POPULATION PHARMACOKINETICS.docx

AMINOGLYCOSIDES (AG) Spectrum of Activity ONLY gram negative aerobic organisms Can be used for synergy for some gram positive organisms Must be combined with a cell wall active agent  Aminoglycosides, A History Produced by Streptomyces tenebrarius Drugs within class: gentamicin, tobramycin, ami...

AMINOGLYCOSIDES (AG) Spectrum of Activity ONLY gram negative aerobic organisms Can be used for synergy for some gram positive organisms Must be combined with a cell wall active agent  Aminoglycosides, A History Produced by Streptomyces tenebrarius Drugs within class: gentamicin, tobramycin, amikacin, streptomycin, plazomicin Mechanism of Action: Inhibits 16S portion of the 30S mRNA AKA: protein synthesis inhibitor ~ Supplemental MoA: binds to LPS of gram-negative organisms creating transient holes Bactericidal  PD parameter: Peak concentration (Cp) over MIC Can also have a long post – antibiotic effect Absorption: terrible oral absorption Formulations: IV, IM, Inhaled, eye drops IV is generally infused over 30 to 60 minutes Distribution: Hydrophilic, positively charged, low protein binding Vd limited to vasculature of 0.2 – 0.3 L/kg -> use IBW with dosing Metabolism: doesn’t really occur Elimination: predominantly renal Lots of toxicity to worry about Nephrotoxicity associated with elevated troughs Ototoxicity associated with extremely high peaks Dosing Overview Traditional Dosing TDM is Always Necessary with AG but Timing Depends on the Strategy Narrow therapeutic index and high risk for toxicity Traditional Dosing TDM: Peak 1 hr after the 2nd or 3rd dose Efficacy parameter Trough 30 min prior to 3rd or 4th dose Toxicity parameter Drug infusion times: Gentamicin/ Tobramycin/Amikacin: 1 hour ALWAYS assess if the levels were appropriately drawn Traditional Dosing Goal Levels Cpk goal: 8-10 times greater than the MIC for effective kill Ctr goal: undetectable to avoid accumulation Steady state not achieved because the kidneys need a break without drug Less concern for resistance because of the post-antibiotic effect (PAE) Step- Wise Approach to Calculate Initial Regimen with Traditional Dosing Determine the appropriate body weight Calculate the CrCl Calculate the Ke Calculate the Vd Choose the appropriate desired Cpk and Ctr Calculate the τ Round to the nearest 8, 12, 24, 36, 48, or 72 hrs Calculate the Ko Double check the regimen is okay. Calculate the expected peak and trough for the selected τ & Ko This step is important as steps 6 and 7 involve rounding Population PK vs Weight Based Initial AG Traditional Dosing Indicated When You Don’t Have Patient Specific PK Data Synergy Dosing Not intended as monotherapy MUST be combined with a cell wall active agent for gram- positive organisms Only really used with gentamicin Dosing: Typical regimen: 1 mg/kg IV q8h (assuming good CrCl) Same IBW rules TDM: No peak levels generally. We care more about the trough Want a gentamicin trough that is undetectable (< 1 - 2 mg/L) EXTENDED INTERVAL (EI) DOSING Dosing Overview Overview of Traditional vs Extended Interval (EI) Dosing Strategies Extended Interval Dosing Preferred dosing strategy General: higher doses with longer intervals Must know when EI dosing is NOT appropriate Optimizes pharmacodynamics of the drug ↑ Concentration: MIC dependent killing Takes advantage of the PAE ↓ chance for resistance Decreases risk for toxicity Allows for undetectable troughs -> AG free period ↓ Nephrotoxicity TDM is Always Necessary with AG but Timing Depends on the Strategy Narrow therapeutic index and high risk for toxicity Extended Interval: Random 6-14 hrs after start of infusion Expected infusion times: Gentamicin/ Tobramycin/Amikacin: 1 hour Goal levels: Dose Adjustments What Can Go Wrong? Labs drawn while drug is infusing Patient in procedure during scheduled labs Nurse holds the dose because of a previous level Drug rescheduled but labs are not rescheduled Patient refuses labs Drug not given Imagine the possibilities……… AG Regimen Adjustments HARTFORD NOMOGRAM Advantages and Disadvantages of Hartford Nomogram Advantages ↓ Calculations Optimizes PD of drug Uses PAE Disadvantages Based on pop PK Cannot be individualized Cannot extrapolate to all Hartford Nomogram Dose: Weight based: Gentamicin/ Tobramycin: 7 mg/kg Amikacin 15 mg/kg Frequency: Based on CrCl in table Levels – wonky Random level 6 – 14 hrs after the start of the infusion and plot on the Hartford Nomogram to determine if the regimen needs adjustment NOTE: For Amikacin, divide the level by 2 and plot on the graph Step- Wise Approach to Hartford Nomogram EI Initial Dosing Check for EI exclusions Determine the appropriate body weight Calculate the CrCl Calculate the appropriate weight based dose Utilize the CrCl to determine the frequency Summary AGs are concentration dependent protein synthesis inhibitors Correlate efficacy with appropriate peak levels LOTS of toxicities! Correlate nephrotoxicity with a high trough AGs are polar molecules with a small volume of distribution -> use IBW Max CrCl = 120 mL/min Rounding guidance in the question Dosing strategies: Traditional dosing Population PK Adjust levels to reach goal Synergy Extended interval Weight & CrCl based Adjust levels to reach goal Hartford nomogram to adjust frequency Practice!