1Therapeutic Drug Monitoring of AminoglycosidesJohn C. Rotschafer, Pharm. D.ProfessorCollege of Pharmacy University of MinnesotaObjectivesJohn C. Rotschafer, Pharm. D. Participants will be able to develop a therapeutic drug monitoring planfor aminoglycosides with or without serum concentration time data. Participants will be able to make appropriate decisions as to the need for therapeutic drug monitoring Participants will be able to identify situations appropriate for series or peak/trough pharmacokinetic monitoring situations. Participants will be able to identify an appropriated schedule and time for aminoglycoside therapy. Participants will be able to identify appropriate peak and troughconcentrations for conventional and single daily dosing strategies. Participants will be able to develop a plan to monitor the patient for successful resolution of infection or the development of adverse drug reactions to the aminoglycoside.Conventional vs Single Daily Dose for Aminoglycosides Gentamicin or Tobramycin Conventional ~1.5 mg/Kg Q8H or ~5 mg/Kg/day SDD ~7 mg/Kg as one dose every 24 Hrs Amikacin Conventional ~5 mg/Kg Q8H or 7.5 mg/Kg Q12H SDD 15 mg/Kg as one dose every 24 HrsData Poor or Rich EnvironmentWhat to do when:No data PoorPopulation dataPatient specific trough/peak dataPatient specific series PK data BetterEvaluating Aminoglycoside Dose & Interval without ASCTD Parameters required for evaluation: Age Height in inches Weight Serum creatinineEvaluating Aminoglycoside Dose & Interval without ASCTD Patient weight: Actual body weight (ABW) Lean body weight (LBW) in Kgz Males = 50 + 2.3 (# inches over 5 feet) z Female = 45 + 2.3 (# inches over 5 feet)z Note if LBW > ABW use ABW Dosing body weight (DBW)z For patients >30% over LBWz DBW = LBW + 0.4 (ABW – LBW)2Evaluating Aminoglycoside Dose & Interval without ASCTD Calculated Creatinine Clearance(Crcl) in ml/min Method of Cockcroft and Gault Male = ((140 – Age )* LBW) / (72* Scr) Female = 0.85 (Male) Transform Crcl into Kd using Detli method Kd (Hr-1) = 0.0024 (Crcl) + 0.01 Transform Estimated Kd into T1/2 T1/2(Hrs) = 0.693 / KdInitial Evaluation for Conventional Aminoglycoside Therapy Peak concentrations should be ~ 10 x MIC of the likely bacterial pathogen Troughs should be as low as possible given the circumstances surrounding the patient Dose should be evaluated on a mg/kg/day basis and mg/kg per dose basis using the appropriate body weight parameter Dosing interval should be ~ 2 to 3 T1/2’s plus the hour for drug infusion Try to limit total course of therapy to <5 days to reduce risk of nephrotoxicity or ototoxicityThe Sawchuk-Zaske MethodOne Compartment Modeling of Aminoglycoside Serum Concentration Time DataMethod Originated at University of Minnesota, College of Pharmacy & Used World WideResource: http://www.courses.ahc.umn.edu/pharmacy/6124/tutorials/glycoside_kinetics/kinetics1.htmReference Parameters t = Separation time between two points (Hours) t’ = Time of infusion (Hour) Ko= Rate of infusion (mg/Hr) T = Dosage interval (Hours) Vd= Distribution Volume (L or L/Kg) T1/2 = Half-life (Hrs) Kd= Elimination rate constant (Hr -1) Cpmax= Peak concentration (mg/L or mcg/ml) Cpmin= Trough concentration (mg/L or mcg/ml) Cpo= Reference concentration (mg/L or mcg/ml) Cpt= Concentration of drug separated by t from CpoVdAminoglycosideAddedKo (mg/Hr)Rate of Infusion(Dose/t’)AminoglycosideLostKdOne Compartment ModelAssumption there are no other compartments & that all aminoglycoside distribution occurs during infusionLn Cp(mg/L)Resulting Serum Concentration Time Curve with One Compartment ModelingSlope = - Kdt’T – t’Dosage Interval (hrs)True Peak (Cp-max)True Trough (Cp-min)Cpt = Cpo * e –Kd t3LnConc(mg/L)Time Post Infusion (Hrs)6mg/L3 mg/L2 HrsElimination Constant (Kd) & Half Life (T1/2)Kd = (Ln X1- Ln X2) / (Time X1 - Time X2)Kd = (Ln 6 – Ln 3) / (2 – 4)T1/2 = Ln 2 / KdT1/2 = 0.693/0.34624What Does e-Kd*tDo?What then is 1 - e-Kd*t?Ln Cp(mg/L)TimeXX4 mg/L3 mg/LCpt= Cp0* e-Kd * t3 = 4 * e-Kd * ttLn Cp(mg/L)Using Monoexponetial Equation to Solve For Dosing Interval (T)Slope = - Kdt’T – t’Dosage Interval (hrs)True Peak (Cp-max)True Trough (Cp-min)Cpt= Cpo* e –Kd tCpmin = Cpmax * e –Kd (T-t’)Solve for T = ?Why the Complicated Formula???Vd = Ko (1- e(-Kd*t’))Kd (Cpmax –Cpmin e(-Kd*t’))orVd = Dose / Cp or Change in CpCalculation of Vd Aminoglycoside does not enter the body as bolus but rather in a “zero order” process, an infusion rate (mg/Hr) Aminoglycoside is eliminated in a “first order”process, a constant percent per unit of time (50%/T1/2)Vd = Ko (1- e(-Kd*t’))Kd (Cpmax-Cpmin e(-Kd*t’))XXXXCpt= Cpo* e -Kd * tt’ = 1 HrCpminCpmaxLn Cp(mg/L)Time (Hrs)PreLevel0.25 HrsKo Start4In the Calculation of VdNote: Kdby nature has a negative value but in the term e(-kd *t)you do not multiply -Kdby a negative sign making the value positive andIn the term Ko/Kd, Kdhere must be a positive value or you calculate a - VdAminoglycoside (AG) Pharmacokinetic Parameters Vd is dose sensitive in that if the patient received less drug, Vd will be overestimated & if patient receives more, Vd will be smaller Value of Vd may be result of blood loss, fluid or blood products being administered, 3rdspacing or drug inactivation Value of AG PK parameters may be a function of assay method used  Half-life is dose independent if being evaluated >2 real post infusion valuesTherapeutic Drug Monitoring (TDM) of Aminoglycosides Does the patient require an aminoglycoside? Are levels required? Do you have actual serum concentration time data or are you going to use population data? Is the patient at steady state (i.e. ~3-5 T1/2’s into therapy with scheduled doses given on time)? Steady state assumes patient’s underlying fluid status and renal function remain status quoInitial Evaluation of Aminoglycoside Dose & Interval Aminoglycoside serum concentration time data (ASCTD) available No ASCT data available Far more common situation General rule for conventional aminoglycoside therapy (Assume adult with normal renal function)z Daily dose for gentamicin or tobramycin ~ 5 mg/kg/d Amount per dose ~ 1.5 mg / kg or Single Daily Dose z Daily dose for amikacin ~ 15 mg/kg/d Amount per dose ~ 5 to 7.5 mg / kg or