Introduction to Pharmacokinetics and Pharmacodynamics Diane M. Cappelletty, Pharm.D. Assistant Professor of Pharmacy Practice Wayne State University August, 2001
Vocabulary Clearance Renal elimination: filtration aminoglycosides are primarily filtered AMG clearance best approximates GFR beta-lactams (penicillins and cephalosporins) secretion penicillin has highest secretion rates > 80% other beta-lactams are secreted to varying degrees (0-60%)
Vocabulary Clearance Hepatic or Hepatobiliary: antibiotics not routinely monitored dosage adjustments in hepatic insufficiency are not clearly defined macrolides (erythromycin, clarithromycin, azithromycin) clindamycin metronidazole nafcillin, oxacillin, ceftriaxone
Vocabulary Volume of distribution - depends upon: hydrophilicity and lipophilicity of the drug the size of the patient aminoglycosides & β-lactams ~ 0.25-0.3 L/kg hydrophilic drugs, distributes into extracellular water spaces, NOT into fat tissue dehydrated or cachectic patients have a smaller Vd larger for fluid overloaded patients, observed frequently in ICUs for AMG dosing weight is IBW or if obese an adjusted BW
Vocabulary Half-life - time required for a drug concentration to decrease by one-half AMG with normal renal function ~ 2-3h Penicillins with normal renal function ~ 1h Cephalosporins with normal renal function ~ 2h Vancomycin with normal renal function ~ 4-6h
Vocabulary Distribution Phase - time from the end of the infusion for drug concentrations to equilibrate between the tissue and blood Most critical in evaluating peak drug concentrations AMG - complete ~ 15-30 minutes after end of infusion Elimination Phase determination of elimination rate constant
Pharmacokinetics body s effect on the drug Overview half-life, Vd, ke, Cmax, Cmin, protein binding Pharmacodynamics the drugs effect on the biological system (organism) Synergy relationship of drug concentrations to killing activity Post antibiotic effect Methodologies and interpretations
MICs and MBCs MIC (minimum inhibitory concentration) lowest drug concentration that inhibits bacterial growth MBC (minimum bactericidal concentration) lowest drug concentration that kills bacteria MBCs are not routinely tested in clinical labs 32 16 8 4 2 1 Drug A Drug B Drug C Drug D Drug E
Bacteriostatic vs. Bactericidal 0 2 4 6 8 10 12 14 16 18 20 22 24 1 2 3 4 5 6 7 Static Cidal Time (h) B a c t e r i a l C o u n t l 1 0 ( C F U / m l
Pharmacodynamics Two classifications related to drug concentration & killing activity Concentration Independent Concentration Dependent Parameters Time above MIC Peak to MIC ratio AUC to MIC ratio
Concentration Independent Killing Maximal killing activity achieved at about 4-5 times the MIC Pharmacodynamic parameter most important is T > MIC Cell wall active agents penicillins, cephalosporins, glycopeptides Log 10 CFU/ml 9 Ticarcillin 8 7 6 5 4 3 2 0 2 4 6 Time (h) Control 1/4 MIC 1 MIC 4 MIC 16 MIC Craig, Ebert. Scand J Infect Dis 1991.
Concentration Independent Killing To improve the pharmacodynamic profile of betalactam drugs and/or vancomycin, shortening the dosing interval is significantly more beneficial than increasing the dose Cefepime half-life ~ 2 hrs, dosed q8 or 12 hours, MIC = 2-4 mcg/ml time 1 gram 2 gram 0h 70 mcg/ml 140 mcg/ml 2h 35 70 4h 17.5 35 6h 8.75 17.5 8h 4.4 8.75 10h 2.2 4.4 12h 1.1 2.2
Schematic of T > MIC Concentration µg/ml 140 120 100 80 60 40 20 Drug conc. MIC 8 g/ml (7.8 12)*100 = 65% 0 0 2 4 8 12 13 16 20 24 Time (h)
AUC:MIC Ratio Often important parameter for quinolones For gram-negative infections if ratio > 125 there is a good correlation to a good clinical outcome For gram-positive infections the ratio has yet to be established proposed value is > 30
Concentration Dependent Killing Killing activity increases with increasing drug concentrations, maximal killing is achieved at about 20-30 times the MIC Pharmacodynamic parameter most important is Peak:MIC Intracellular active agents aminoglycosides, fluoroquinolones Log 10 CFU/ml 9 8 7 6 5 4 3 2 0 Tobramycin 2 4 6 Time (h) Control 1/4 MIC 1 MIC 4 MIC 16 MIC 64 MIC Craig, Ebert. Scand J Infect Dis 1991.
Post Antibiotic Effect Refers to the time period after removal of an antibiotic (or subinhibitory concentrations) during which there is no bacterial growth AMG conc 12 10 8 6 4 2 MIC 0 0 2 4 6 8 10 12 14 Time (h) Bacterial Colony Count AMG Conc Bacterial Growth
Post Antibiotic Effect Type of antimicrobial agent Against gram-negative bacilli Penicillins, aztreonam, trimethoprim, & sulfonamides possess minimal to no PAE Cephalosporins?? short to intermediate duration (0.5-2h); inconsistent results Aminoglycosides, imipenem, fluoroquinolones intermediate to long (2-3h or more)
Post Antibiotic Effect Mechanism(s) of the PAE Unknown, however, theory is that for each agent & organism the exact mechanisms vary and are multiple Time required for new PBPs to be synthesized Time required to synthesize new ribosomes Time required for dissociation of the antimicrobial/ribosome complexes
PAE & Dosing Regimen 9 Concentration (mcg/ml) 8 7 6 5 4 3 2 1 PAE Divided dose MIC 0 0 1 2 4 8 10 12 13 16 20 24 Time (h)
Drawing Blood for Determination of Serum Levels Concentration (mcg/ml) 10 8 6 4 2 False C max, and false elimination rate (slope is falsely steep) True C max and elimination rate 0 0 1 2 3 4 5 6 7 8 9 10 Time (h)
Antibiotics Dosed Pharmacokinetically Therapeutic and toxic concentration range are very close to each other Aminoglycosides (AMG) (always) gentamicin, tobramycin, amikacin peak concentration dependent upon dosing method and type of infection trough concentration less than 1 mcg/ml Vancomycin (sometimes) peak concentration not clinically relevant for most infections trough concentration 5-10 mcg/ml
Aminoglycoside toxicities Nephrotoxicity and ototoxicity are associated with AUC or elevated trough concentrations NOT peak concentrations Nephrotoxicity and ototoxicity risk factors renal dysfunction age duration of therapy liver dysfunction concomitant use of other toxic drugs
AMG Divided Daily Dosing Gentamicin/Tobramycin 1-2 mg/kg q?h Amikacin 7.5 mg/kg q?h dosing interval increases as renal function decreases to maintain a trough concentration < 1 mcg/ml (gent & tob) < 4 mcg/ml (amik) q12h, q24h, q36h, q48h, q72h Targeted Peak Serum Concentrations Disease State Gent/Tob µg/ml Amik µg/ml Cystitis 3-4 20-25 All other infections 6-8 30-35 Pneumonia 8-10 30-35
AMG High Dose Once Daily Gentamicin/Tobramycin 4-7 mg/kg q24h Amikacin 15 mg/kg q24h Trough concentrations should always be nondetectable Targeted Peak Serum Concentrations Disease State Gent/Tob µg/ml Amik µg/ml Cystitis 6-8 30-40 All other infections 12-16 50-70 Pneumonia 16-20 60-80
Loading Dose Equation Loading Dose = Vd * desired C max If a patient is 60 kg then Vd = 0.3 L/kg * 60 kg = 18 L Disease state is osteomyelitis and gentamicin is the drug requested C max is 6-8 mcg/ml (mg/l) for DDD, Loading dose = 18 L* 8 mg/l = 144 mg dosing interval is renal function dependent or if using HDOD then the target peak is 12-16 and LD = 18 L * 14 mg/l = 252 mg dosing interval is q24h
Synergy The effect of the drug combination is greater than the sum of the effects of the individual agents Mechanism: increased uptake of one drug caused by the second drug (AMG + beta-lactam) sequential blockade (TMP/SMX) beta-lactamase inactivation (amoxicillin/clavulanate)
Synergy Traditional testing for synergy: Fractional Inhibitory Concentration (FIC) FIC < 0.5 = synergism; FIC > 4 = antagonism Killing Curves > 2 log increase in killing over the most active single agent Synergy testing is not routinely performed in clinical laboratories. Exception: screening for likelihood of synergy of gentamicin or streptomycin with ampicillin or vancomycin against entercocci
Synergy Rationale for combination therapy: enhance killing of organism (synergy) minimize the development of resistance Combinations routinely used in clinical practice for the synergistic effect: against gram-negative bacilli aminoglycosides + beta-lactams against enterococci gentamicin or streptomycin + ampicillin gentamicin or streptomycin + vancomycin against staphylococci nafcillin or vancomycin + gentamicin + rifampin
Example Test Question Pharmacodynamics relate killing activity of antibiotics to pharmacokinetic parameters. Which of the following parameters is most associated with the killing activity of quinolones? A. peak:mic ratio B. T > MIC C. AUC:MIC ratio D. A and C
In Conclusion... Pharmacokinetic parameters half-life, clearance, volume of distribution, C max, C min Pharmacodynamic parameters T > MIC, Peak:MIC ratio, AUC:MIC ratio Concentration Dependent vs. Independent killing Post-antibiotic effect Synergy Most important with concentration dependent drugs Useful in treating both gram-positive and gram-negative infections