Recent Advances in BCS and Drug Product (BioPredictive) Dissolution Gordon L Amidon College of Pharmacy Charles Walgreen Jr. Professor of Pharmacy University of Michigan Ann Arbor, MI 48109-1065 Moscow, Oct 28, 2013

Major Considerations in Pharmaceutical Products Must Insure Labeling Must Insure Product Does What the Label States Must Set Pharmaceutical Standards Insure Therapeutic Interchangeability World Market is Generic = Multi Source Products Singular Fact: Patients Have (almost) No Choice

Oral Drug Product Performance

Predicting Absorption(Fabs) vs. Systemic Availability (Fsys)

Pharmaceutical Standards Identity Purity Safety and Efficacy Potency  Dose  Bioavailability BIOEQUIVALENCE!

Bioequivalence: Orange Book Bioequivalent Drug Products. This term describes pharmaceutical equivalent or alternative products that display comparable bioavailability when studied under similar experimental conditions. Section 505 (j)(8)(B) of the Act describes one set of conditions under which a test and reference listed drug5 shall be considered bioequivalent: the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or

Bioavailability (21 CFR 320)* This term means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. * Code of Federal Regulations (US Government)

Bioequivalence (BE): Today

Bioequivalence (BE) Paradigm (Oral) Similar Plasma Levels  Similar Efficacy Similar In Vivo Dissolution  Similar Plasma Levels Similar In Vitro Dissolution  Similar In Vivo Dissolution

Bioavailability (21 CFR 320)* This term means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. * Code of Federal Regulations (US Government)

General BE Confidence Interval Test

Transport View of BE Science

BE connects the product in the bottle with the claims on the label!

BE: Transport (Absorptive) View

Transport Bioequivalence(BE) If Two Drug Products, Same Drug, present the drug to the absorbing membrane the same way, (C[x,y,z,t]), they will be bioequivalent (BE)

Predicting Absorption

Absorption Rate Same Absorption Rate Same metabolism rate Same Plasma Levels

Oral BE and Dissolution Amidon et al., Clinical pharmacology and Therapeutics, 90, 467 (2011)

The Case for ‘Dissolution’ Bioperformance Dissolution Phase III Clinically tested Product In Vivo Dissolution of Phase III Product = Bioperformance Dissolution In Vitro Dissolution? Amidon, KS, et al. Clin. Pharmac. Therap., 90, 467, 2011

August 2000 FDA Guidance G.L. Amidon et. al., Pharmaceutical Research, 12, 413 (1995).

Biopharmaceutical Classification High Solubility Low Solubility Class 1 High Solubility High Permeability (Rapid Dissolution) Class 2 Low Solubility High Permeability Permeability High Class 3 High Solubility Low Permeability Class 4 Low Solubility Low Permeability Permeability Low Amidon et al., Pharm Res 12: 413-420, 1995

BCS: Definitions High Permeability Fraction Absorbed>90% (85%) Permeability is Surrogate (Human/Animal/Caco2) High Solubility->Highest Dose Soluble 250 ml pH 1-7.5 (6.8), pKa

High Permeability Drug: Fabs>90%

High Solubility Drug Vs = Volume of Solution <250 ml, FDA Glass of Water= 8 oz. (240 ml) Vs = Volume of Solution <250 ml, pH=1-7.5 (6.8) Highest Dose Strength Do=Dose/250/C s <1

BCS of Worlds Drugs

Drug database of oral immediate-release (IR) drugs on 200 top-selling US, GB, ES, JP, and KR drug products US: 113 oral IR drugs (56.5%) GB: 102 oral drugs (51.0%) ES: 106 oral drugs (53.0%) JP: 113 oral drugs (56.5%) KR: 87 oral drugs (43.5%) Based on 200 top-selling drug products in 5 countries, and WHO Essential drugs (EML), drug databases of Combined List (346 drugs), Western List (147 drugs), Eastern List (163 drugs) was made and analyzed on molecular properties and BCS classification.

Comparison of the percentage of oral IR drugs of permeability class on the Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists

Comparison of the percentage of oral IR drugs of solubility class in the Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists

BCS Worlds Drugs

Bioperformance Dissolution (Definition) An in vitro dissolution methodology that is predictive of in vivo dissolution This methodology is not a QC methodology It is not a regulatory methodology It IS a drug product development methodology

Bioperformance Dissolution Sub-Classification Proposal BCS Class Drug Solubility pH 1.2 Drug Solubility pH 6.8 Drug Permeability Preferred Procedure I High >85% Dissolution in 15 min; 30 min, f2., pH = 6.8. II-A Low 15 min at pH=1.2, then 85% Dissolution in 30 min., pH = 6.8; F2>50; 5 points minimum; not more than one point > 85%. II-B >85% Dissolution in 15 min., pH = 1.2. II-C 15 min at pH=1.2; then 85% Dissolution in 30 min., pH = 6.8 plus surfactant*; F2>50; 5 points minimum, not more than one point > 85%. III >85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8. IV-A 15 min. at pH = 1.2; then 85% Dissolution in 30 min., pH = 6.8,; F2>50; 5 points minimum.; not more than one point > 85%. IV-B IV-C

Bioperformance Dissolution: One Consideration GI Physiology pH Buffer Transit Fasted/Fed

Human In Vivo Buffer: Bicarbonate Stomach 10mM 4-21mM, Average= 15mM 30mM 70mM Human GI Bicarbonate Pharmaceutical buffers pH 1.2, 0.1N HCl 1. USP 2. FaSSIF 3. Others J.G. Hardman, et al., eds., Goodman and Gilman’s The pharmacological basis for therapeutics, 10th ed., Chapter 39, p1038. N.W. Tietz, et al., eds., Clinical guide to laboratory tests., 3rd ed., p 84. W. G. Karr, et al., Intubation Studies Of The Human Small Intestine. Iv. Chemical Characteristics Of The Intestinal Contents In The Fasting State And As Influenced By The Administration Of Acids, Of Alkalies And Of Water. J Clin Invest 14: 893-900 (1935).

A Pharmaceutical Product with CO2

CO2 in the Environment

Pharmaceutical Buffers United State Pharmacopeias (USP) buffer 50 mM pH 6.8 phosphate buffer Fasted State Simulated Small Intestinal Fluids (FaSSIF1) 29 mM NaH2PO4 q.s. to pH 6.5 with NaOH 3 mM Na taurocholate 0.75 mM lecithin 106 mM NaCl Other buffers covering pH 1.2-7.5 Simulated gastric fluids (SGF): pH 1.2 HCl FeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate buffer pH 7.5 phosphate buffer Buffer choice of analytical chemists with addition of SLS, Tween, and CTAB. 1: Vertzoni M. et al., Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J. Pharmacy & Pharmacology, 2004, 56:453-462.

Equilibrium (?) In the Intestine CO2 (g) Bicarbonate Equilibrium H2CO3 HCO3− + H+ Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.   HCO3− CO32− + H+ Ka2 = 5.61×10−11 ; pKa2 = 10.33 at 25 °C Gas Phase Equilibrium CO2(gas) = CO2(dissolved) where kH=29.76 atm/(mol/L) at 25°C (Henry constant)   CO2(aq) + H2O = H2CO3 (aq) Then of course we have CO2 transport in the Intestine Transporters, Exchangers, intracellular equilibrium PCO2 (Intestine)~200 mmHg CO2 (aq) + H2O = H2CO3

Bicarbonate Buffer Physiological Relevance GI Lumen Bicarbonate is secreted by the cells throughout the GI tract. Bicarbonate in the lumen of the GI tract modulates luminal pH. GI Epithelial Cell Blood

Bicarbonate Buffer: Reactions and Rates

Film Model Flux and Flux using Cussler’s Reaction Enhancement Factor Flux with Reaction Enhancement Factor EL Cussler, “Diffusion and Mass Transport”, 2009, Wiley

Predicted and Experimental Flux in Bicarbonate Buffer at pH 6 Predicted and Experimental Flux in Bicarbonate Buffer at pH 6.5: Ibuprofen Solubility=3.3x10-4 M, pKa=4.43, Diffusion Coefficient =7.93x10-6 cm2/s

BABE 1960-Present Mainly Empirical: Cmax and AUC Regulatory Dominated Little Biopharmaceutical Mechanism ADME very complex-> Empirical Pharmacokinetics Dominated the Science Analytical and Computational Technology Regulatory Standards from the ~1970’s BA & BE

Bioequivalence (BE) Today: Oral Historically a Relative Bioavailability (BA) Based View Misses the underlying scientific issues IN Vivo Dissolution BE Testing is Same Drug Once Absorbed PK is the Same The Science of BE is at the Absorption Site For Oral Dosage Form in the GI Tract The Question is: What is the Best BE Test

BioPredictive Dissolution (BPD) BCS Class I, IIa, III Rapid Dissolution BCS Class IIb,c More Complex Modified Release -Move Complex

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Predicting Absorption

Time Dependent Absorption

Diffusion vs. Pharmacokinetic Views of Absorption: A Simpler Well Mixed View Software e.g. GastroPlus®

Predicting Absorption(Fabs) vs. Systemic Availability (Fsys)

Predicting Absorption

Transport View Of Oral Absorption