PR5304 Bioavailability (AY24-25S1) PDF

PR5304 Fundamental Topics in Pharmaceutical Science Concepts of Bioavailability Gigi CHIU Associate Professor [email protected] 1 Learning Outcomes At the end of this session, you should be a...

PR5304 Fundamental Topics in Pharmaceutical Science Concepts of Bioavailability Gigi CHIU Associate Professor [email protected] 1 Learning Outcomes At the end of this session, you should be able to: 1. Explain the two parameters that govern drug absorption and how they are applied in the BCS classification of drugs. 2. Explain the importance of dissolution testing in drug product development. 3. Describe the key features of the USP dissolution studies. 4. Describe the key features of a cell culture based model to study drug permeation and absorption. 5. Differentiate the two terms: absolute bioavailability and relative bioavailability. 6. Explain the various factors which affect absorption and thus bioavailability and pharmacological performance of a drug and its respective dosage form. 2 Let’s get started … Overall distribution of administration route of FDA-approved pharmaceutical products Source | Pharmaceutics 2018, 10, 263; doi:10.3390/pharmaceutics10040263 3 Distribution of dosage forms for each administration route A generic drug is a medication created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. Source | Pharmaceutics 2018, 10, 263; doi:10.3390/pharmaceutics10040263 4 Advantages of Oral Route Free of pain/discomfort and wound infection (in contrast to injections) Free of complications at site of administration Avoid social stigmatization (if patient needs to inject themselves) Most natural way of administration High compliance rate for patients of diverse medical conditions Save time and cost of treatment 5 Despite the advantages … Release from dosage form into solution Headache Pain Stability in killer physiological fluids Transport across biomembranes Pre-systemic metabolism Bioavailability considerations 6 Key points on Biopharmaceutics & Bioavailability Biopharmaceutics is the study of disintegration deaggregation how the physicochemical Tablet properties of drugs, dosage forms and routes of administration affect the rate dissolution and extent of drug absorption. DRUG in SOLUTION For a drug to be effective, absorption sufficient amount has to reach its site of action from its site of DRUG in BIOLOGICAL administration. FLUIDS or TISSUES DRUG exerts THERAPEUTIC EFFECT 7 Bioavailability: Rate & Extent of Drug Absorption Time to peak concentration (tmax): This parameter is related to the rate of absorption of the drug and can be used to assess this rate. Drug concentration in plasma Area under the plasma conc-time curve Peak (tmax, Cmax) (AUC): This parameter is related to the total AUC amount (i.e. extent) of drug absorbed into the systemic circulation following the administration of a single dose. time 8  Elimination only (no absorption process) For the intravenous (IV) route of administration, all the drug amount is introduced directly to the bloodstream; Drug concentration in blood therefore, we are sure that all of the drug reaches the blood (or systemic) IV single dose circulation and it is 100% bioavailable. Oral single dose For all other routes, an absorption process needs to take place for the drug to enter the bloodstream, and thus, the whole dose of the drug may not reach the blood circulation (i.e., less than 100% bioavailable). time Absorption > Elimination > Elimination Absorption 9 Absolute Bioavailability The percentage of an administered dose of a drug that reaches the systemic circulation IV single Drug concentration in blood intact. Oral single A comparison of non-intravenous (i.e. extravenous) route to intravenous route of administration. Absolute bioavailability = AUCEV / DoseEV AUCIV / DoseIV [EV – extravenous; IV – intravenous ] time 10 Plasma conc-Time Curve & Pharmacologic parameters Drug concentration in plasma Peak (tmax, Cmax) MTC = Minimum toxic concentration Therapeutic Intensity range MEC = Minimum effective concentration onset duration AUC time Cmax = Peak height concentration tmax = Time to peak concentration AUC = Area under plasma conc-time curve 11 Relative Bioavailability Very often, the AUC obtained from a “test” dosage form may be compared to that of a reference dosage form (oral drug solution known to be well absorbed or a commercial product of known clinical efficacy), and this parameter is known as relative bioavailability. It is useful to determine the effects of changing the formulations on the bioavailability of a particular drug. Relative bioavailability = AUCT / DoseT [T – test; STD – standard] AUCSTD / DoseSTD 12 Biopharmaceutics Classification System (BCS) BCS classifies drugs based on solubility and permeability. The goal is to establish an IVIVC (in vitro-in vivo correlation) which is a predictive mathematical model describing the relationship between an in vitro property (e.g. rate or extent of drug dissolution) and a relevant in vivo response (e.g. amount of drug absorbed) for an oral dosage form. Class I Class II High solubility Low solubility High permeability High permeability Class III Class IV High solubility Low solubility Low permeability Low permeability 13 In vitro Dissolution Studies U.S. FDA requires dissolution testing data to control the quality of pharmaceutical products, and specific guidelines have been developed. 1. For each drug, the USP drug monographs would provide detailed guidelines on how to conduct the dissolution analysis: Type of dissolution medium Volume of dissolution medium pH Ionic strength Type of apparatus (Apparatus 1 or Apparatus 2) 2. At regular intervals, an aliquot of the dissolution medium is taken for the analysis of the dissolved drug content. Guidelines for the analytical method are also specified. 3. Cumulative amount and also % of labeled drug content are calculated. 4. USP requires the time for 75% of the labeled amount of drug dissolved. 14 USP-approved Dissolution Apparatus Apparatus 1: Rotating basket Apparatus 2: Paddle Basket rotates at specific rpm Paddle rotates at specific rpm and can stand harsh media and can stand harsh media Kept at 37 °C; Volume of Kept at 37 °C; Volume of medium = 900 mL; 0.1 M HCl medium = 900 mL; 0.1 M HCl FYI / Further reading on USP Dissolution here 15 Permeation across biomembranes Intestinal mucosa is the site of absorption. Biological membranes are complex structures made of lipids and proteins. Most drugs permeate by simple diffusion. Whether a drug can cross the biomembrane will be indicated by its ability to partition into the lipophilic membrane environment. 16 In addition to diffusion, other mechanisms exist to allow drug permeation. Carrier-mediated transport: Facilitated diffusion Involves a carrier or membrane transporter CANNOT go against the drug concentration gradient Requires NO energy Driven by the drug concentration gradient Saturable process Exhibits competitive inhibition by substrate analogues Carrier-mediated transport: Active transport Involves a carrier or membrane transporter Can go against the drug concentration gradient Requires energy Transcellular: across the cells Saturable process Paracellular: between the cells Can be inhibited by metabolic inhibitors Exhibits competitive inhibition by substrate analogues 17 Caco-2 monolayer to study drug permeation Monolayer of differentiated human colon adenocarcinoma cells. Resemble cells in the small intestine, whereby microvilli structure, transporter systems, and tight junctions in between cells are present for modelling drug permeation. The monolayer requires 15-21 days to form properly, and before experiments, the monolayer integrity is checked either by the non-permeation of a marker molecule or by measuring transepithelial electrical resistance (TEER). Source | Aulton’s 6th edition, Fig 21.3 18 Factors affecting Oral Bioavailability 19 Influence of Physiological Factors pH variation within the physiological site (e.g. stomach) would affect the ionization of the drug and therefore dissolution and absorption. Food consumption triggers various physiological changes in the g.i. tract that affects drug absorption. Source | Pharmaceutics. 2020 Jul; 12(7): 672. doi: 10.3390/pharmaceutics12070672 20 Drug factors Lipinski’s Rule of Five (by Christopher A. Lipinski in 1997) Developed based on observations of orally administered drugs are relatively small and moderately lipophilic molecules. Describes molecular properties important for a drug's pharmacokinetics in the human body, but does not predict if a compound is pharmacologically active. Indicates that poor oral absorption is more likely to occur when there are more than: (i) 5 hydrogen-bond donors, (ii) 10 (5 × 2) hydrogen-bond acceptors, (iii) a molecular weight greater than 500 (5 × 100), (iv) a calculated Log P (cLogP) greater than 5. Source | Adv Drug Delivery Reviews. 1997; 46 (1–3):3–26. doi:10.1016/S0169-409X(00)00129-0 21 Drug types of varying degree of complexities, molecular masses, intestinal permeability Small molecules Monoclonal Nucleic acid therapeutics Peptides antibodies and Proteins 22 Influence of excipients on drug absorption Excipients are usually considered as inert as they lack therapeutic or biological activities. However, some excipients are capable of modifying the extent and/or the rate of absorption of drug. Scenarios / Cases: Diluent Lubricant Disintegrant PollEv 23 Approaches to improve oral bioavailability Source | Aulton’s Pharmaceutics 6th edition Fig 20.1 24 Summary At the end of this session, you should be able to: 1. Explain the two parameters that govern drug absorption and how they are applied in the BCS classification of drugs. √ 2. Explain the importance of dissolution testing in drug product development. √ 3. Describe the key features of the USP dissolution studies. √ 4. Describe the key features of a cell culture based model to study drug √ permeation and absorption. 5. Differentiate the two terms: absolute bioavailability and relative bioavailability. √ 6. Explain the various factors which affect absorption and thus bioavailability and √ pharmacological performance of a drug and its respective dosage form. 25 In-class Case Discussion 26 FYI / Further reading on Amorphous Solid Dispersion here 27