The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale‐up and post‐approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate‐release (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in‐vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate‐limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

[1]  L L Augsburger,et al.  Evaluation of in vitro release rate and in vivo absorption characteristics of four metoprolol tartrate immediate-release tablet formulations. , 1997, Pharmaceutical development and technology.

[2]  H Lennernäs,et al.  Jejunal permeability and hepatic extraction of fluvastatin in humans , 1996, Clinical pharmacology and therapeutics.

[3]  S. Frokjaer,et al.  Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[4]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[5]  Malcolm Rowland,et al.  Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 29-30, 2002). , 2004, AAPS pharmSci.

[6]  S. Bryson Clinical Pharmacokinetics: Concepts and applications. , 1983 .

[7]  H. Lennernäs,et al.  Regional Intestinal Permeability in Rats of Compounds with Different Physicochemical Properties and Transport Mechanisms , 1997, The Journal of pharmacy and pharmacology.

[8]  B. Eriksson,et al.  A Dose-ranging Study of the Oral Direct Thrombin Inhibitor, Ximelagatran, and Its Subcutaneous Form, Melagatran, Compared with Dalteparin in the Prophylaxis of Thromboembolism after Hip or Knee Replacement: METHRO I , 2002, Thrombosis and Haemostasis.

[9]  A. Macpherson,et al.  Intestinal permeability: an overview. , 1995, Gastroenterology.

[10]  H. Lennernäs,et al.  The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man. , 1993, British journal of clinical pharmacology.

[11]  I. Wilding,et al.  The effects of pharmaceutical excipients on small intestinal transit. , 1995, British journal of clinical pharmacology.

[12]  Anders Karlén,et al.  Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability. , 2003, Journal of molecular graphics & modelling.

[13]  H Lennernäs,et al.  Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. , 1998, Journal of medicinal chemistry.

[14]  M. Fromm,et al.  Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique , 2001, Clinical pharmacology and therapeutics.

[15]  Vinod P. Shah,et al.  Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions , 2002, Pharmaceutical Research.

[16]  Duane D. Miller,et al.  Emerging trends in oral delivery of peptide and protein drugs. , 2003, Critical reviews in therapeutic drug carrier systems.

[17]  H. van de Waterbeemd,et al.  ADMET in silico modelling: towards prediction paradise? , 2003, Nature reviews. Drug discovery.

[18]  Wolfgang Sadee,et al.  5′-Amino Acid Esters of Antiviral Nucleosides, Acyclovir, and AZT Are Absorbed by the Intestinal PEPT1 Peptide Transporter , 1998, Pharmaceutical Research.

[19]  O. Corrigan The biopharmaceutic drug classification and drugs administered in extended release (ER) formulations. , 1997, Advances in experimental medicine and biology.

[20]  R. Neubert,et al.  In‐vitro and in‐vivo studies of cefpirom using bile salts as absorption enhancers , 2003, The Journal of pharmacy and pharmacology.

[21]  R. Foster,et al.  The Nifedipine Gastrointestinal Therapeutic System (GITS) , 2012, Clinical pharmacokinetics.

[22]  H. Lennernäs,et al.  Multiple transport mechanisms involved in the intestinal absorption and first‐pass extraction of fexofenadine , 2003, Clinical pharmacology and therapeutics.

[23]  B. Eriksson,et al.  A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. , 2002, Thrombosis and haemostasis.

[24]  G. Edwards,et al.  Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. , 2004, Journal of pharmaceutical sciences.

[25]  H. Lennernäs,et al.  Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine , 2003, The Journal of pharmacy and pharmacology.

[26]  B. Schug,et al.  The biopharmaceutics classification system (BCS): class III drugs - better candidates for BA/BE waiver? , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[27]  K. Johnston,et al.  Nanoparticle Engineering Processes for Enhancing the Dissolution Rates of Poorly Water Soluble Drugs , 2004, Drug development and industrial pharmacy.

[28]  H. Lennernäs,et al.  Transport Characteristics of Fexofenadine in the Caco-2 Cell Model , 2004, Pharmaceutical Research.

[29]  H. Lennernäs Intestinal drug absorption and bioavailability: beyond involvement of single transport function , 2003, The Journal of pharmacy and pharmacology.

[30]  Sarfaraz K. Niazi Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System , 2004, Handbook of Pharmaceutical Manufacturing Formulations, Third Edition.

[31]  L. Beauchamp,et al.  Amino Acid Ester Prodrugs of Acyclovir , 1992 .

[32]  M. Kasuga,et al.  Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2, and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[33]  H. Lennernäs,et al.  The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique. , 2003, British journal of clinical pharmacology.

[34]  Shelley S. Sehnert,et al.  Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability , 2004 .

[35]  William J Egan,et al.  Prediction of intestinal permeability. , 2002, Advanced drug delivery reviews.

[36]  H. van de Waterbeemd,et al.  Property-based design: optimization of drug absorption and pharmacokinetics. , 2001, Journal of medicinal chemistry.

[37]  P. Swaan,et al.  Molecular determinants of recognition for the intestinal peptide carrier. , 1997, Journal of pharmaceutical sciences.

[38]  F. Fahey,et al.  Biphasic solid and liquid gastric emptying in normal controls and diabetics using continuous acquisition in LAO view , 1992, Digestive Diseases and Sciences.

[39]  I. Wilding,et al.  A scintigraphic study to investigate the potential for altered gut distribution of loperamide from a loperamide-simethicone formulation in man. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[40]  G. Amidon,et al.  The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[41]  S. Frokjaer,et al.  Intestinal solute carriers: an overview of trends and strategies for improving oral drug absorption. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[42]  Raviraj M. Kulkarni,et al.  Nanosuspensions: a promising drug delivery strategy , 2004, The Journal of pharmacy and pharmacology.

[43]  A. Hoffman,et al.  Expandable gastroretentive dosage forms. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[44]  H. Lennernäs,et al.  The influence of caprate on rectal absorption of phenoxymethylpenicillin: experience from an in‐vivo perfusion in humans , 2002, The Journal of pharmacy and pharmacology.

[45]  Mei-Ling Chen,et al.  Summary workshop report: biopharmaceutics classification system--implementation challenges and extension opportunities. , 2004, Journal of pharmaceutical sciences.

[46]  Ulf Norinder,et al.  Molecular Descriptors Influencing Melting Point and Their Role in Classification of Solid Drugs , 2003, J. Chem. Inf. Comput. Sci..

[47]  W. L. Chiou,et al.  A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans. , 2001, International journal of clinical pharmacology and therapeutics.

[48]  B. Abrahamsson,et al.  Evaluation of Solubilizers in the Drug Release Testing of Hydrophilic Matrix Extended-Release Tablets of Felodipine , 1994, Pharmaceutical Research.

[49]  J. Proudfoot,et al.  A structure-permeability study of small drug-like molecules. , 2003, Bioorganic & medicinal chemistry letters.

[50]  H. Lennernäs,et al.  The Effect of a Drug‐delivery System Consisting of Soybean Phosphatidyl Choline and Medium‐chain Monoacylglycerol on the Intestinal Permeability of Hexarelin in the Rat , 1998, The Journal of pharmacy and pharmacology.

[51]  Mehran Yazdanian,et al.  The “High Solubility” Definition of the Current FDA Guidance on Biopharmaceutical Classification System May Be Too Strict for Acidic Drugs , 2004, Pharmaceutical Research.

[52]  Hans Lennernäs,et al.  Comparison Between Permeability Coefficients in Rat and Human Jejunum , 1996, Pharmaceutical Research.

[53]  H. Lennernäs,et al.  Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women , 1997, Pharmaceutical Research.

[54]  Marival Bermejo,et al.  PAMPA--a drug absorption in vitro model 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[55]  S. Davis,et al.  Alimentary tract andpancreas Transit ofpharmaceutical dosage forms through the , 1986 .

[56]  J. Dressman,et al.  Forecasting the Oral Absorption Behavior of Poorly Soluble Weak Bases Using Solubility and Dissolution Studies in Biorelevant Media , 2002, Pharmaceutical Research.

[57]  Han van de Waterbeemd,et al.  Drug bioavailability : estimation of solubility, permeability, absorption and bioavailability , 2003 .

[58]  C. Gleiter,et al.  Clinical Pharmacokinetics of Candesartan , 2002, Clinical Pharmacokinetics.

[59]  Michael Levin Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System , 2001 .

[60]  U. Bredberg,et al.  Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[61]  B. Testa,et al.  Lessons learned from marketed and investigational prodrugs. , 2004, Journal of medicinal chemistry.

[62]  Lawrence X. Yu,et al.  The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs. , 2004, Molecular pharmaceutics.

[63]  G L Amidon,et al.  Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol. , 2004, Journal of pharmaceutical sciences.

[64]  H Lennernäs,et al.  Jejunal permeability in humans in vivo and rats in situ: investigation of molecular size selectivity and solvent drag. , 1999, Acta physiologica Scandinavica.

[65]  D. Meijer,et al.  Drug uptake systems in liver and kidney. , 2003, Current drug metabolism.

[66]  H vandeWaterbeemd,et al.  The fundamental variables of the biopharmaceutics classification system (BCS): a commentary. , 1998 .

[67]  Yuichi Sugiyama,et al.  Impact of Drug Transporter Studies on Drug Discovery and Development , 2003, Pharmacological Reviews.

[68]  B. Goldin,et al.  Intestinal microflora: metabolism of drugs and carcinogens. , 1990, Annals of medicine.

[69]  M. Machida,et al.  Biopharmaceutics Classification by High Throughput Solubility Assay and PAMPA , 2004, Drug development and industrial pharmacy.

[70]  M. Alpsten,et al.  Gastrointestinal transit of amoxicillin modified-release tablets and a placebo tablet including pharmacokinetic assessments of amoxicillin. , 1996, Scandinavian journal of gastroenterology.

[71]  B Agoram,et al.  Predicting the impact of physiological and biochemical processes on oral drug bioavailability. , 2001, Advanced drug delivery reviews.

[72]  H. Lennernäs,et al.  Characterization of jejunal absorption and apical efflux of ropivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[73]  Bertil Abrahamsson,et al.  Can the USP paddle method be used to represent in‐vivo hydrodynamics? , 2003, The Journal of pharmacy and pharmacology.

[74]  G. Amidon,et al.  Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. , 2004, Molecular pharmaceutics.

[75]  J. Dressman,et al.  Upper Gastrointestinal (GI) pH in Young, Healthy Men and Women , 1990, Pharmaceutical Research.

[76]  H Lennernäs,et al.  Chitosans as absorption enhancers of poorly absorbable drugs. 3: Influence of mucus on absorption enhancement. , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[77]  J. Dressman,et al.  Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts , 2004, The Journal of pharmacy and pharmacology.

[78]  H. Lennernäs,et al.  Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2. , 2004, Molecular pharmaceutics.

[79]  J. Dressman,et al.  Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine , 2004, The Journal of pharmacy and pharmacology.

[80]  C. O’Driscoll,et al.  Estimation of absorption parameters from the non‐steady‐state phase in the rat gut perfusion model , 2003, The Journal of pharmacy and pharmacology.

[81]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[82]  W. H. Barr,et al.  Differential absorption of amoxicillin from the human small and large intestine , 1994, Clinical pharmacology and therapeutics.

[83]  Michael S Lajiness,et al.  Molecular properties that influence oral drug-like behavior. , 2004, Current opinion in drug discovery & development.

[84]  A. Barve,et al.  Linear Correlation of the Fraction of Oral Dose Absorbed of 64 Drugs Between Humans and Rats , 1998, Pharmaceutical Research.

[85]  H Lennernäs,et al.  Human intestinal permeability. , 1998, Journal of pharmaceutical sciences.

[86]  B. Edgar,et al.  Plasma concentration profiles and antihypertensive effect of conventional and extended-release felodipine tablets. , 1990, British journal of clinical pharmacology.

[87]  H. Lennernäs,et al.  Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo , 1996 .

[88]  T. Fujita,et al.  Enhanced Permeability of Insulin across the Rat Intestinal Membrane by Various Absorption Enhancers: Their Intestinal Mucosal Toxicity and Absorption‐enhancing Mechanism of n‐Lauryl‐β‐D‐maltopyranoside , 1999, The Journal of pharmacy and pharmacology.

[89]  Lawrence X. Yu,et al.  Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[90]  J. Dressman,et al.  Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. , 1997, Journal of pharmaceutical sciences.

[91]  Ben J Boyd,et al.  Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach. , 2004, Journal of pharmaceutical sciences.

[92]  H. Yamamoto,et al.  Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/Peptide transporter PepT1. , 1999, Gastroenterology.

[93]  Kim L. R. Brouwer,et al.  The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts , 2004, Pharmaceutical Research.

[94]  H Lennernäs,et al.  Membrane transport of drugs in different regions of the intestinal tract of the rat. , 1998, Journal of pharmaceutical sciences.

[95]  F. Podczeck,et al.  The use of formulation technology to assess regional gastrointestinal drug absorption in humans. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[96]  H Lennernäs,et al.  Human Jejunal Effective Permeability and Its Correlation with Preclinical Drug Absorption Models , 1997, The Journal of pharmacy and pharmacology.

[97]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[98]  Gordon L. Amidon,et al.  Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs , 2002, Pharmaceutical Research.

[99]  S. Adibi,et al.  Hormonal regulation of oligopeptide transporter Pept-1 in a human intestinal cell line. , 1999, American journal of physiology. Cell physiology.

[100]  H. Lennernäs,et al.  Direct estimation of the in vivo dissolution of spironolactone, in two particle size ranges, using the single-pass perfusion technique (Loc-I-Gut) in humans. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[101]  D. Fleisher,et al.  Drug, Meal and Formulation Interactions Influencing Drug Absorption After Oral Administration , 1999, Clinical pharmacokinetics.

[102]  Hans Lennernäs,et al.  Jejunal Absorption and Metabolism of R/S-Verapamil in Humans , 1998, Pharmaceutical Research.

[103]  S. Sarna Cyclic motor activity; migrating motor complex: 1985. , 1985, Gastroenterology.

[104]  G. Amidon,et al.  Characterization of the Oral Absorption of Some β-Lactams Effect of the α-Amino Side Chain Group , 1993 .

[105]  G. Grass,et al.  Physiologically-based pharmacokinetic simulation modelling. , 2002, Advanced drug delivery reviews.

[106]  H. van de Waterbeemd The fundamental variables of the biopharmaceutics classification system (BCS): a commentary. , 1998, European Journal of Pharmaceutical Sciences.

[107]  Y. Kato,et al.  Application of chitin and chitosan derivatives in the pharmaceutical field. , 2003, Current pharmaceutical biotechnology.

[108]  G L Amidon,et al.  The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. , 1990, Gastroenterology.

[109]  P. Beaune,et al.  Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. , 1990, The Journal of pharmacology and experimental therapeutics.

[110]  Hongmao Sun,et al.  A Universal Molecular Descriptor System for Prediction of LogP, LogS, LogBB, and Absorption , 2004, J. Chem. Inf. Model..

[111]  R. Bergstrand,et al.  Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine — and its potential clinical relevance , 2004, European Journal of Clinical Pharmacology.