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. • 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.

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)

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.

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

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

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

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

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

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

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

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)

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

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

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

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

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.

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?

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

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Clinical Pharmacokinetics of AMINOGLYCOSIDES