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Clinical Pharmacokinetics of AMINOGLYCOSIDES

Clinical Pharmacokinetics of AMINOGLYCOSIDES. Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Faculty of Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur. INTRODUCTION. Gentamicin, Tobramycin, Netilmycin, Amikacin, Kanamycin, Streptomycin.

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Clinical Pharmacokinetics of AMINOGLYCOSIDES

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  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. • Serious and life-threatening infections eg.: Sepsis, endocarditis, pneumonia, meningitis, febrile neutropenia. • Especially Gram negative organism • Enterobacteriaceae • Escherichia coli • Klebsiella sp. • Proteus mirabilis • Pseudomonas sp. • Acinetobacter sp. • Haemophilus influenza • Fast action, bactericide, not affected to inoculums size.

  3. SIDE EFFECTS & TOXICITY • Adverse/Side effects • Skin rash • Anaphylaxis • Electrolytes imbalance • Toxicity • Nephrotoxicity (17% of patients) • Increase risk with vancomycin, diuretics • Hearing problems (8% of patients) • Vestibular toxicity (3% of patients)

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

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

  6. KEY PARAMETERS • Genta., Netil., Tobra. P 4 – 10 T < 2 mg/L Amikacin P 20 – 30 T < 10 mg/L • Vd 0.25 L/kg • CL - PopulationGenta 0.73CLCr + 0.06 *( CLCr & CLGenta in ml/kg/min ) - Functionally Anephric 0.0043 L/kg/H - Surgically Anephric 0.0021 L/kg/H - Hemodialysis 1.8 L/H • Ke - PopulationGenta 0.0024CLCr(Wt)+0.01 *( CLCr in ml/kg/min, Ke in /H ) • t½ - Normal renal function 2 – 3 H - Functionally Anephric 30 – 60 H

  7. FACTORS INFLUENCING PK • Age of the patient • Renal functions • Vd •  : ICU, cystic fibrosis, CHF, ascites, surgery, mechanical ventilator •  : Dehydration, obese • CL •  : ICU, burn, cystic fibrosis, dialysis, pregnancy •  : Renal failure

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

  9. INITIATING GENTAMICIN DOSE REGIMEN (CONT’) • With SrCr value - Adult • Calculate the CLCr value (ml/kg/min): CLCr = G x (140 – Age) SrCr SrCr in mol/L • Estimate the CLGenta (L/H): CLGenta = (0.73 (CLCr) + 0.06) Wt x 0.06 • Estimate the Ke (H-1): Ke = 0.0024 (CLCr)(Wt) + 0.01 • Calculate the Vd (L): Vd = CLGenta/Ke

  10. INITIATING GENTAMICIN DOSE REGIMEN (CONT’) • Adult (cont’) • Calculate the  from Ke, targeted Cpeak, Ctrough:  = ln (Cpeak/Ctrough) + tsampling, peak Ke • Calculate the initial dose: Cmax = Cpeak eKe(tsampling, peak) DMbolus = CmaxVd (1 – e-Ke) mg DMinf = KeCmaxVd (1 – e-Ke)mg/H inf. (1 – e-Keti) * DMinf to be given =DMinf x ti

  11. ADJUSTING GENTAMICIN DOSE REGIMEN(IV BOLUS / SLOW BOLUS) • Calculate the pt’s Ke (from achieved Cpeak & Ctrough, ): Ke = ln (Cpeak/Ctrough)/ ( - tsampling, peak) • Estimate the pt’s t½: t½ = 0.693/Ke • Calculate the Amax: Amax = D / (1 – e-Ke) • Calculate theCmax: • Estimate the pt’s Vd: Vd = Amax / Cmax • Calculate the pt’s CLGenta: CLGenta = Ke x Vd

  12. ADJUSTING GENTAMICIN DOSE REGIMEN (CONT’) • New dose regimen estimation *Use the patient’s PK parameter • Calculate the targeted Cmax target from targeted Cpeak • Estimate the targeted Amax: Amax = Cmax x Vd • Estimate the new  from targeted Cpeak & Ctrough:  = (ln (Cpeak/Ctrough)/Ke ) + tsampling, peak • Dose needed = Amax ( 1 – e-Ke)

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

  14. SINGLE DAILY DOSE THERAPY • One 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 MIC • Less toxicity incidence

  15. SINGLE DAILY DOSE THERAPY (CONT’) • Initiating the therapy: • Initial DM = 5-7 mg x Body Wt • Initial dosing interval is determined by CLcr CLcr(ml/min) >60 40 – 50 30 – 39 Dosing interval 24 H 36 H 48 H • Sampling and dose adjustment: • Sample taken at 8 - 14 hours post infusion • Then 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. Lab results: C&S Klebsiella sp., SrCr 120 mol/L, Urea 9 Suggest the best Gentamicin dose regimen to achieve Cpeak = 8.0 mg/L and Ctrough = 1.0 mg/L.

  18. CASE 2 • Mrs. PG, 70 years old patient was diagnosed to have endocarditis. Body weight is 45 kg. Given IVbolus Gentamicin 100 mg Q8H Lab results: C&S S. aureus., SrCr 150 mol/L, Urea 7, Cpeak = 12.2 mg/L, Ctrough = 3.0 mg/L Adjust the Gentamicin dose regimen to achieve Cpeak = 6.0 mg/L and Ctrough = 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. Was given IVbolus Gentamicin 80 mg Q12H Lab results: C&S P. aeruginosa., SrCr 100 mol/L, Urea 7, On D4 of Gentamicin: Cpeak = 6 mg/L, Ctrough = 0.5 mg/L Immediately after the Ctrough was taken, IVbolus Gentamicin 140 mg Q8H was initiated. Estimate the Cpeak & Ctrough after one dose of this new regimen

  20. THANK YOU

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