THER 201 Bioavailability & Bioequivalence PDF

THER 201: Pharmacologic Basis of Therapeutics BIOAVAILABILITY AND BIOEQUIVALENCE Leonila A. Estole-Casanova, MD, MSc, FPOGS, FPSRM | October 14, 2024 OUTLINE Amount of Drug Reaching...

THER 201: Pharmacologic Basis of Therapeutics BIOAVAILABILITY AND BIOEQUIVALENCE Leonila A. Estole-Casanova, MD, MSc, FPOGS, FPSRM | October 14, 2024 OUTLINE Amount of Drug Reaching the Plasma I. Bioavailability II. Bioequivalence The amount of drug absorbed is usually the amount that will be A. Definition A. Definition reaching the systemic circulation B. Absolute vs Relative B. Importance Can be computed by multiplying the BA factor (F) by the dose. Bioavailability C. Hatch Waxman 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔 𝑅𝑒𝑎𝑐ℎ𝑖𝑛𝑔 𝑡ℎ𝑒 𝑃𝑙𝑎𝑠𝑚𝑎 = 𝐹 ✕ 𝐷𝑜𝑠𝑒 C. Factors affecting Amendments to Example: Bioavailability FFD&C Act of 1984 → The oral bioavailability of the digoxin 250 µg is 0.7 or 70%. D. Clinical Significance D. Pharmaceutical vs What is the effective or absorbed dose? Therapeutic → For digoxin 250 µg given orally, the effective or absorbed dose Bioequivalence is: E. Parameters in 0. 7 ✕ 250 µ𝑔 = 175 µ𝑔 Bioequivalence F. Criteria for → Therefore, 175 µg of digoxin was absorbed in the systemic Bioequivalence circulation or plasma and will be able to reach their G. Purpose of cellular/molecular sites of action. Bioequivalence Routes of Administration III. Summary For drugs given intravascularly, F = 1 or 100% IV. References → ALL of the drug is completely absorbed V. Appendix For all extravascular routes of administration, F < 1 or 100% I. BIOAVAILABILITY (BA) Table 1. Routes of Administration and Bioavailability A. DEFINITION Route Bioavailability (%) Fraction of unchanged drug that reaches the systemic Intravenous (IV) 100 (by definition) circulation after administration by any route, taking into account Intramuscular (IM) 75 to ≤ 100 both absorption and local metabolic degradation Subcutaneous (SC) 75 to ≤ 100 Described as the extent of drug entry into the systemic circulation Oral (PO) 5 to < 100 Designated as F, the fraction of drug absorbed Rectal (PR) 30 to < 100 Can also be expressed as percentage (%) of the administered Inhalation 5 to < 100 dose Transdermal 80 to ≤ 100 Why do we have to know the bioavailability of a drug? → Most drugs must reach the systemic circulation to be able to reach their molecular and cellular sites of action. Measuring of BA Area Under the Curve [AUC] → Area under the plasma concentration curve → Plasma drug concentration vs. time curves The AUC of the oral route is much lower than that of the AUC of the IV route → The drug injected through the IV route will be directly administered to the systemic circulation Figure 2. Routes of Administration and Bioavailability B. ABSOLUTE VS RELATIVE BIOAVAILABILITY Absolute Bioavailability Systemic availability of a drug after extravascular administration (e.g. oral, rectal, transdermal or subcutaneous). Measured by comparing the respective AUCs after extravascular and lV administration A tabulated value of absolute oral bioavailability has been determined from a comparison of area under the plasma drug Figure 1. Determination of Bioavailability. concentration-time curve between the oral dose and intravenous reference dose Exam 01 Trans 04 TG9B: Racelis, Regachuelo, Reganion, Resubal, Resurreccion, Ricardo TH: Tovera 1 of 7  Relative or Apparent Bioavailability Presence of a Reverse Transporter associated with Bioavailability of the drug from a drug product as compared to a Glycoprotein recognized standard. Drugs will be actively pumped out from the gut cells back to → Which is NOT through IV administration the lumen → The fraction of dose systemically available from an oral → Instead of the normal pumping of drugs from lumen to gut cell product is difficult to ascertain. → Present in epithelial and cancer cells In relative BA, the bioavailability of the drug in the formulation is Summary compared to the bioavailability of the drug in a standard dosage formulation Table 2. Causes of Incomplete Absorption. → Usually a solution of the pure drug evaluated in a cross-over Causes of Incomplete Drugs study Absorption → In contrast to absolute BA, where you compare the AUC with Lack of / variable absorption Digoxin that of IV administration from gut When do you determine the relative bioavailability? Too hydrophilic drugs Atenolol → Relative BA is determined when there is no data on the IV form Too hydrophobic drugs Acyclovir → Ex: Comparing amoxicillin capsule to amoxicillin suspension Presence of reverse Present in epithelial and cancer Compute AUC of the test drug over AUC of the recognized transporter associated with cells reference standard glycoprotein First Pass Effect → Where: ▪ AUCA is the test drug ▪ AUCB is the recognized reference standard On Formulas: Dr. Estole-Casanova mentioned to remember the formulas on absolute and relative bioavailability. C. FACTORS AFFECTING BIOAVAILABILITY Extent of Absorption (Bioavailability) Incomplete absorption causes issues with bioavailability. Variable Absorption from the GIT Figure 4. "Pre-systemic or First-Pass" Metabolism or Clearance. First recognized in the 1970s → Noted unexplained levels of plasma concentrations of digoxin, Figure 4: which is a digitalis glycoside → To get from the lumen of the small intestine into the systemic circulation: ▪ The drug must not only penetrate the intestinal mucosa, it must also run the gauntlet of enzymes that inactivate it in the gut wall and liver. Metabolism of drugs by enzymes found in the gastrointestinal wall and liver before reaching the systemic circulation Oral formulations of a drug undergoing extensive first-pass effect: → Should be administered through larger doses than equivalent IV formulation of same drug → First-pass metabolism acted by the enzymes can substantially decrease the amount of active drug reaching the systemic circulation ▪ This will lead also to a decrease in bioavailability[2022 Trans] Drugs undergoing this effect: Figure 3. Digoxin concentration in serum of Drugs X, Y, Z vs Time (hours). → Lidocaine ▪ One of the local anesthetic agents Figure 3: ▪ Aminoamide → The order of decreasing AUCs or digoxin concentrations in ▪ Oral administration is not practical due to extensive serum is as follows: first-pass effect ▪ Drug X > Drug Y > Drug Z − Usually administered by subcutaneous injection to ▪ Conclusion: Bioavailability tests should then be done to bypass first-pass effect ensure that values of absorption would have less variability → Morphine Hydrophilicity & Hydrophobicity of Drugs ▪ Has more or less 30% bioavailability and 70% will have Drugs which have high hydrophilic properties (atenolol) first-pass effect CANNOT readily cross the lipid cell membrane ▪ Administered through subcutaneous injection to bypass → Leads to incomplete absorption first-pass effect Drugs which have high hydrophobic properties (acyclovir) can → Propranolol cross the lipid membrane ▪ Bioavailability = 26%; 74% metabolized in liver → Cannot pass through body fluids (water layer) ▪ If a patient has liver cirrhosis, bioavailability may be higher. → Also leads to incomplete absorption − Due to no or less first-pass effect − Dose must be lowered THER 201 Bioavailability and Bioequivalence 2 of 7  Rate of Absorption Requirements for a Generic Drug Measured by time to reach maximum plasma concentration (Tmax) Compared to reference listed drug (RLD) or ‘brand-name’ drug Determined by the site of administration and drug formulation → Same active ingredients → Same route of administration → Same dosage form → Same strength → Same conditions of use Two Types of Drug Application New Drug Application Assessment of bioavailability of new drug formulation → Need bioavailability studies Regulatory approval for a new/innovator drug → Clinical trials and data submission to prove drug’s safety and efficacy Abbreviated New Drug Application (ANDA) - Bioequivalence (BE) Study Comparison of a test formulation with that of a reference standard Figure 5. Rate of absorption depends on site of administration → Generic drug must be bioequivalent with reference standard (brand-name drug) Figure 5: Regulatory approval for a GENERIC products → The order of amount of time needed to achieve Tmax from → Does NOT require clinical trials highest to lowest is as follows: ▪ Oral capsule > Oral tablet > Sublingual/buccal > Table 3. Requirements of the Two Types of Drug Application. Intramuscular > Intravenous NDA ANDA - BE Study − Intravenous: 100% Bioavailability; Tmax = 0 Chemistry Chemistry o Due to immediate maximum plasma concentration Manufacturing Manufacturing after direct administration to systemic circulation Controls Controls Labeling Labeling D. CLINICAL SIGNIFICANCE Testing Testing The amount of active drug needed to exert action at the target sites is assumed to be directly proportional to the amount of Animal Studies that drug entering the systemic circulation Clinical Studies Bioequivalence Bioavailability of a given drug product entering systemic Bioavailability circulation can be used to indirectly measure the amount of drug How do we assure the quality of generic drugs? that may possibly reach the biological site of action First 5 steps of review process are identical to NDA process Since determination of drug levels at biological site of action is → Chemistry, Manufacturing, Controls, Labeling, Testing impossible, the use of a surrogate marker is needed Bioequivalence for complicated products is discussed with the → Drug levels in the blood at different time points same staff that reviewed the brand product ▪ Usually done in bioequivalence studies Scientific literature is published II. BIOEQUIVALENCE (BE) Product is known to be safe A. DEFINITION Bioequivalence Study When two pharmaceutically equivalent drug products have active An extension of the concept of relative bioavailability ingredients with rates and extents of absorptions that are NOT Compares the bioavailability of the active ingredient present in a significantly different under suitable test conditions given drug product against a previously tested comparator drug product with established bioavailability characteristics B. IMPORTANCE Compares the bioavailability of a particular drug from a test Bioequivalence Testing dosage form (generic product) and a recognized standard dosage → To ensure the quality of generic drug products form (innovator product) → To establish that there are NO differences in the safety and Arises when a patent on an innovator drug expires efficacy between a generic and innovator drug product → Other manufacturers wish to market the same drug C. HATCH-WAXMAN AMENDMENTS TO FFD&C ACT OF 1984 formulation Considered one of the most successful pieces of legislation ever How do we assure the quality of generic drugs? passed Pharmacokinetic studies Created the generic drug industry Pharmacodynamic studies Increased availability of generics Comparative clinical studies → 1984: Only 12% prescriptions were generic In vitro dissolution studies → 2000: 44% prescriptions were generic Allowed generic firms to rely on findings of safety and efficacy of Pharmacokinetic Studies innovator, comparator, or branded drug after expiration of Two Major Pharmacokinetic Methods to assess BE patents and exclusivities → Plasma level-time studies → No need to repeat expensive clinical and preclinical trials ▪ Measurement of drug concentration in blood, plasma, or Goals of Therapy serum after drug administration → Efficacious ▪ Most direct and objective way to determine systemic drug → Safe bioavailability → Affordable → Urinary excretion studies THER 201 Bioavailability and Bioequivalence 3 of 7  D. PHARMACEUTICAL VS THERAPEUTIC BIOEQUIVALENCE → In vivo bioequivalence is self-evident ▪ Aqueous solutions (absorbed faster vs. solid dosage forms) Pharmaceutical Alternative − IV solutions Contain the same molar amount of the same active − Intramuscular pharmaceutical moiety(s) but differ in dosage form (e.g., − Subcutaneous tablets versus capsules), and/or chemical form (e.g. different − Oral Solutions salts, different esters) − Otic or Ophthalmic solutions Examples: − Topical Preparations → Tetracycline phosphate or tetracycline hydrochloride − Solutions for nasal administration equivalent to 250 mg tetracycline base ▪ Powders for reconstitution as solution → Metformin 500 mg tablet immediate release tablet or ▪ Gasses Metformin 850 mg extended release tablet Sometimes it is not enough Pharmaceutical Equivalence → Pharmaceutical equivalence by itself does NOT necessarily Contain the same molar amount of the same active imply therapeutic equivalence pharmaceutical ingredient(s) (API) in the same dosage form, if ▪ Example: Class IV oral immediate release products they meet comparable standards, and if they are intended to be Biopharmaceutics Classification System for Oral Immediate administered by the same route. Release Products Example: Is pharmaceutical equivalence enough? → Diazepam 5 mg oral tablets → No Bioequivalence Scientific framework for classifying drug substances based on Must be pharmaceutical equivalents or pharmaceutical their aqueous solubility and intestinal permeability alternatives with the same bioavailabilities (i.e. are not This classification was made to address pharmaceutical significantly different with respect to rate and extent of absorption equivalence not being enough after administration of the same molar dose under the same Oral Immediate Release Products are classified based on their conditions) aqueous solubility and intestinal permeability Must meet certain criteria Principle: If two drug products yield the same concentration → It should not be significantly different from the generic profile along the GI tract, they will result in the same plasma profile after oral administration Therapeutic Equivalence Table 5. Classification system for Oral Immediate Release Products Pharmaceutical equivalents or pharmaceutical alternatives, after administration in the same molar dose, their effects, with Class Solubility Permeability Biowaiver Eligibility respect to both efficacy and safety, are essentially the same I High High Yes when administered to patients by the same route under the II Low High Yes, only if weak acids conditions specified III High Low Yes, only if very May differ in color, flavor, configuration, packaging, rapidly dissolving preservatives, and expiration date IV Low Low No Must be: Why is pharmaceutical equivalence not enough sometimes? → Safe and effective For Class IV products, there are possible differences in: → Pharmaceutical equivalents → Drug particle size → Bioequivalent → Excipients → Adequately labeled → Manufacturing equipment or process → Manufactured in compliance with current Good Manufacturing → Site of manufacture Practice (GMP) These could lead to differences in product performance in vivo Summary Policies following the mandate of the FDA for safe, Table 4. Alternatives and Equivalence. efficacious and quality pharmaceutical products in the Pharmaceutical Alternative Pharmaceutical Equivalence Philippines: Same molar amount Same molar amount Different dosage form Same dosage form Administrative Order No. 67 s.1989 and/or chemical form Same administration route → Issues for the enforcement of the requirement for Bioequivalence Therapeutic Equivalence bioavailability studies for registration of products Pharmaceutical alternatives Pharmaceutical alternatives → Implications or pharmaceutically or pharmaceutically ▪ The generic is up to the same standard as the branded equivalent equivalent innovator drug Same bioavailabilities Same dose and effects Bureau Circular No. 13-A s.1999 → A moratorium for the conduct of BE studies was imposed Is pharmaceutical equivalence enough? because of the unavailability of Philippine-based testing Case to case basis facilities Sometimes pharmaceutical equivalence is enough (based on → Mandatory BE study report submission applicably only to intestinal permeability and aqueous solubility) Rifampicin-containing oral preparations → Biowaiver: Bureau Circular No. 2006-008 ▪ Document stating that in vivo bioavailability and → Moratorium was lifted from previous Bureau Circular No. bioequivalence studies may be waived or are NOT 13-A s.1999 necessary for product approval → Bioequivalence study report requirement added to 11 more ▪ Applied to a regulatory drug approval process when drug drug molecules: application is approved based on evidence of equivalence ▪ Atenolol, Metoprolol, Propranolol, Nicardipine, Nifedipine, other than the expensive/time-consuming BA and BE Diltiazem, Gliclazide, Metformin, Phenytoin, studies Pyrazinamide, Theophylline THER 201 Bioavailability and Bioequivalence 4 of 7  FDA Circular No. 2013-014 Blood Concentration-Time Curve → Included the list of products which will require the submission of satisfactory BE study reports (in addition to Rifampicin and 11 other products listed in Bureau Circular No. 2006-008). More BE study report submissions: ▪ Class 4 drugs (low solubility, low permeability) based on the revised WHO criteria for Biopharmaceutics Classification System (BCS) ▪ Class 2 drugs (high permeability) not eligible for biowaiver based on the revised WHO criteria for BCS ▪ Subsequent generic products to be marketed after the patent expiration of innovator − Principle: The innovator drug has proven its safety and efficacy in view of available satisfactory clinical Figure 7. Serum Concentration after a Single Oral Dose (Enlarged in Appendix). data/studies. o When its patent expires, pharmaceutical Parameters to Assess in a Blood Concentration-Time Curve manufacturers may produce generic versions of the 1. AUC0-t innovator product Most important parameter o Provided they can establish product Measurement of the extent of drug bioavailability interchangeability through BE Studies or Biowaiver, Reflects the total amount of active drug that reaches the whichever is applicable. systemic circulation ▪ All modified-release pharmaceutical products for oral 2. Cmax administration designed to act systemically Maximum or peak concentration observed in the plot → Products that may avail of Biowaiver provided that they Represents peak exposure of API or metabolite in plasma, meet all applicable WHO criteria for application of the serum, or whole blood Biowaiver procedure (including certain products covered in 3. Tmax Bureau Circular No. 2006-008) Time required to reach maximum drug concentration (Cmax) → Principle: An applicant should be able to provide after drug administration documented evidence (either through peer-reviewed Peak drug absorption occurs at Tmax scientific literature or in its absence, actual laboratory Cmax and Tmax assess rate of absorption of the drug testing) that a product may avail of Biowaiver based on the ▪ Cmax is more important solubility and permeability of it API, and the dissolution AUC assesses the extent of absorption characteristics of the dosage form. Otherwise, submission Why are Cmax and AUC more important? of a satisfactory BE study report is required. Rate and extent of exposure are the most important factors in ▪ Class 1 drugs (high permeability, high solubility) based comparing different formulations on the revised WHO criteria for BCS → AUC is used to measure extent ▪ Class 2 drugs (high permeability, low solubility) with weak → Cmax is the main consideration in measuring for rate acidic properties based on the WHO criteria for BCS → CL, Vd, and half life are NOT expected to be very different if ▪ Class 3 drugs (low permeability, high solubility) base the Cmax and AUC are the same don’t the revised WHO criteria for BCS ▪ Because of this, only Cmax and AUC need to be measured. E. PARAMETERS IN BIOEQUIVALENCE F. CRITERIA FOR BIOEQUIVALENCE Figure 6. Standard two-treatment crossover study in bioequivalence trials. Figure 6: → Randomized complete crossover single-dose study ▪ First, Group A receives a brand drug while Group B receives a test drug. Figure 8. AUC of Formulations A and B (roughly equal) (Enlarged in Appendix). ▪ After a washout period (time to eliminate the effects of the Figure 8:[2022 Trans] 1st drug), Group A and B switches. → Cmax of Formulation A reached a concentration above the ▪ Group A takes the test drug while Group B takes the brand minimum toxic concentration (MTC) drug. ▪ As such, Formulation B is safer → After administering the drugs, data is taken at specific time ▪ Formulations A and B are NOT bioequivalent intervals to create a Blood Concentration-Time Curve The criteria for bioequivalence must be met before concluding that two drug formulations are bioequivalent Bioequivalence cannot be determined solely by looking at graphs → It is necessary to examine the values of the various parameters THER 201 Bioavailability and Bioequivalence 5 of 7  → Battlecry of Bioequivalence Statistical Analysis (Two One-Sided Tests Procedure) ▪ “We want to be the same!” AUC and Cmax If a drug is not bioequivalent, does it mean that it is not a good → Bioequivalence is achieved when 90% confidence intervals drug? (CI) fit between 80% - 125% → Not necessarily bad → It only means that the data of the innovator drug CANNOT apply to the generic drug → It means that the generic drug needs studies on its own to show safety and efficacy Is bioequivalence enough to assure quality? → No, there must be consistency in manufacturing → There must be cGMP or current good manufacturing practice compliance. Current Good Manufacturing Practice Require that manufacturers, processors, and packagers of drugs, medical devices, some food, and blood take proactive steps to ensure that their products are safe, pure, and effective. Address issues which include recordkeeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. Figure 9. Possible BE Results (90% CI). III. SUMMARY Figure 9: Bioavailability → Pink graph: Bioequivalent since it fits between 80% -125% → Fraction of unchanged drug that reaches the systemic → Orange graph: Not bioequivalent since it fits at