thus, a graph comparing the rate of drug excretion with respect to time should be similar in shape as the plasma level time curve for that drug. The total time for the drug to be excreted, in and, the slope of the curve segment A B is related to the rate of drug absorption, whereas point C is related to the total time required after drug administration for the drug to be absorbed and completely excreted t =. The t is a useful parameter in bioequivalence studies that compare several drug products. Rate of excretion Acute pharmacological response In some cases, the quantitative measurement of a drug in plasma or urine lacks an assay with sufficient accuracy and/or reproducibility. For locally acting, non systemically absorbed drug products, such as topical corticosteroids, plasma drug concentrations may not reflect the bioavailability of the drug at the site of action. An acute pharmacodynamic effect, such as an effect on forced expiratory volume, FEV1 (inhaled bronchodilators) or skin blanching (topical corticosteroids) can be used as an index of drug bioavailability. In this case, the acute pharmacodynamic effect is measured over a period of time after administration of the drug product. Volume 1(3) May-June 2013 Page 356

7 Measurements of the pharmacodynamic effect should be made with sufficient frequency to permit a reasonable estimate for a time period at least three times the half-life of the drug. This approach may be particularly applicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic distribution. The use of an acute pharmacodynamic effect to determine bioavailability generally requires demonstration of a dose response curve. Bioavailability is determined by characterization of the dose response curve. For bioequivalence determination, pharmacodynamic parameters including the total area under the acute pharmacodynamic effect time curve, peak pharmacodynamic effect, and time for peak pharmacodynamic effect are obtained from the pharmacodynamic effect time curve. The onset time and duration of the pharmacokinetic effect may also be included in the analysis of the data. The use of pharmacodynamic endpoints for the determination of bioavailability and bioequivalence is much more variable than the measurement of plasma or urine drug concentrations. Effects such as change in ECG or EEG readings, pupil diameter, etc are related to the time course of a given drugs. Bioavailability can be determined by construction of pharmacologic effect time curve as well as dose response graph. The drawback of this method is that, the response tends to more variable. Moreover, the observed response may be due to an active metabolite whose concentration is not proportional to concentration of parent drug responsible for the pharmacological effect. Therapeutic response: Theoretically, this method is most definite among all. It s based on observing clinical response to a drug formulation given to a patient suffering from disease for which the drug is intended to be used. A major drawback is that quantification of observed response is unreliable for assessment of bioavailability. In- vitro dissolution study: Drug dissolution studies may under certain conditions give an indication of drug bioavailability. Ideally, the in-vitro drug dissolution rate should correlate with in-vivo drug bioavailability (see and on in-vivo in-vitro correlation, IVIVC). Dissolution studies are often performed on several test formulations of the same drug. The test formulation that demonstrates the most rapid rate of drug dissolution in vitro will generally have the most rapid rate of drug bioavailability in vivo. Closed compartment apparatus: Non sink condition Open compartment apparatus: Perfect sink condition Dialysis system: This method is useful for very poorly aqueous soluble drugs for which maintenance of sink condition would require large volume of dissolution fluid. Clinical observations: Well-controlled clinical trials in humans establish the safety and effectiveness of drug products and may be used to determine bioavailability. However, the clinical trials approach is the least accurate, least sensitive, and least reproducible of the general approaches for determining in-vivo bioavailability. The FDA considers this approach only when analytical methods and pharmacodynamic methods are not available to permit use of one of the approaches described above. Comparative clinical studies have been used to establish bioequivalence for topical antifungal drug products (eg, ketoconazole) and for topical acne preparations. For dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be considered acceptable only when analytical methods cannot be developed to permit use of one of the other approaches. Analytical methodology: The selected analytical method should be Sufficiently sensitive to permit detection of low concentration of drug. Reproducible Must be specific for unmetabolized drug as well as capable of determining concentration of drug in presence of metabolites, constituents of blood/ urine. Stable Isotope Studies: This approach involves the simultaneous administration of test product and the reference product, using each subject as his own control. The reference contains the drug, which has been synthesized to contain a stable isotope such as such as 2H, 15N, 13C or 18Oin a position in a drug molecule that is not Volume 1(3) May-June 2013 Page 357

8 susceptible to metabolism and does not result in kinetic differences due to presence of isotope. The sample is collected and the comparisons are made of quantity of labeled and unlabeled drug in each sample, using sophisticated detection systems involving mass spectroscopy. A method for the calculation of bioavailability in slow release formulations in the presence of withinindividual variability: In the present study they propose a model-independent method based on the combination of the area under the curve of serum drug levels and the mean residence time for evaluating the amount of bioavailability when within-individual variability is present in the serum clearance of the drug, administered as a slow release formulation (SRF), and this follows linear pharmacokinetic behavior. The method assumes that the modifications in the area under the curve of the serum levels induced by the within-individual variability in the kinetic behavior of the drug lead to a variation of the same proportions in the mean residence time of the serum levels curve and that this parameter can be used as a correction factor in the ratio of the areas under the curve of serum levels in bioavailability studies. The method allows one to calculate the fraction of dose absorbed from the SRF without having to measure the disposition clearance of the drug either when using the reference formulation or when the drug is administered as a SRF. The method is easy to apply and has a minimum mathematical complexity. The validity of the method was evaluated using simulated data with either no error or containing a random error of 10%. Bioavailability Problems: There are a number of examples of drugs products which have exhibited bioavailability problems in the past. These examples are all pre-1976 [Gibaldi, 1984]. This is an indication that more attention is now being given to formulation development during drug development. Three chlorpropamide formulations were tested and the peak plasma concentration after administration of one brand was less than half the peak concentration after the other two formulations (figure.1.). Figure.1. Plot of Cp versus Time The text reports a number of bioavailability problems with digoxin. One example is particularly interesting. Doctors in Israel noticed 15 cases of digoxin toxicity between Oct/Dec 1975 with almost no reports for the same period the previous year. It was found that the local manufacturer had changed the formulation to improve dissolution without telling the physicians. Urinary data suggested a two-fold increase in availability of the new formulation. Again there are a number of examples in the text. One report described an incidence of phenytoin intoxication in Australia in 1968 and Apparently the tablet diluent was changed from calcium sulfate to lactose. Later studies showed that the bioavailability was higher from the dosage form containing lactose. Other drugs with problems in the past include Acetazolamide, Aminosalicylate, Ampicillin, Aspirin, Ascorbic Acid, Chloramphenicol, Chlorothiazide, Diazepam, Furosemide, Iron, Levodopa + 10 (Gibaldi, 1984). CONCLUSION Today, various pharmaceutical companies are developing generic drug products. Bioequivalence study is important for generic drug approval process. It is our hope that, this review will provide an easy quick overview for Regulatory consideration required for bioequivalence study. This review covers major aspect of requirement of bioequivalence study along with the regulatory specification. Volume 1(3) May-June 2013 Page 358

9 REFERENCES ISSN: (Print) Asif M Tamboli, Pavan Todkar, Priti Zope and FJ Sayyad, An Overview on Bioequivalence: Regulatory Consideration for Generic Drug Products Journal of Bioequivalence & Bioavailability, 2(4), 2010, Dalton JT and Yates CR, Bioavailability of Drugs and Bioequivalence, Encyclopedia of pharmaceutical technology, Third Edition, Volume 1, Swarbrick J, Editor, 2007, Informa Healthcare. USA Inc, Davit BM, Conner DP, fabian-firtsch B, Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications, AAPS J, 10, 2008, Karalis V, Macheras P, Van Peer A, Bioavailability and Bioequivalence: Focus on Physiological Factors and Variability, Pharm Res, 25, 2008, Volume 1(3) May-June 2013 Page 359

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