Drug Absorption and Bioavailability Juan J.L. Lertora, M.D., Ph.D. Director Clinical Pharmacology Program October 1, 2015 Office of Clinical Research Training and Medical Education National Institutes of Health Clinical Center 1
GOALS of Drug Absorption and Bioavailability Lecture Factors Affecting Drug Absorption Estimation of Bioavailability Clinical Significance of Differences in Bioavailability Prediction of Bioavailability in High- Throughput Drug Candidate Screening 2
Guidance for Industry-FDA-CDER Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs General Considerations DRAFT GUIDANCE March 2014 Biopharmaceutics http://www.fda.gov/downloads/drugs/guidancecompliance RegulatoryInformation/Guidances/UCM389370.pdf 3
Factors Affecting DRUG ABSORPTION Biopharmaceutic Factors - Tablet compression - Coating and Matrix - Excipients Interactions - Food - Other Drugs - Bacteria Physiological Factors 4
[PHENYTOIN] µg/ml Change in PHENYTOIN Excipients Results in Epidemic Toxicity* WEEKS * Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70 5
Factors Affecting DRUG ABSORPTION Biopharmaceutic Factors INTERACTIONS - Food - Other Drugs - Bacteria Physiologic Factors 6
ENTERIC METABOLISM OF DIGOXIN* * Lindenbaum J, et al. N Engl J Med 1981;305:789-94. 7
Factors Affecting DRUG ABSORPTION Biopharmaceutic Factors Interactions PHYSIOLOGICAL FACTORS 8
Drug Absorption Passive Non-Ionic Diffusion: Primary mechanism for most drugs. 9
Drug Absorption - Specialized Transport Mechanisms Large Neutral Amino Acid Transporter: L-Dopa, Methyldopa, Baclofen 10
Drug Absorption - Specialized Transport Mechanisms Oligopeptide Transporter (PEPT-1): Amino-beta-lactams ACE Inhibitors Valacyclovir 11
Drug Absorption - Specialized Transport Mechanisms Monocarboxylic Acid Transporter: Salicylic acid Pravastatin 12
Drug Absorption - Specialized Transport Mechanisms Organic Anion Transporting Polypeptide: Sulfasalazine (OATP2B1) Fexofenadine (OATP1A2) 13
FALLACIES Concerning Gastric Drug Absorption Weakly Acidic Drugs absorbed only in the stomach (ph partition hypothesis) Weakly Basic Drugs absorbed in the small intestine (ph partition hypothesis) Gastric ph is always acidic In fact, most drug absorption occurs in the SMALL INTESTINE 14
ASPIRIN Absorption From STOMACH and SMALL INTESTINE* TABLE 1: ASPIRIN (ASA) ABSORPTION FROM SIMULTANEOUSLY PERFUSED STOMACH AND SMALL INTESTINE (3) ph ASA ABSORPTION (micromol/100 mg protein/hr) STOMACH SMALL BOWEL ASA SERUM LEVEL (mg/100 ml) 3.5 346 469 20.6 6.5 0 424 19.7 * From: Hollander D, et al. J Lab Clin Med 1981;98:591-8 15
Variation in Gastric and Intestinal ph* * Meldrum SJ, et al. Br Med J 1972;2:104-6. 16
PHYSIOLOGICAL FACTORS Affecting Drug Absorption - Rate of gastric emptying is a major determinant of initial delay in drug absorption. - Intestinal motility is a determinant of the extent of drug absorption. 17
PATTERNS OF GASTRIC MOTOR ACTIVITY FASTING (Cyclical Pattern < 2 HR) Phase 1 - Quiescence Phase 2 - Irregular Contractions Phase 3 - Major Motor Complex Burst Phase 4 - Transition Period 18
Interdigestive Intestinal Motor Activity in Humans* *From: Rees WDW, et al. Dig Dis Sci 1982;27:321-9. 19
PATTERNS OF GASTRIC MOTOR ACTIVITY POST PRANDIAL (Up to 10 hr delay) - Pylorus constricted - Antral contractions reduce particle size 20
GI TRANSIT - SUSTAINED-RELEASE CARBAMAZEPINE FORMULATION* EXTENT RELEASED 75% 56% *From: Wilding IR, et al. Br J Clin Pharmacol 1991;32:573-9. 21
ACETAMINOPHEN (μg/ml) Variation in Peak Levels ACETAMINOPHEN* LEVELS MEASURED 1-HOUR POST DOSE PATIENTS * Prescott LF. Med Clin N Am 1974;42:907-16. 22
Gastric Emptying Rate Affects ACETAMINOPHEN Absorption* WITH METOCLOPRAMIDE ALONE TROUGH LEVEL WITH PROPANTHELINE *From: Nimmo J, et al. Br Med J 1973;1:587-9. 23
Factors Affecting RATE and EXTENT of Drug Absorption 24
RESERVE LENGTH RESERVE LENGTH is the anatomical length over which absorption of a drug can occur MINUS the length at which absorption is complete. 25
Effect of METOCLOPRAMIDE on Digoxin Absorption* *From: Manninen V, et al. Lancet 1973;1:398-99. 26
Effect of PROPANTHELINE on Digoxin Absorption* *From: Manninen V, et al. Lancet 1973;1:398-99. 27
Factors Affecting RATE and EXTENT of Drug Absorption 28
Normal Intestinal Villi 29
Broad Intestinal Villi in a Patient with SPRUE 30
Digoxin Levels in Patients with INTESTINAL MALABSORPTION* DOSE FOR BOTH GROUPS = 0.25 mg/day. CONTROLS MALABSORPTION [DIGOXIN] (ng/ml) 1.3 ± 0.3 0.4 ± 0.3 URINE D-XYLOSE EXCRETION (gm/5 hr) 5 8 1.1 4.1 NORMAL RANGE * From: Heizer WD, et al. N Engl J Med 1971;285:257-9. 31
Factors Affecting RATE and EXTENT of Drug Absorption 32
P-GLYCOPROTEIN EFFLUX PUMP INTESTINAL LUMEN OUT MEMBRANE IN SLIDE COURTESY OF M. GOTTESMAN 33
DRUG BIOAVAILABILITY OF SOME P-GLYCOPROTEIN SUBSTRATES > 70% ABSORPTION 30% - 70% ABSORPTION < 30% ABSORPTION F % DRUG F % DRUG PHENOBARBITAL 100 DIGOXIN 70 CYCLOSPORINE 28 LEVOFLOXACIN 99 INDINAVIR 65 TACROLIMUS 25 METHADONE 92 CIMETIDINE 60 MORPHINE 24 PHENYTOIN 90 CLARITHROMYCIN 55 VERAPAMIL 22 METHYLPREDNISOLONE 82 ITRACONAZOLE 55 NICARDIPINE 18 TETRACYCLINE 77 AMITRIPTYLINE 48 SIROLIMUS 15 DILTIAZEM 38 SAQUINAVIR 13 ERYTHROMYCIN 35 ATORVASTATIN 12 CHLORPROMAZINE 32 DOXORUBICIN 5 F % 34
> 70% BIOAVAILABILITY OF SOME P-GLYCOPROTEIN SUBSTRATES SYSTEMIC CIRCULATION 50% 25% 75% NET ABSORPTION GUT WALL 100% P-gp 50% P-gp SMALL BOWEL 100% 50% 25% 25% UNABSORBED EFFECTIVE ABSORBING SURFACE 35
FACTORS AFFECTING RATE AND EXTENT OF DRUG ABSORPTION 36
Sites of FIRST-PASS Elimination INTESTINAL MUCOSA CYP Enzymes P-Glycoprotein LIVER CYP Enzymes 37
FIRST-PASS METABOLISM PORTAL VEIN 38
First-Pass Metabolism ± P-Glycoprotein Transport ALDOSTERONE CYCLOSPORINE* ISOPROTERENOL LIDOCAINE MORPHINE* NORTRIPTYLINE ORGANIC NITRATES PROPRANOLOL * Known P-Glycoprotein Substrates 39
Factors Affecting RATE and EXTENT of Drug Absorption 40
GOALS of Drug Absorption and Bioavailability Lecture Factors Affecting Drug Absorption ESTIMATION OF BIOAVAILABILITY Clinical Significance of Differences in Bioavailability Prediction of Bioavailability 41
BIOAVAILABILITY BIOAVAILABILITY is the RELATIVE AMOUNT (F) of a drug dose that reaches the systemic circulation unchanged and the RATE at which this occurs. 42
Serum Concentration-Time Curve after a Single Oral Dose 43
Significance of AUC de E dt de CL D F E CL CL E E 0 C C dt dt AUC 44
Calculation of AUC Trapezoidal Rule From: Rowland M, Tozer TN. Clinical Pharmacokinetics. p 470. 45
AUC A > B BUT IS A BETTER THAN B? 46
ABSOLUTE Bioavailability % Absorption D D IV oral AUC AUC oral IV x 100 Comparison here is between an ORAL and an IV Formulation 47
RELATIVE Bioavailability % Relative B.A. D D Ref. Test AUC AUC Test Ref. x 100 Comparison here is between 2 ORAL Formulations 48
IS THE NEW FORMULATION BETTER? 49
RELATIVE Bioavailability % Relative B.A. D D Ref. Test AUC AUC Test Ref. x 100 AUC Values have to be Normalized for Dose 50
ASSESSMENT of Bioavailability AUC Estimates can be used to estimate Extent of Drug Absorption Recovery of Parent Drug in Urine can be used to estimate Extent of Drug Absorption How is ABSORPTION RATE assessed? - T MAX - Integrated Pharmacokinetic Analysis of Absolute Bioavailability. 51
Extent of Absorption from Renal Excretion of Unchanged Drug Since : F D E and E F D oral CL CL E So : % Absorption E R R (oral) D D IV oral and E E CL CL D R (oral) R (IV) IV E R X E R CL CL 100 E R E R (IV) 52
ASSESSMENT OF Bioavailability AUC Estimates Can Be Used to Estimate Extent of Drug Absorption. Recovery of Parent Drug in Urine Can Be Used to Estimate Extent of Drug Absorption. HOW IS ABSORPTION RATE ASSESSED? - T MAX - Integrated Pharmacokinetic Analysis of Absolute Bioavailability. 53
INTERACTION OF DRUG ABSORPTION AND DISPOSITION PROCESSES ABSORPTION DISPOSITION DRUG IN PLASMA. ABSORPTION FUNCTION IV DOSE ORAL DOSE * = G(t) H(t) X(t) 54
MODEL Used to Analyze Kinetics of Drug Absorption k a is absorption rate k o is rate of nonabsorptive loss 55
Calculation of Bioavailability from First-Order Absorption Model F k a k a k o 56
Methods for Assessment of ABSOLUTE BIOAVAILABILITY CONVENTIONAL: IV and ORAL doses given on two separate occasions. - Requires two study sessions - Requires two sets of blood samples - Assumes no change in disposition parameters between studies STABLE. ISOTOPE: - One study and set of blood samples - Special synthesis requirements - Mass Spectrometer Assay required 57
NAPA- 13 C 2 58
Simultaneous Administration of Oral NAPA and IV NAPA-C 13 * * From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9. 59
MODEL Used to Analyze Oral NAPA and IV NAPA-C 13 Kinetics* * From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9. 60
BIOAVAILABILITY Estimates From Kinetic Analysis and URINE RECOVERY 61
Factors Affecting RATE and EXTENT of Drug Absorption 62
NAPA PK Model After IV Dose Dose V F SPLANCHNIC V C IV SPACE CL F PARTLY REFLECTS SPLANCHNIC BLOOD FLOW CL E V S SOMATIC 63
% ABSORPTION Relationship Between CL F and Extent of NAPA Absorption* 95 90 85 80 75 70 R 2 = 0.8, p = 0.045 65 0.8 1 1.2 1.4 1.6 1.8 2 CL F (L/min) * From Atkinson AJ Jr, et al. Clin Pharmacol Ther 1989;46:182-9. 64
Additional Considerations Absolute Bioavailability Studies Absolute Bioavailability is usually studied in healthy subjects, NOT in the patient population for whom the drug is intended. The Stable Isotope Method is ideally suited for studies in special populations (e.g. Pediatrics, Pregnant Women, other) 65
RELATIVE Bioavailability Terms Bioequivalence: AUC and Cmax within 80% - 125% of reference compound. Bioinequivalence: Greater difference in bioavailability. Therapeutic Equivalence: Similar clinical effectiveness and safety. Therapeutic Inequivalence: Important clinical difference in bioavailability. 66
Standard Bioequivalence Study Single-dose, two-way, crossover design Usually in healthy subjects. Two one-sided statistical test procedure Is the test product less bioavailable relative to a reference product? (80% limit) Is the reference product less bioavailable relative to the test product? (125% limit)* *All data expressed as a ratio of average AUC and Cmax for test product/reference product (125% reciprocal of 80%) 67
GOALS of Drug Absorption and Bioavailability Lecture Factors Affecting Drug Absorption Estimation of Bioavailability Clinical Significance of Differences in Bioavailability Prediction of Bioavailability 68
AUC A > B: Therapeutic Significance? 69
AUC A > B: B Ineffective 70
AUC A > B: A and B Equally Effective 71
Equal AUC but Different K a : B is Ineffective 72
Equal AUC but Different K a : A is Toxic 73
RELATIVE BIOAVAILABILITY CONCLUSIONS BIOEQUIVALENCE = THERAPEUTIC EQUIVALENCE BIOINEQUIVALENCE NOT NECESSARILY = THERAPEUTIC INEQUIVALENCE 74
GOALS of Drug Absorption and Bioavailability Lecture Factors Affecting Drug Absorption Estimation of Bioavailability Clinical Significance PREDICTION of Bioavailability as part of High- Throughput Drug Candidate Screening 75
WHY DRUG DEVELOPMENT FAILS Unsuitable Biopharmaceutical Properties Unsuitable Clinical Pharmacokinetics * Pharmacology (PD) Doesn t Work in Humans Unexpected Toxicity is Encountered * Ronald E. White, Bristol-Myers Squibb (From Good Ligands to Good Drugs, AAPS-NIGMS Symposium, February 19-21, 1998) 76
BIOPHARMACEUTIC Drug Classification * CLASS I: High Solubility-High Permeability CLASS II: Low Solubility-High Permeability CLASS III: High Solubility-Low Permeability CLASS IV: Low Solubility-Low Permeability * From: Amidon GL, et al. Pharm Res 1995;12:413-20 77
Three CRITICAL Biopharmaceutical Properties Drug Solubility Relative to Dose GOOD = Highest Dose in 250 ml H 2 0, PH 1.0-7.5 Dissolution Rate of Formulation GOOD = 85% Dissolution in 15 min Intestinal Permeability of Drugs 78
Correlation of Rates of Drug DISSOLUTION and Oral ABSORPTION * From Rackley RJ. In Young D, Devane JG, Butler J, eds. In vitro-in vivo correlations. p. 1-15. 79
Three CRITICAL Biopharmaceutical Properties Drug Solubility Relative to Dose Dissolution Rate of Formulation INTESTINAL PERMEABILITY of Drug 80
Bioavailability vs. Jejeunal Permeability* MEASUREMENT REQUIRES REGIONAL JEJEUNAL PERFUSION * From Amidon GL et al. Pharm Res 1995;12:413-20. 81
Bioavailability vs. Caco-2 Cell Permeability P app * * From Arturson P, Karlsson J. Biochem Biophys Res Commun 1991;175:880-5. 82
Evaluation of Caco-2 Cell Model ADVANTAGES - In Vitro Method - Suitable for High-Throughput DISADVANTAGES - Paracellular Permeability - Drug Metabolizing Enzymes and Transporters - No Hepatic First-Pass Metabolism 83
BIOPHARMACEUTIC DRUG CLASSIFICATION * CLASS I: HIGH SOLUBILITY-HIGH PERMEABILITY - in vitro in vivo correlation generally good - but no way to account for 1 st pass metabolism * From: Amidon GL, et al. Pharm Res 1995;12:413-20 84
BIOPHARMACEUTIC DRUG CLASSIFICATION * CLASS II: LOW SOLUBILITY-HIGH PERMEABILITY - rate of absorption limited by dissolution rate - in vitro in vivo correlation tenuous since many factors may affect dissolution * From: Amidon GL, et al. Pharm Res 1995;12:413-20 85
BIOPHARMACEUTIC DRUG CLASSIFICATION * CLASS III: HIGH SOLUBILITY-LOW PERMEABILITY - Intestinal reserve length is marginal. - If dissolution is rapid, bioavailability will reflect intestinal permeability and transit time. * From: Amidon GL, et al. Pharm Res 1995;12:413-20 86
BIOPHARMACEUTIC DRUG CLASSIFICATION * CLASS IV: LOW SOLUBILITY-LOW PERMEABILITY - in vitro in vivo correlation poor - good bioavailability not expected * From: Amidon GL, et al. Pharm Res 1995;12:413-20 87
THE BOTTOM LINE CLASS I DRUGS: HIGH SOLUBILITY-HIGH PERMEABILITY - Preferred as development candidates - FDA may waive repeat in vivo testing if initial formulation has good bioavailability*. * Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, CDER Guidance for Industry, August 2000. 88