Aminoglycoside Pharmacokinetics Tom Johns, PharmD, BCPS Director, Pharmacy Services UF Health Shands Hospital Concentration-Dependent vs Independent Bacterial Killing Craig, et al Scand J Infect Dis, 1991;Suppl (74). 5/9/2014 2 Elimination Eliminated primarily by glomerular filtration in the kidney  Half-life  Adults: 2-4 hours  Children: 0.5-2.5/Neonates: 2-9 hours  Prolonged in renal insufficiency  Removed by hemodialysis (~ 10% per hour); removed less by peritoneal dialysis  5/9/2014 3 Tri-phasic Elimination Alpha – distribution of drug from blood to tissues Beta – elimination of drug through the kidneys Gamma – very slow release of drug from tissue binding sites (kidneys, ears); concentration not detectable by current assays 5/9/2014 4 Adult Dosing Guidelines  Determine dose and interval necessary to achieve desired concentrations Site of Infection Gent/tobra conc (mcg/mL) CF, chronic bronchiectasis Pneumonia, septic shock Bacteremia, skin/soft tissue, intra-abdominal, pyelonephritis UTI Gram(+) synergy Peaks 10-12; trough < 1.5 Peaks 8-10; trough < 1.5 Peaks 6-8; trough < 1.5  Peaks 4-6; trough < 1.5 Peaks 3-5; trough 0.5-1.5 Amikacin range (mcg/mL): peaks 20-35; trough < 8 5/9/2014 5 Aminoglycoside Blood Draws  Peak-30 minutes after end of infusion (dose usually infused over 30 minutes)  Trough-immediately prior to dose (in reality most schedule the trough 30 minutes prior to next dose) 5/9/2014 6 Stepwise Dose Individualization 1) Collect patient specific information 2) Determine dosing weight 3) Estimate volume of distribution (Vd) 4) Estimate creatinine clearance 5) Estimate elimination rate constant (ke) 6) Estimate serum half-life (t1/2) 7) Calculate dosing interval 8) Calculate dose 5/9/2014 7 Patient Case #1 A 35 year old WF is admitted to the hospital with a diagnosis acute pyelonephritis. The physician in charge orders ampicillin 1g iv q4h and gentamicin (to be dosed by pharmacy). Her TBW is 70 kg and height is 160 cm. Serum creatinine is 0.7 mg/dl on the day of admission. 5/9/2014 8 1-Patient Specific Information Age, sex  Height  Total body weight (TBW)  Renal function: serum creatinine  Infectious disease being treated  goal peak/trough concentrations  5/9/2014 9 2-Dosing Weight    Ideal body weight (IBW) IBW (males) = 50 kg + 2.3 (ht-inches > 60 in) 50 kg + 0.9 (ht-cm >150 cm) IBW (females) = 45.5 kg + 2.3 (ht-inches > 60 in) 45.5 kg + 0.9 (ht-cm >150 cm) Adjusted body weight (ABW) - if TBW > 20% over IBW ABW= IBW + [(TBW-IBW) 0.4] If TBW < IBW, use TBW for all calculations 5/9/2014 10 3-Volume of Distribution Normal adult s/p surgery, renal failure, ascites Cystic fibrosis, burns Child Neonate Range Average (L/kg) (L/kg) 0.22-0.33 0.25 0.27-0.32 0.3-0.35 0.3-0.45 0.4-0.7 0.30 0.32 0.37 0.55 Use dosing weight in step #2 for this calculation. 5/9/2014 11 4-Calculate Creatinine Clearance  Cockcroft-Gault Equation CrCl (mL/min) = (140-age) IBW (x 0.85 for females) 72 (SCr) SCr = serum creatinine in mg/dL 5/9/2014 12 5-Elimination Rate Constant (ke)     Estimate based on population equation Dettli Equation: ke (h-1) = 0.00293 (CrCl) + 0.014 (gent/tobra) ke (h-1) = 0.0024 (CrCl) + 0.01 (amikacin) 6-Half-life (t1/2)  t1/2 (hr) 5/9/2014 = 0.693/ke 13 7-Calculate Dosing Interval (τ) τ= ln (Cpmax desired/Cpmindesired) ke + ti ti= infusion time (hours) τ=dosing interval (hours)   Shortcut: Estimate dosing interval by multiplying t1/2 by 3 Round to nearest conventional interval: 8,12, 18, 24,36,48 5/9/2014 14 8-Calculate Dose Dose = (Cpmaxdesired)(ke)(Vd)(ti)(1-e-keτ ) (1-e-keti)  ti=infusion time (hrs), τ=dosing interval (hrs)  Round doses to nearest 10 mg for adults for adults  Shortcut: 1mg/kg for low peak range, 2 mg/kg for mid-peak range, 2.5-3 mg/kg for high peak range 5/9/2014 15 Serum Drug Concentration Evaluation 1) Plot measured concentrations on graph 2) Determine patient’s true PK parameters: ke, t1/2, Cpmax, Cpmin, Vd 3) Adjust dose and/or interval to achieve desired serum drug concentrations Cpmax = extrapolated peak Cpmin = extrapolated trough, true trough Used to calculate Vd Clinical peak=1/2 hour after end of infusion (this is our targeted peak for efficacy determination) 5/9/2014 16 Plot Serum Concentrations 5/9/2014 17 5/9/2014 18 Calculate PK Parameters      ke = ln (C2/C3) ∆t t1/2 = 0.693/ke Cpmax = C2 ∆ t = τ – infusion time – time from measured trough to true trough – time from measured peak to true peak Extrapolated peak occurs at end of infusion, t = difference between ext. peak (Cmax*) and measured peak (C2) e-(ke)(t) Clinical peak = Cpmaxe –ke(0.5) Clinical peak occurs ½ hour after end of infusion 5/9/2014 19 Calculate PK Parameters   Cpmin = (C3)e-(ke)(t) Vd= True trough occurs immediately prior to dose. t = difference between true trough (Cmin*) and measured trough C1/C3 ( D/ti) [1-e-(ke)(ti)] ke [Cpmax- (Cpmine-(ke)(ti))] Use extrapolated peak and true trough for this calculation. 5/9/2014 20 Calculate New Dose and/or Interval     Calculate using patient’s true PK parameters Subtherapeutic peak  Increase dose Supratherapeutic trough  Lengthen dosing interval Supratherapeutic peak with non-toxic trough  Lower dose 5/9/2014 21 Monitoring for Toxicity    Renal/ototoxicity associated with sustained trough > 2 mcg/mL Repeat trough level every 5-7 days depending on:  changes in patient’s renal function  changes in SCr  changes in urinary output Monitor for ototoxicity:  hearing loss, tinnitus, vertigo 5/9/2014 22 Patient Case #2 DP is a 58 year old male admitted with prostate cancer. Admitting labs were: SCr: 1.2 mg/dl TBW=90 kg Height=176 cm Initial blood culture was negative; urine culture grew >100,000 gram negative rods (identification and sensitivities were pending). The physician asked you for a recommendation for tobramycin dosing. 1. What is the goal peak and trough? 2. Calculate estimated ke, half-life, volume of distribution and an initial regimen for this patient. 5/9/2014 23 Patient Case #2 DP is started on tobramycin (120 mg IV q12h) based upon your recommendation. Peak and trough to be drawn around third dose. The 3rd dose is infused from 1800-1830. Laboratory values are reported as : Trough 2 mcg/ml drawn at 1730 Peak 8 mcg/ml drawn at 1900 1. 2. 3. 4. Calculate the ke and t1/2. Calculate the Cpmax, Cpmin, and Vd. Calculate the clinical peak. What is your recommendation for further therapy 5/9/2014 24 Once Daily Dosing of Aminoglycosides 5/9/2014 25 Aminoglycoside Pulse Dosing  Rationale:  Concentration-dependent killing  Post-antibiotic effect  Period of continued bacterial growth suppression despite serum levels less than MIC of organism  Tissue penetration  Toxicity related to sustained elevated troughs  Renal accumulation is saturable 5/9/2014 26 Aminoglycoside Pulse Dosing     Gentamicin and tobramycin  7 mg/kg based on dosing weight Amikacin  15-20 mg/kg based on dosing weight Obtain random level and apply to nomogram Repeat random level every 5-7 days (based on clinical judgment)  More frequent if Scr rises ≥ 0. 5 mg/dL above baseline 5/9/2014 27 Once-a-day Aminoglycosides These values are double for amikacin. 5/9/2014 28 Aminoglycoside Pulse Dosing  Avoid in:  CrCl < 40 mL/min (Age > 65)  Pregnancy  Endocarditis 5/9/2014 29 Case #1 JW is a 41y/o WM diagnosed with a ruptured appendix with abscess. Antimicrobial therapy (along with surgery) was initiated with piperacillin 5gm iv q8h, metronidazole 500mg iv q12h, and gentamicin per protocol. Ht 165cm, Wt 100kg, Scr 1.5 mg/dL    Is this patient a candidate for pulse dosing? Calculate appropriate initial dose and interval. Describe appropriate monitoring parameters. 5/9/2014 30 Case #2 YR is a 24y/o BF s/p vaginal delivery 2 days ago. She has been spiking a fever during this time; postpartum endometritis is suspected. Antimicrobial therapy with ampicillin 1gm iv q6h, clindamycin 600mg iv q8h, and tobramycin per protocol. Cultures are pending. Ht 157cm, TBW 60kg, SCr 0.5 mg/dL  Is this patient a candidate for pulse dosing aminoglycoside?  If so, what dose is appropriate?  First dose is administered at 1200.  Random tobramycin level was drawn at 2200 and reported as 4.2 mcg/ml.  What is your recommended dosing interval? 5/9/2014 31 Clinical Pearls      Carefully assess sampling and dose administration times for accuracy Don’t allow sample to sit for extended periods of time at room temperature Review nursing notes to identify:  problems with administration (IV access, patient off the floor)  changes in urine output Visit the patient to assess:  accuracy of physical description (height, weight, age)  disease resolution (WBC count, fever) Monitor culture and sensitivity results to determine appropriateness of aminoglycoside 5/9/2014 32