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Key Pharmacokinetic Concepts – Single Dose and Steady State Drug Administration Pankaj B. Desai. Ph.D. Professor of Pharmacokinetics and Biopharmaceutics.

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Presentation on theme: "Key Pharmacokinetic Concepts – Single Dose and Steady State Drug Administration Pankaj B. Desai. Ph.D. Professor of Pharmacokinetics and Biopharmaceutics."— Presentation transcript:

1 Key Pharmacokinetic Concepts – Single Dose and Steady State Drug Administration Pankaj B. Desai. Ph.D. Professor of Pharmacokinetics and Biopharmaceutics Director, Drug Development Graduate Program

2 Morning Agenda: Wake Up and Smell the Coffee (Cytochrome P450 1A2 Substrate)  Overview of ADME principles  Important PK Parameters  First Pass Metabolism  Compartmental & Non- Compartmental Analyses  Single Dose Kinetics  Multiple Dose Kinetics  Drug-Drug Interactions  Inter-Subject Variability CYP1A2 Substrate

3 ADME ISSUES IN ANT Issues I-CANCER DRUG DEVELOPMENT ADME

4 Clinical Pharmacology First in Human -Pharmacokinetically Guided Dose Escalation/ Drug Tolerance Study Pharmacokinetics-Pharmacodynamics Drug Metabolism Mass Balance with Radiolabeled Compounds Bioequivalence:Generic compounds Single and multiple doses Conventional versus controlled release formulations Bioavailability of metabolites Drug-Drug/Drug Dietary Product Interactions Special Populations

5 Drug Input & Different Routes of Administration 1.I.V. and I.A. injections: Bolus dosing Zero-Order Input (Infusions) 2.Extravascular Administration First Order (mostly passive diffusion) Zero Order (active transport and controlled release systems)

6 Factors Affecting Drug Distribution Phyisco-chemical properties of the drug Small vs. Large mol.wt. Compounds Hydrophilic vs. Lipophilic compounds pH of the milieu and pKa of the drug Perfusion rate (blood flow/min/g tissue) Protein binding Anatomical restrictions CNS- protected by the blood brain barrier Transport across placenta Salivary Drug Excretion (S/P ratios) Excretion of the drug in milk (M/P ratios)

7 Apparent Volume of Distribution Mathematical term to correlate amount & concentration Merely a tool to understand the EXTENT of drug distribution- not a real physiological volume Compare to the volume of body waters Best calculated from I.V. Dosing as I.V. Dose/C p o DrugL/KgL/70 kg Sulfisoxazole Phenytoin Phenobarbital Diazepam Digoxin7490

8 Apparent Volume of Distribution Conc = 2 mg/ml Vd = 50 ml Beaker without Charcoal 100 mg Conc = 0.2 mg/ml Vd = 500 ml Beaker with Charcoal 100 mg Total body Water 40 L, ~55 % body wt (w/w) TBWTBW Plasma Water-3.5 L, ~4.5 % body wt (w/w) Total extracellular water - 15 L, 20 % body wt (w/w) ECWECW Total Intracellular water –20 L, 30 % body wt (w/w)

9 Major Drug Elimination Pathways (Coordinated defense mechanism) RenalBiliary Biotransformation Excretion HEPATIC Extra-Hepatic Phase IPhase II

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12 Glomerular Filtration Kidney receives 1.1 L of blood (20 – 25%) of cardiac output 10 % is filtered at the glomerulus Compounds with Mol.wt < 20,000 filtered GFR = 120 ml/min CL R of Inulin - a measure of GFR Filtered freely into the tubule Not influenced by protein binding and neither secreted nor reabsorbed Rate of filtration = Fu. Cp.GFR Not a very effective drug extraction process (maximal ~ 0.11 or 10 %)

13 Active Secretion Detected when the overall rate of urinary drug excretion exceeds the rate of filtration Secretory processes (proteins) located predominantly within the proximal tubules Mechanisms exist for secreting acids (anions) and bases (cations) from plasma into the tubular lumen Energy-dependent Saturable processes Subject to competitive inhibition Effect of Protein-Binding Depends upon secretion efficiency and contact time at the secretory sites Restrictive (dependent on the F ub ) vs. Non-Restrictive (perfusion-rate limited)

14 Reabsorption Must occur when CL R < fu.GFR Reabsorption occurs all long the nephron, associated with reabsorption of water; majority however occurring from the proximal tubules Predominantly a passive diffusion process Driven by concentration-gradient across the tubular lumen Active secretion occurs for many endogenous compounds such as vitamins, electrolytes, glucose and amino acids Urine-Plasma Ratio (U/P) based on Henderson- Hasselbalch equation Influence of pKa and pH of urine

15 Major Tissues Involved in Drug Metabolism Liver Small intestines Kidney Lung Other portals of entry into the body and protected organs. -e.g. nasal mucosa

16 Representation of drug metabolism and excretion by the hepatocyte

17 Biliary Excretion is Transporter Mediated

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19 Phase I and Phase II Drug Metabolizing Enzymes Phase I enzymes: Predominantly cytochrome P450 (CYP)

20 Drug Metabolism by CYPs CYP2D6 (25%) Includes: Tricyclic antidepressants, SSRI's, haliperidol, propanolol, atomoxetine Detxromethorphan, CYP3A (50%) CYP2E1 (Chlorzoxazone) CYP1A2 5% CYP2A6 (Coumarin) Includes: lovastatin cyclosporin nifedipine midazolam ethinylestradiol Ritonavir Midazolam testosterone CYP2C9 (15%) Includes: warfarin phenytoin tolbutamide Losartan Theophylline, caffeine, Olanzapine CYP2C8 Paclitaxel Rosiglitazon e cerivastatin CYP2B6 bupropion, tamoxifen, efavirenz

21 Phase II Reactions Also known as Synthetic (conjugation) reactions Major reaction: Transfer of the conjugating moiety to the drug Enzymes involved are “transferase” Glucuronosyl transferase Sulfotransferases N-acetyltransferase Methyltransferase Glycine transferase Glutathione-S-transferase

22 Drug Biotransformation Reactions Active Drug to Inactive Metabolite AmphetaminePhenylacetone Phenobarbital Hydroxyphenobarbital Taxol 6  -hydroxytaxol Active Drug to Active Metabolite Codeine Morphine Procainamide N-acetylprocainamide tamoxifen 4-hydroxytamoxifen

23 Drug Biotransformation Reactions Inactive Drug to Active Metabolite HetacillinAmpicillin Sulfasalazine Sulfapyridine + 5 ASA CyclophosphamideNitrogen mustard Active Drug to Reactive Intermediates Acetaminophen Reactive metabolites (hepatic necrosis) Benzo(a)pyrene Reactive metabolite (carcinogenic)

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26 Nomenclature Basis:Amino acid sequence Families: Less than 40 % a.a. sequence assigned to different gene families (gene families 1, 2, 3, 4 etc.) Subfamilies: 40 – 55 % identical sequence (2A, 2B, 2C, 3A etc.) CYP3A4 Family Subfamily Isoform

27 CYP Nomenclature (Contd.) Cytochrome P450 Nomenclature, e.g. for CYP2D6 CYP = cytochrome P450 2 = genetic family D = genetic sub-family 6 = specific gene NOTE that this nomenclature is genetically based: it has NO functional implication

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29 Examples of reactions catalyzed by cytochrome P450: Hydroxylation of aliphatic carbon Examples of CYP mediated Oxidative Metabolism

30 Examples of reactions catalyzed by cytochrome P450: Heteroatom dealkylation Examples of CYP mediated Oxidative Metabolism

31 Clearance Concepts

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33 Compartmental Modeling

34 One-Compartment Open Model I.V. bolus D B 1 Cp 1 Vd k 10 K 10 = overall Elimination Rate Constant

35 I.V. Bolus

36 Two-compartment Open model 1 - hybrid rate constant (distribution) z - hybrid rate constant (terminal) Cp 1 V C D p I.V. bolus D t C t Vt k 12 k 21 Tissue Central or Plasma

37 Two-compartment Open Model Elimination only

38 Blood flow to human tissues TissuePercent Body Weight Percent Cardiac Output Blood Flow (ml/100 g tissue/min) Adrenals Kidney Liver Hepatic Portal Brain Skin Muscle (basal) Connective Tissue Fat

39 Extravascular dose Dp Cp Vd k 10 kaka Site of absorption e.v. dose

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41 NCA Used to estimate AUC Bioavailability Clearance Volume of Distribution Average Steady State Concentration

42 AUC Trapezoidal Rule AUC= ½(t3-t2)(C2+C3)

43 AUC

44 Example Cp(last)= 2.75/0.1419

45 Bioavailability Absolute Bioavailability Relative Bioavailability

46 Bioequivalence Two products are considered to be bioequivalent if the concentration time profiles are so similar that they are likely to produce clinically relevant differences in either efficacy or toxicity. Common measures used to assess differences are Tmax, Cmax and AUC.

47 Other Parameters CL = Di.v/AUC AUMC = ½(t2-t1)(C1t1 +C2t2) MRT (Mean Residence Time) = AUMC/AUC or MRT = 1/K or CL/V Vss = CL. MRT

48 Multiple Dosing –Overall Aims Key Concepts Principle of Superposition Drug Accumulation and Steady State Persistence Factor and Accumulation Factor Peak, Trough and Steady State Average Levels Applications Determination of drug concentrations and amounts following multiple i.v. and e.v. doses (K a > > K 10 ) » max, min and during a dosing interval Determination of dosing regimens – Doses (Maintenance and Loading) and Dosing Interval » C p max consideration » C p min consideration » C p max and C p min consideration Practical Considerations in Decision Making

49 Drug Accumulation Depends on Frequency of Administration

50 Multiple I.V. Dosing The AUC within a dosing interval at steady state is equal to the total AUC of a single dose.

51 Peak, Trough and Css Average Accumulation Index - C ss max /C max 1 AUC at Steady State = AUC 0 ∞

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53 Impact of Half-life and dosing interval Half-Life on

54 Goals of the Dosing Regimen

55 Dosing Regimen: Loading and Maintenance Doses

56 Constant Rate Regimens

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58 Sources of Variability Genetic factors Genetic differences within population Racial differences among different populations Environmental factors and drug interactions Enzyme induction Enzyme inhibition Physiologic considerations Age Gender Diet/nutrition Pathophysiology Drug dosage regimen Route of drug administration Dose dependent (nonlinear) pharmacokinetics Sources of Variability

59 Therapeutic Class Anti-epileptic Drugs Anti-Infective Agents Anti-Cancer Drugs Miscellaneous Carbamazepine Phenobarbital Phenytoin Topiramate Felbamate Rifampicin Rifabutin Rifapentine Clotrimazole Sulfadimidine Suflinpyrazone Efavirenz Amprenavir Nelfinavir Ritonavir Capravirine Paclitaxel Docetaxel Cyclophosphamide Ifophosphamide Tamoxifen 4-hydroxy- tamoxifen SU5416 Lovastatin Troglitazone Omeprazole Prednisolone Probencid Phenylbutazone Diazepam fexofenadine Hyperforin Examples of CYP3A Inducers

60 Induction of CYP1A2 (Ethoxyresorufin O-deethylase) by SU5416 in Primary Human Hepatocytes Stopeck et.al. Clin. Cancer Research, 2002 Salzberg et.al, Investigational New Drugs 24: 299–304, 2006)

61 Example of Auto-Induction – SU5416 Oral Treatment AUC Day 8AUC Day 15 AUC Day 21/22 Induction of clearance Once weekly (n=3) 156 ± ± ± 9010% Twice weekly (n=3) 329 ± ± ± 32140% Daily dosing (n=3) 412 ± ± 369 ± 1698% Stopeck et.al. Clin. Cancer Research, 2002 Salzberg et.al, Investigational New Drugs 24: 299–304, 2006)

62 Letrozole Alone Letrozole + Tamoxifen ( 6 weeks & > 4 months) Dowsett, M. et al. Clin Cancer Res 1999;5: Effect of Tamoxifen (TAM) Mediated CYP3A4 Induction Effect of Tamoxifen (TAM) Mediated CYP3A4 Induction 62

63 Pharmacogenomics November; 9(11): 1695–1709. PXR

64 Midazolam Plasma Conc. Profile Time(hrs ) Midazolam Conc. (ng/ml) Day 0 Day 1 Day Effect of CYP3A/PXR Genotypes on CYP3A Induction

65 Inhibition of Drug Metabolizing Enzymes Inhibitor absent Active drug CYP3A Inactive drug Inhibitor present Active drug CYP3A Inactive drug Inhibitor Saquinavir + Ritonavir Saquinavir AIDS Mar 15;11(4):F29-33

66 Plasma Rosuvastatin concentration-time profile in the absence and presence of Darunavir/Ritonavir Before DRV/RTVAfter DRV/RTV

67 Graduate Students -Rucha Sane – Niresh Hariparsad – Fang Li – Ganesh Mugundu Collaborators – Arthur Buckley, Ph.D., College of Pharmacy – Julie Nelson, Ph.D., Department of Molecular Genetics, Biochemistry and Microbiology -Elizabeth Shaughnessy, MD - Judith Feinberg, MD Brian Goodwin, Ph.D., GlaxoSmithKline – Stephen Storm, Ph.D. University of Pittsburgh - Funding Sources - Aventis Pharmaceutical, Eli Lily & Co, Bristol Myers Squibb - Womens Health (UC), American Cancer Society - NIH, Susan G. Komen Breast Cancer Foundation Former Student/Post-Doc Srikanth Nallani, Ph.D., FDA Desai Lab with the UC President


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