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4. pharmacokinetics and pharmacodynamics of gamithromycin

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  • 1. Presenter: Ronald K Tessman, DVM, PhD, DACVIM, DACVPM 1
  • 2. Special thanks to: Laura Letendre, PhD and Rose Huang, PhD For presentation development and technical assistance
  • 3. Outline • Principles of drug disposition – ADME properties of drugs – Routes of administration • Pharmacokinetics (PK) of Gamithromycin – Absorption – Distribution – Clearance • Pharmacodynamics (PD) Gamithromycin in  lungs – Comparison of Gamithromycin and Tulathromycin 3 PK parameters
  • 4. Drug disposition 4
  • 5. Path of a drug in‐vivo:  parenteral administration IV Tissues/Organs SC Distribution Absorption Absorption Excretion in  Drug &  Systemic Circulation Urine Metabolite Distribution Free Drug Bound Drug Metabolism Liver Drug & Metabolite Biliary Excretion Excretion Absorption Excretion in  Drug &  Intestine Feces Metabolite 5
  • 6. Parenteral routes Epidermis Dermis Subcutaneous Fat tissue Muscle 6
  • 7. Fast acting Gamithromycin pharmacokinetics  Absorption and systemic exposure 7
  • 8. Pharmacokinetics study • Treatment groups – 3 mg/kg IV dose; n =12 – 3, 6, or 9 mg/kg SC; n = 4/group • Cattle characteristics – 12 male castrate and 12 female angus cattle – Less than 1 year old – Weight = 182 to 260 kg • Analysis – Gamithromycin plasma concentration – Pharmacokinetics PR&D0099101:Evaluation of the pharmacokinetic profile of Gamithromycin in plasma from cattle treated  with a single intravenous dose (3mg/kg) or a single subcutaneous dose at 3, 6, or 9 mg/kg of Gamithromycin. 8
  • 9. Complete absorption of  Gamithromycin Concentration (ng/mL) Gamithromycin Fast, complete  absorption Predictable  Time (day) Pharmacokinetic  profile PR&D0099101 9
  • 10. Prolonged absorption phase of  Gamithromycin 200 P lasm a C o ncentratio n (ng /m L) 180 Absorption rate = Elimination rate 160 Gam ithro m ycin 140 120 100 80 Fast absorption 60 •80% of max  40 within 15 mins 20 •Max within 1 Hr 0 0 2 4 6 8 10 12 High concentrations  maintained for 6 Hrs Time (hour) plateau 30 min to 6  Hrs PR&D0099101 10
  • 11. Dose proportionality • Dose adjustments are  made with the  assumption of dose  proportionality ZACTRAN has a  Target dose predictable response PR&D0099101 11
  • 12. Summary of pharmacokinetic results • Absorption is fast – 80% of max within 15 minutes – Maximum within 1 hour • Absorption is complete – Bioavailability is 100% • Predictable and proportional exposure with dose  from 3 to 9 mg/kg 12
  • 13. Long lasting Gamithromycin pharmacokinetics Clearance and distribution 13
  • 14. Definitions 14
  • 15. Concentration gradient driving distribution Membrane Plasma Protein Tissue Plasma Extracellular fluid Gamithromycin plasma protein binding = 26% 15
  • 16. Volume of distribution: a proportionality constant Membrane Plasma Protein Tissue Plasma Extracellular fluid Amount of drug in the body (t) = Vd * plasma concentration 16
  • 17. Volume distribution 17
  • 18. Physical chemical properties  Important to PK • Log P: preference for  water or oil? • Solubility in water • pKa: how much drug is  ionized at each pH? www.molecularstation.com 18
  • 19. Gamithromycin Physical chemical properties • Lipophilic 6 N R Me – Log P = 4.69 Me 7 5 S 8 H • High H2O solubility  Me H 4 H 9 10 OH S 3 R R Me H3C N CH3 – 50 mg/mL HO OH R 2 R 1O Me S 11 12 O HO O Me • Dibasic R 13 S – pKa = 9.78 and 8.88 O 15 14 O OMe Me H Me OH O Me 19
  • 20. Ionization of Gamithromycin in plasma pH = pKa ‐ 2      ~100% ionized If pH = pKa 1:1 ratio pH = pKa + 2       ~100% neutral Plasma  pH 7.4;   pKa = 9.78  Ionized Neutral 20 Neutral 1   Ionized 240
  • 21. Ion trapping allows lung accumulation Macrophage – Acidic Plasma ‐ pH 7.4 Cytosol ‐ pH 7.2 e.g. pH of 4.8 Membrane Membrane Non‐Ionized Non‐Ionized Neutral 1: Ionized 240 Neutral 1: Ionized 380 Neutral 1: Ionized 95000 For a pKa of 9.78 21
  • 22. Pulmonary distribution study • Treatment groups – 6 mg/kg SC; n = 33 • Cattle characteristics – 18 male and 15 female, crossbred beef calves – Aged 7‐8 months – Weight 100‐300 kg • Gamithromycin analysis • Plasma • Lung tissue homogenate • Other biofluids PR&D0198501 : Evaluation of the Duration of the Concentration of Gamithromycin in Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period 22
  • 23. Gamithromycin tissue distribution 10 days after dosing Systemic circulation Ratio  Tissues/Organs 487:1 Above  MIC PR&D0198501 23
  • 24. Lung and plasma pharmacokinetics PR&D0198501 24
  • 25. Metabolism study • Treatment groups – 6 mg/kg SC; n = 14 • Cattle characteristics – 7 steers and 7 heifers, healthy beef calves – Aged 6‐7 months – Weight 190‐240 kg • Gamithromycin analysis – Plasma – Feces and urine – Tissues and organs • Liver, kidneys, lungs, muscle, abdominal fat and injection site – Total radioactive residues of Gamithromycin – Metabolite profiles PR&D0078101 : Distribution and Excretion of Total Residues after the Subcutaneous Dosing in Cattle with Gamithromycin and PR&D0078501: Metabolite Profiles  in Selected Cattle Tissue Samples from PR&D0078101 25
  • 26. Elimination of Gamithromycin Drug  metabolism  is limited Metabolites  proven  inactive and  safe PR&D0078101, PR&D0078501  26
  • 27. Summary of Gamithromycin Metabolism/distribution studies • Protein binding is low (26%) • Extensive tissue distribution – Lung >> plasma – Intracellular ion trapping in the lung • Quick systemic clearance of free drug • Excreted primarily un‐metabolized in the bile • Metabolites are not active 27
  • 28. Effectively concentrates  in the lung Gamithromycin pharmacodynamics 28
  • 29. 29
  • 30. Time dependence of Gamithromycin activity • Post‐antibiotic Effect (PAE) describes what  happens to the test organism after the  antibiotic is removed • Common for macrolide class • Gamithromycin PAE from 4.1 to 8.6 hours • Consistent with other reported macrolides 30
  • 31. Gamithromycin concentration  dependence studied PR&D0169301: Activity of the Gamithromycin against Histophilus somni strains  associated with bovine respiratory disease: Determination of antibacterial kill kinetics. 31
  • 32. Bronchoalveolar lavage study • Treatment groups – 6 mg/kg SC in the neck; n = 33 • Cattle characteristics – Crossbred beef calves – 7‐8 months old – 100‐300 kg • Analysis – Gamithromycin concentrations in the • Plasma • Pulmonary Epithelial Lining Fluid (PELF) • Lung tissue homogenate • Bronchoalveolar lavage (BAL) cells – Pharmacokinetics PR&D0198501 : Evaluation of the Duration of the Concentration of Gamithromycin in Plasma, PELF, Lung Tissue Homogenate, BAL Cells in Cattle using an LCMS Method throughout a Therapeutic Time Period 32
  • 33. Uptake kinetics in clinically relevant  tissues and fluids Interstitial Fluid Bronchoalveolar biophase Capillary Wall PELF  Alveolar  (Pulmonary Epithelial Lining Fluid) Epithelium Alveolar macrophages PR&D0198501: Disposition of Gamithromycin in plasma,  pulmonary epithelial lining fluid, bronchoalveolar cells, and lung tissue in cattle 33
  • 34. Bronchoalveolar lavage • Use – Quantification of Gamithromycin in the BAL fluid – BAL fluid • Pulmonary epithelial lining fluid & cell content  (predominately alveolar macrophages) • First line of defense against commensals and invading  pathogens – Strong support for fast acting and long lasting 34
  • 35. Therapeutic lung concentrations Peak lung concentration  (12 hrs) 100000 Gamithromycin Concentration 10000 Fast  bacteria kill 1000 Rapid  100 therapeutic  Lung (ng/g) BAL cells (ng/mL) efficacy 10 PELF (ng/mL) MIC of 1 ug/mL 1 0 2 4 6 8 10 12 14 16 Time, days PR&D0198501 35
  • 36. Therapeutic lung concentrations BAL and lung homogenate have high exposure  (AUC). Concentrations are reached quickly – above MIC in  30 mins. Long lasting: above MIC for 10‐15 days. PR&D0198501 36
  • 37. Time above MIC Figure 1. Time over which concentrations of gamithromycin in lung tissues exceed MIC90 BAL cells Whole lung PELF Above MIC in  H. somni BAL cells for 15  days P. multocida M. haemolytica 0 5 10 15 20 Time in days European MIC90 µg/ml BRD isolates M. haemolytica 0.5 P. multocida 1.0 PR&D0198501 H. somni 1.0 37
  • 38. Summary • Conclusions and clinical relevance – Fast absorption – Preferential concentrates in PELF, BAL cells and lung tissue – Concentrations in excess of the MIC90 for the common  bacterial pathogens: • Mannheimia haemolytica • Pasteurella multocida • Histophilus somni – Present in specific biophases within 30 minutes of  administration – Persists for 7 days (PELF) to greater than 15 days (BAL cells  and lung tissue) following administration of a single dose PR&D0198501 38
  • 39. ZACTRAN Comparison to Tulathromycin 39
  • 40. Tulathromycin references • Nowakowski, M.A., et al., "Pharmacokinetics and Lung Tissue Concentrations of Tulathromycin a New Triamilide Antibiotic Cattle" Veterinary Therapeutics. 5. 1. 2004. Print. • Evans, N. "Tulathromycin: An Overview of a New Triamilide Antimicrobial for Livestock Respiratory Disease" Veterinary Therapeutics. 6. 2. 2005. Print. 40
  • 41. Pharmacokinetic K comparison Tulathromycin Lung Gamithromycin Lung Gamithromycin Plasma ZACTRAN Data: PR&D0198501 Tulathromycin Data: Veterinary Therapeutics V5, N1, Spring 2004, p60.  41
  • 42. Pharmacokinetic  comparison Absorption and distribution Fast acting Gamithromycin lung concentrations > MIC within 15 mins Higher concentrations than Tulathromycin in lung 42
  • 43. Pharmacokinetic  comparison Clearance Fast uptake plasma to tissue Persistent activity in tissue Efficient terminal elimination 43
  • 44. Pharmacokinetic  comparison Distribution Gamithromycin: higher lung concentrations 44
  • 45. Conclusion • All advantages associated with the macrolide class • Fast and complete absorption • Fast and extensive lung distribution • Lung concentrations > MIC – From 15 minutes (Fast Acting) – To 10‐15 days (Long Lasting) • Effectively concentrates in the lung tissue faster  than Tulathromycin 45
  • 46. Questions
  • 47. Pharmacokinetics at the  Recommended dose of 6 mg/kg SC 1000 Gamithromycin Plasma Concentration 100 Fast absorption (ng/mL) 10 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (day) PR&D0099101 47