3C-Pharmacodynamics: actual data - UCL

Pharmacodynamics: actual dataHow shall we dosetime-dependentconcentration-dependentantibiotics ?With the support of Wallonie-Bruxelles-InternationalUCL PK/PD Course April 20113C-1

from pharmacokinetics to pharmacodynamics...0.4Pharmacokineticsconc. vs timePharmacodynamicsconc. vs effectConc.Effect0.00 25TimeConc. (log)10-3Effect1PK/PDeffect vs time00TimeUCL PK/PD Course April 20113C-2

from pharmacokinetics to pharmacodynamics...ConcentrationC maxAUC > MICCmax / MICAUC / MICTime ~ conc > MICMICt > MIC0 6 12 18 24Time (h)UCL PK/PD Course April 20113C-3

Main PK/PD properties of antibioticsAvailable antibiotics can be divided in 3 groups :• time - dependent (T > MIC)• AUC / MIC - dependent• both AUC / MIC and peak / MIC -dependentUCL PK/PD Course April 20113C-4

Antibiotics Group # 1(after W.A. Craig, 2000; revised 2002 and 2003)1. Antibiotics with time-dependent effectsand no or little persistent effectsAB-lactamsPK/PD parameterTimeaboveMICGoalMaximizethe exposuretimeUCL PK/PD Course April 20113C-5

How long should you stay above the MIC ?40 %Moderate infections• cefotaxime• neutropenic mice• K. pneumoniae• lung infectionSerious infections100 %UCL PK/PD Course April 20113C-6

More experimental datawith penicillins, cephalosporins and carbapenems ...different pathogens• same shape ofdose response• diff. in T > MICfor a static effect(penicill. > carbap.)• diff E max(penicill. < carbap.)Andes & Craig Int. J. Antimicrob. Agents 2002, 19: 261-268UCL PK/PD Course April 20113C-7

1. Increase the unitary dosis ?How to optimize T > MIC ?ConcentrationMICdosis = 1Time (h)UCL PK/PD Course April 20113C-8

1. Increase the unitary dosis ?How to optimize T > MIC ?Concentrationdosis = 2But useless peak !!MICdosis = 1Time (h)gain...UCL PK/PD Course April 20113C-9

How to optimize T > MIC ?2. Increase the number of administrations ?ConcentrationSeems more logical …MICTime (h)UCL PK/PD Course April 20113C-10

-lactams : applications...• Respiratory tract infections (oral route)…• Serious infections (intravenous route)UCL PK/PD Course April 20113C-11

Optimizing dosage for amoxycillinoral amoxycillin (MIC = 1 mg/l)T > MIC (%)100806040204X/day3X/day2X/day1X/dayT > MIC40 - 60 %00 500 1000 1500 2000individual dosisUCL PK/PD Course April 20113C-12

Optimizing dosage for amoxycillinoral amoxycillin (MIC = 1 mg/l)T > MIC (%)100806040204X/day3X/day2X/day1X/dayT > MIC40 - 60 %00 500 1000 1500 2000Appropriate dose =500 mg 3-4 X/d or 1000 mg 2 X/dindividual dosisUCL PK/PD Course April 20113C-13

Optimizing dosage for cefuroximeoral cefuroxime (MIC = 1 mg/l)100804X/day3X/dayT > MIC (%)6040202X/dayT > MIC40 - 60 %01X/day0 125 250 375 500individual dosisUCL PK/PD Course April 20113C-14

Optimizing dosage for cefuroximeT > MIC (%)100806040200oral cefuroxime (MIC = 1 mg/l)4X/day3X/day2X/day1X/day0 125 250 375 500Appropriate dose =125 mg 4 X/d or 250 mg 3 X/d or 500 mg 2 X/dindividual dosisT > MIC40 - 60 %UCL PK/PD Course April 20113C-15

Oral - lactams and S. pneumoniaeAn MIC of 2 µg/ml is the limit that you can coverin optimal conditions, i.e. with a 3 x / dayadministration and a total daily dosis of 3 g for amoxicillin 1-1.5 g for cefuroxime-axetilPK/PD breakpoint for oral - lactams:MIC < 2 µg/mlUCL PK/PD Course April 20113C-16

-lactams : applications...• Respiratory tract infections (oral route)…• Serious infections (intravenous route)UCL PK/PD Course April 20113C-17

Typical pharmacokinetics of an IV -lactamtimeserum concentration for(hours) 0.5 g 1 g 2 g2 25 50 1004 12.5 25 506 6 12 258 3 6 1210 1.5 3 612 0.75 1.5 3* Single administration unique; half-life 2h ; V d= 0.2 l/kgUCL PK/PD Course April 20113C-18

Typical pharmacokinetics of an IV -lactamtimeserum concentration for(hours) 0.5 g 1 g 2 g2 25 Where would 50 you 100 like to be ?4 12.5 25 506 6 12 258 3 6 1210 1.5 3 612 0.75 1.5 3* Single administration unique; half-life 2h ; V d= 0.2 l/kgUCL PK/PD Course April 20113C-19

Optimisation of IV -lactamsfor "difficult" organisms• 2 g every 12 h T > MIC = 100 %if MIC 3 mg/L !• 2 g every 8 h T > MIC = 100 %if MIC 12 mg/LMore frequent administrations is the best way toincrease the activity of -lactams in difficult-to-treatinfections...PK / PD breakpoint forIV -lactams : MIC < 8 µg/mlUCL PK/PD Course April 20113C-20

3. Continuous infusionCan we do still better ?ConcentrationConcentration always above the MIC !MICTime (h)UCL PK/PD Course April 20113C-21

Yes :Continuous infusion: the solution ?• Optimized mode of administration• Possibility to obtained stable concentrations as high as20 to 40 mg/LBut be careful …• To the stability of the molecule– the -lactam ring is intrinsically breakable … temperature !!!• To incompatibilities with other molecules alsoadministered by continuous infuisonCaution rules need to be respected ….UCL PK/PD Course April 20113C-22

Yes :Continuous infusion: the solution ?• Optimized mode of administration• Possibility to obtained stable concentrations as high as20 to 40 mg/LThere will be a special course on-lactams by continuous infusion !!But be careful …• To the stability of the molecule– the -lactam ring is intrinsically breakable … temperature !!!• To incompatibilities with other molecules alsoadministered by continuous infuisonCaution rules need to be respected ….UCL PK/PD Course April 20113C-23

Antibiotics Group # 2(after W.A. Craig, 2000; revised 2002 and 2003)2. Antibiotics with time-dependent effects,no or little influence of concentration,but marked persistent effectsABglycopeptidestetracyclinesmacrolidesstreptograminsoxazolidinonesPK/PD parameterAUC / MICGoaloptimizethe amount ofantibioticUCL PK/PD Course April 20113C-24

Antibiotics Group # 3(after W.A. Craig, 2000; revised 2002 and 2003)3. Antibiotics with concentration-dependentbactericidal activity and prolonged persistenteffects (post-antibiotic effects)ABaminoglycosidesfluoroquinolonesdaptomycinPK/PD parameterPeak andAUC / MICGoaloptimize thepeak andthe amount ofantibioticUCL PK/PD Course April 20113C-25

Aminoglycosides: get a peak !UCL PK/PD Course April 20113C-26

Aminoglycosides: get a peak !Peak/MIC > 81. Appropriate mode ofadministrationIV route2. Calculation of the necessarypeak valueminimal peak: = MIC x 83. Calculation of the adequate dosispeak = dosis / Vddosis = peak x Vddosis = MIC x 8 x VdUCL PK/PD Course April 20113C-27

Aminoglycosides: get a peak !243 mg / kg - 1 X day20concentration (mg/l)16128400 4 8 12 16 20 24time (h)MIC = 2 peak/MIC ~ 6MIC = 0.5 peak/MIC ~ 24* aminoglycoside with half-life= 1 h and V d = 0.25 l/kgUCL PK/PD Course April 20113C-28

Aminoglycosides: get a peak !Increase the dose!246 mg / kg - 1 X jour20concentration (mg/l)16128400 4 8 12 16 20 24time (h)MIC = 2 peak/MIC ~ 12MIC = 0.5 peak/MIC ~ 48* aminoglycoside with half-life= 1 h and V d = 0.25 l/kgUCL PK/PD Course April 20113C-29

Aminoglycosides: which dosis for which MIC ?peak/MICdosis peak (mg/L) if MIC =(mg/kg) for V d = 0.25 l/kg 4 2 1 0.51 4 1 2 4 82 8 2 4 8 163 12 3 6 12 244 16 4 8 16 326 24 6 12 24 488 32 8 16 32 64UCL PK/PD Course April 20113C-30

Aminoglycosides: which dosis for which MIC ?peak/MICdosis peak (mg/L) if MIC =(mg/kg) for V d = 0.25 l/kg 4 2 1 0.5There will be a special course on1 4 1 2 4 82aminoglycosides 8 dose optimization 2 4 8 ! 163 12 3 6 12 244 16 4 8 16 326 24 6 12 24 488 32 8 16 32 64UCL PK/PD Course April 20113C-31

Optimization of aminoglycoside usagedo not try to treat with aminoglycosides bacteria with MIC• > 2 µg/ml for molecules with maximal daily dosis of 6 mg/kg• > 4 µg/ml for molecules with maximal daily dosis of 15 mg/kgPK / PD breakpoints for AG• Genta, Netil, Tobra : 2 µg / ml• Amika / Isépa : 4 µg / mlUCL PK/PD Course April 20113C-32

Fluoroquinolones: get a peak and an AUC !increase the amount administered,in order to optimize AUC/MICConcentrationMICPeak/MICand peak/MICAUC/MICshould be > 125should be > 10Get both a peak and a AUC !!Time (h)MIC data: J. Verhaegen et al., 2001UCL PK/PD Course April 20113C-33

How to optimize the AUC / CMI ratio ?AUC = dosis / ClAdjust the daily dosis~ target AUCAdapt the number of administrations~ pharmacokinetics of the drugUCL PK/PD Course April 20113C-34

AUC and peak after one dose are directly relatedto this dose10a “theoretical” example...Concentration3 5 2.51 gAUC= 2410.5 gAUC= 12.3 1.5 0.750Time (hours)6UCL PK/PD Course April 20113C-35

24h-AUC is inversely related to the drug clearance(BUT so is NOT the peak …)101ga “theoretical” example... 5Concentration31t½ 1 ht½ 0.5 ht½ 2 hAUC= 48AUC= 24.3AUC= 120Time (hours)6UCL PK/PD Course April 20113C-36

24h-AUC is correlated to the number of unit doses(BUT, again, so is NOT the peak …)10 5a “theoretical” example...Concentration1g2 x 1g31AUC= 48.3AUC= 240Time (hours)12UCL PK/PD Course April 20113C-37

PK/PD of fluoroquinolones in a nutshellRemember:• 24h-AUC is proportional to the daily dose• peak is proportional to the unit dose...• get a 24h-AUC /MIC > 125, and• get a peak / MIC ratio > 8efficacy• get this with the total daily doseand the appropriate unit dose …UCL PK/PD Course April 20113C-38

AUC / MIC = 125 : a magic number ?Patients respond to quinolonesas a function of the 24 h-AUC ofthe quinolone they receive andthe MIC of the offendingorganism(example for Gram - infectionsseen in the "Methods")Forrest et al (1993) AAC 37:1073-81.UCL PK/PD Course April 20113C-39

But remember that, for Gram (+),the immune status is critical ... (as seen in the methods)Relationship Between 24 Hr AUC/MIC and Mortalityfor Fluoroquinolones against S. pneumoniae in Immunocompetent vs.Immunocompromised animal ModelsPercent mortality100806040200Emax at30 ...Percent mortality100806040200Emax at125 ...1 2.5 5 10 25 50 10024 Hr AUC/MICnon-neutropenic3 10 30 100 300 100024 hr AUC/MICneutropenicAdapted from W.A. Craig : 7th ISAP Educational Workshop, San Diego, CA, 2002UCL PK/PD Course April 20113C-40

Defining PK/PD breakpoints for fluoroquinolonesPK/PD Bkpts (mg/L)Drug Dosage AUC/MIC peak / MIC(mg/24h) (24h)norfloxacin 800 0.1 0.2ciprofloxacin 500 0.1 0.2ofloxacin 400 0.2-0.4 0.3 - 0.4levofloxacin 500 0.4 0.4 - 0.5moxifloxacin 400 0.4 0.4UCL PK/PD Course April 20113C-41

Adjust the dosis to the MICDaily dosage of AUC * MIC for anlevofloxacin AUC 24h /MIC = 125250 28 0.2500 56 0.41000 112 0.8* based on normal half-lifes;CL ~ 100 mg/dldoses for an adult of 65 kgUCL PK/PD Course April 20113C-42

But keep the unitary dose in the allowed limit …!Peak -related side effects :SNC toxicityInhibition of CYP 450 activitychondrotoxicityphototoxicityUCL PK/PD Course April 20113C-43

Choose the most active moleculedrug Dosage AUC * MIC for MIC(mg/24h) AUC/MIC = 125 S. pneumoofloxacin 400 66 0.5 2levofloxacin 500 73 0.4 1ciprofloxacin 1000 40 0.3 0.5-2moxifloxacin 400 48 0.4 0.01-0.5UCL PK/PD Course April 20113C-44

PK/PD: take home message1. For each drug, choose on a PK/PD basis the appropriate• scheme of administration• daily dosis2. Adapt the dosage to the susceptibility of the target organism,• based on MIC data for the individual patient• based on local epidemiologyUCL PK/PD Course April 20113C-45

PK/PD : from today to tomorrowtoday : applying these conceptscan help us to reachan optimized efficacybut let's prepare tomorrow:how can we use this scienceto avoid resistance development ?Section 4 AUCL PK/PD Course April 20113C-46