1. Clinical Pharmacokinetics of AMINOGLYCOSIDES Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Faculty of Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur

2. INTRODUCTION Gentamicin, Tobramycin, Netilmycin, Amikacin, Kanamycin, Streptomycin.Gentamicin, Tobramycin, Netilmycin, Amikacin, Kanamycin, Streptomycin. Serious and life-threatening infectionsSerious and life-threatening infections eg.: Sepsis, endocarditis, pneumonia, meningitis, febrile neutropenia. febrile neutropenia. Especially Gram negative organismEspecially Gram negative organism EnterobacteriaceaeEnterobacteriaceae Escherichia coliEscherichia coli Klebsiella sp.Klebsiella sp. Proteus mirabilisProteus mirabilis Pseudomonas sp.Pseudomonas sp. Acinetobacter sp.Acinetobacter sp. Haemophilus influenzaHaemophilus influenza Fast action, bactericide, not affected to inoculums size.Fast action, bactericide, not affected to inoculums size.

3. SIDE EFFECTS & TOXICITY Adverse/Side effectsAdverse/Side effects Skin rashSkin rash AnaphylaxisAnaphylaxis Electrolytes imbalanceElectrolytes imbalance ToxicityToxicity Nephrotoxicity (17% of patients)Nephrotoxicity (17% of patients) Increase risk with vancomycin, diureticsIncrease risk with vancomycin, diuretics Hearing problems (8% of patients)Hearing problems (8% of patients) Vestibular toxicity (3% of patients)Vestibular toxicity (3% of patients)

4. PHARMACOKINETIC CHARACTERISTICS Administration and BioavailabilityAdministration and Bioavailability IV : 100% (bolus/short infusion 30 – 60 min).IV : 100% (bolus/short infusion 30 – 60 min). IM : 100%, peak at 30 -90 min after the dose.IM : 100%, peak at 30 -90 min after the dose. Oral : <5% (if ulcers)Oral : <5% (if ulcers) IP : 53% (variable)IP : 53% (variable) IT : 100%IT : 100% Inhalation (ETT) : 30% produced level < 1 mg/L.Inhalation (ETT) : 30% produced level < 1 mg/L.

5. PHARMACOKINETIC CHARACTERISTICS (CONT’) DistributionDistribution Three compartment model after IV bolusThree compartment model after IV bolus No significant plasma protein binding (10%)No significant plasma protein binding (10%) Tissue penetrationTissue penetration Good: Sinovium, peritoneum, ascites and pleuralGood: Sinovium, peritoneum, ascites and pleural fluid fluid Slow: Bile, faeces, prostate and amnionic fluidSlow: Bile, faeces, prostate and amnionic fluid Not into: CNS and vitreous fluidNot into: CNS and vitreous fluid Cross the placentaCross the placenta Excreted 90% by glomerulus filtrationExcreted 90% by glomerulus filtration PK varies with initial therapyPK varies with initial therapy

6. KEY PARAMETERS Genta., Netil., Tobra.P 4 – 10 T < 2 mg/LGenta., Netil., Tobra.P 4 – 10 T < 2 mg/L AmikacinP 20 – 30 T < 10 mg/L V d 0.25 L/kgV d 0.25 L/kg CL- Population Genta 0.73CL Cr + 0.06CL- Population Genta 0.73CL Cr + 0.06 *( CL Cr & CL Genta in ml/kg/min ) *( CL Cr & CL Genta in ml/kg/min ) - Functionally Anephric0.0043 L/kg/H - Surgically Anephric0.0021 L/kg/H - Hemodialysis1.8 L/H K e - Population Genta 0.0024CL Cr (Wt)+0.01K e - Population Genta 0.0024CL Cr (Wt)+0.01 *( CL Cr in ml/kg/min, K e in /H ) *( CL Cr in ml/kg/min, K e in /H ) t½- Normal renal function2 – 3 Ht½- Normal renal function2 – 3 H - Functionally Anephric30 – 60 H

7. FACTORS INFLUENCING PK Age of the patientAge of the patient Renal functionsRenal functions V dV d  : ICU, cystic fibrosis, CHF, ascites, surgery,  : ICU, cystic fibrosis, CHF, ascites, surgery, mechanical ventilator mechanical ventilator  : Dehydration, obese  : Dehydration, obese CLCL  : ICU, burn, cystic fibrosis, dialysis, pregnancy  : ICU, burn, cystic fibrosis, dialysis, pregnancy  : Renal failure  : Renal failure

8. INITIATING GENTAMICIN DOSE REGIMEN Without Sr Cr valueWithout Sr Cr value Adult:Adult: Start 3 – 6 mg/kg/D (in divided doses) Q8HStart 3 – 6 mg/kg/D (in divided doses) Q8H Children:Children: Start 4 – 10 mg/kg/D (in divided doses) Q8HStart 4 – 10 mg/kg/D (in divided doses) Q8H Neonate:Neonate: Start 2 – 7.5 mg/kg/D (in divided doses) Q12H, ODStart 2 – 7.5 mg/kg/D (in divided doses) Q12H, ODExample: Adult patient with 50kg of body weight Dose needed = 5mg/D x 50kg = 250mg/D Regimen = IV bolus/short inf. Gentamicin 80mg Q8H

9. With Sr Cr valueWith Sr Cr value - Adult Calculate the CL Cr value (ml/kg/min):Calculate the CL Cr value (ml/kg/min): CL Cr = G x (140 – Age) Sr Cr  Sr Cr in  mol/L Estimate the CL Genta (L/H):Estimate the CL Genta (L/H): CL Genta = (0.73 (CL Cr ) + 0.06) Wt x 0.06 Estimate the K e (H -1 ):Estimate the K e (H -1 ): K e = 0.0024 (CL Cr )(Wt) + 0.01 Calculate the V d (L):Calculate the V d (L): V d = CL Genta /K e INITIATING GENTAMICIN DOSE REGIMEN (CONT’)

10. Adult (cont’)Adult (cont’) Calculate the  from K e, targeted C peak, C trough :Calculate the  from K e, targeted C peak, C trough :  = ln (C peak /C trough ) + t sampling, peak  = ln (C peak /C trough ) + t sampling, peak K e K e Calculate the initial dose:Calculate the initial dose: C max = C peak e K e (t sampling, peak ) D M bolus = C max V d (1 – e -K e  )  mg D M inf = K e C max V d (1 – e -K e  )  mg/H inf. (1 – e -K e t i ) (1 – e -K e t i ) * D M inf to be given = D M inf x t i INITIATING GENTAMICIN DOSE REGIMEN (CONT’)

11. Calculate the pt’s K e (from achieved C peak & C trough,  ):Calculate the pt’s K e (from achieved C peak & C trough,  ): K e = ln (C peak /C trough )/ (  - t sampling, peak ) Estimate the pt’s t½:Estimate the pt’s t½: t½ = 0.693/K e Calculate the A max :Calculate the A max : A max = D / (1 – e -K e  ) Calculate the C max :Calculate the C max : Estimate the pt’s V d :Estimate the pt’s V d : V d = A max / C max Calculate the pt’s CL Genta :Calculate the pt’s CL Genta : CL Genta = K e x V d ADJUSTING GENTAMICIN DOSE REGIMEN (IV BOLUS / SLOW BOLUS)

12. New dose regimen estimationNew dose regimen estimation *Use the patient’s PK parameter Calculate the targeted C max target from targeted C peakCalculate the targeted C max target from targeted C peak Estimate the targeted A max :Estimate the targeted A max : A max = C max x V d Estimate the new  from targeted C peak & C trough :Estimate the new  from targeted C peak & C trough :  = (ln (C peak /C trough )/K e ) + t sampling, peak Dose needed = A max ( 1 – e -K e  )Dose needed = A max ( 1 – e -K e  ) ADJUSTING GENTAMICIN DOSE REGIMEN (CONT’)

13. (Please refer to Sawchuck-Zaske Method for multiple short infusion in Vancomycin lecture) ADJUSTING GENTAMICIN DOSE REGIMEN (SHORT INFUSION) VANCOMYCIN LECTURE VANCOMYCIN LECTURE

14. SINGLE DAILY DOSE THERAPY One high dose per dayOne high dose per day Post Antibiotic Effect (2 – 6 hours): significant effects after 2 hours the bacteria been exposed with concentration of 5 – 10 times MICPost Antibiotic Effect (2 – 6 hours): significant effects after 2 hours the bacteria been exposed with concentration of 5 – 10 times MIC Less toxicity incidenceLess toxicity incidence

15. SINGLE DAILY DOSE THERAPY (CONT’) Initiating the therapy:Initiating the therapy: Initial D M = 5-7 mg x Body WtInitial D M = 5-7 mg x Body Wt Initial dosing interval is determined by CLcrInitial dosing interval is determined by CLcr CLcr(ml/min)>60 40 – 50 30 – 39 Dosing interval24 H 36 H 48 H Sampling and dose adjustment:Sampling and dose adjustment: Sample taken at 8 - 14 hours post infusionSample taken at 8 - 14 hours post infusion Then plot the concentration on ODA normogramThen plot the concentration on ODA normogram

16. SINGLE DAILY DOSE THERAPY (CONT’) q 48 hrs or longer Trough must be <1 q 36 hrs q 24 hrs

17. EXAMPLE OF CASES CASE 1 Mr. DY, 56 years old patient was diagnosed to have pneumonia. Body weight is 65 kg.Mr. DY, 56 years old patient was diagnosed to have pneumonia. Body weight is 65 kg. Lab results: C&S Klebsiella sp., Sr Cr 120  mol/L, Urea 9 Suggest the best Gentamicin dose regimen to achieve C peak = 8.0 mg/L and C trough = 1.0 mg/L.

18. CASE 2 Mrs. PG, 70 years old patient was diagnosed to have endocarditis. Body weight is 45 kg.Mrs. PG, 70 years old patient was diagnosed to have endocarditis. Body weight is 45 kg. Given IV bolus Gentamicin 100 mg Q8H Lab results: C&S S. aureus., SrCr 150  mol/L, Urea 7, C peak = 12.2 mg/L, C trough = 3.0 mg/L Adjust the Gentamicin dose regimen to achieve C peak = 6.0 mg/L and C trough = 1.0 mg/L. When to start this new dosage regimen?

19. CASE 3 Mr. HH, 35 years old patient was diagnosed to have septic shock. Weight =100 kg & height = 170 cm.Mr. HH, 35 years old patient was diagnosed to have septic shock. Weight =100 kg & height = 170 cm. Was given IV bolus Gentamicin 80 mg Q12H Lab results: C&S P. aeruginosa., SrCr 100  mol/L, Urea 7, On D4 of Gentamicin: C peak = 6 mg/L, C trough = 0.5 mg/L Immediately after the C trough was taken, IV bolus Gentamicin 140 mg Q8H was initiated. Estimate the C peak & C trough after one dose of this new regimen

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