Disclosures. Efficacy of the drug. Optimizing Dosing Based on PKPD- An overview. Dose Finding - The Past

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1 Disclosures Optimizing Dosing Based on PKPD- An overview Johan W. Mouton MD PhD FIDSA FAAM Professor pharmacokinetics and pharmacodynamics Research grants advisory boards speaker This Patient Needs Antibiotics. But Which Ones, And Which Dose? Dose Finding - The Past Cartoon removed Cartoon removed Efficacy of the drug Signing the amendment of Kefauver and Harris, 1962 Potency of a drug (MIC) Exposure to the bug In vivo (PK) 1

2 ACTVITY in vitro (MIC) CONCENTRATIONS in vivo (PK) DOSING regimen 1st Question: ANTIMICROBIAL EFFICACY (Microbiological Cure) Does the dose matter? Other factors CLINICAL EFFICACY (Clinical Cure) Mouton et al., Drug Resistance Updates 211 Probability of cure after treatment with fluconazole Oropharyngeal Candidiasis n=132 Treatment with fluconazol Doses 1 4 mg Culture-results with MIC-values Probability of cure after treatment with fluconazole Oropharygeal Candidiasis n=132 Individual Dose MIC-values per individual Determine Dose/MIC for each patient Microbiological outcome (candida cured) Clinical outcome Higher dose Lower efficacy? Rodriguez- Tudela et al, AAC 27 Efficacy of the antimicrobial 2nd Question: Does the Dose matter in relation to the MIC (potency?)? Potency of a drug (MIC) Exposure to the bug In vivo (Dose; PK) Cartoon removed 2

3 MIC Measure of Potency antibacterial activity MIC Lowest concentration with no visible growth after 18 hour incubation MIC = 2 mg/l prob cure Probability of cure after treatment with fluconazole Oropharygeal Candidiasis n= EC R² Dose/MIC Prob cure correlates with Dose/MIC POSITIVE correlation with dose INVERSE correlation with MIC Each data point represents the proportion of patients cured within a group representing a certain AUC/MIC value Rodriguez- Tudela et al, AAC 27 Dose is just a means for Exposure Pharmacokinetic parameters : Measures of Exposure AUC is usually linearly related to Dose AUC concentration PEAK AUC T > MIC Mouton et al In Antimicrobial Pharmacodynamics in Theory and Clinical Practice Pharmacokinetic parameters : Measures of Exposure AUC and Peak are usually linearly related to Dose time MIC Does the dosing regimen matter? Concentration mg/l q6 25 q q Mouton et al. Drug Resist Updat :17-17 Time (h) Dose mg/kg MIC.125 mg/l total length of bars corresponds to Time > MIC 3

4 Ceftazidime in patients with nosocomial pneumonia Dose is just a means for Exposure randomized, double-blind phase 3 clinical trial (NCT21964): comparing the efficacy of ceftobiprole with the combination CAZ and linezolid Ceftazidime 3dd 2 gr 2h infusion N=39 patients included NO clear dose response relationship BUT. Muller et al, JAC :9-96 Ceftazidime in patients with nosocomial pneumonia randomized, double-blind phase 3 clinical trial (NCT21964): comparing the efficacy of ceftobiprole with the combination CAZ and linezolid Ceftazidime 3dd 2 gr 2h infusion Extensive and sparse sampling of ceftazidime Ceftazidime in patients with nosocomial pneumonia randomized, double-blind phase 3 clinical trial (NCT21964): comparing the efficacy of ceftobiprole with the combination CAZ and linezolid Ceftazidime 3dd 2 gr 2h infusion Extensive and sparse sampling of ceftazidime MICs of strains N=39 patients included NO clear dose response relationship BUT. 16 without PK estimates N=39 patients included N=17 with MIC N=154 with MIC and PK-estimates 22 without Gram negatives in cultures Muller et al, JAC :9-96 Muller et al, JAC :9-96 PK-data PK population model Individual PK parameters Clinical phase 3 study Individual exposure to CAZ %ft>mic Culture-results with MIC-values MIC-values per individual Exposure-response Emax model microbiological eradication benefit 1 1 Individual exposures to CAZ Categorised (%ft>mic per 1%) Eradication rate per group 154 patients Microbiological outcome Clinical outcome Muller et al, JAC :9-96 4

5 Ceftazidime in patients with nosocomial pneumonia Probability plot of the logistic regression analysis for ceftazidime showing the relationship between %ft>mic (Gram-negatives at baseline/eot) and probability of cure at TOC BENEFIT Muller et al, JAC :9-96 Muller et al, JAC :9-96 Probability plot of the logistic regression analysis for ceftobiprole showing the relationship between %ft>mic and probability of cure at TOC nosocomial pneumonia The PKPD relationship is based on MIC AND PK exposure P=.14 BENEFIT Optimize dose based on: Exposure response relationship PK characteristics MIC (distribution) Muller et al, AAC :2512 How Can We Use This Information? Individual exposure determines outcome What is the individual exposure? %ft >MIC Target Attainment - ceftazidime Volunteers % CI 2 Average ceftazidime 1g q8h volunteers MIC mg/l Mean exposure %ft >MIC ICU % CI 2 Average ceftazidime 1g q8h ICU MIC mg/l 1 1 Can we improve on that? Can we predict (how)? Mouton et al, Clin Ther 25 27:762 5

6 %ft >MIC Target Attainment - ceftazidime Volunteers % CI 2 Average ceftazidime 1g q8h volunteers MIC mg/l ALL exposure %ft >MIC ICU % CI 2 Average ceftazidime 1g q8h ICU MIC mg/l Ceftazidim in ICU patients : observed variability concentration mg/l time h Mouton et al, Clin Ther 25 27:762 Optimizing therapy Pharmacodynamic Target prob cure EC R².9938 Higher MIC then expected Less susceptible micro-organisms Resistance Dose/MIC Lower/other EXPOSURE then expected Dose / dosing regimen Clearance in individual Infectionsite Abdulla, Rotterdam EXPAT study results, ECCMID 217 Ceftazidime AGE effects 6 gr tdd NP/ CIP At which age is it starting to be an issue? CART Analysis Cmin Mouton & Muller Unpublished data Mouton & Muller Unpublished data 6

7 Ceftazidime AGE effects 6 gr tdd NP/ CIP Multiple logistic regression Ceftobiprole, Cure, TOC Cmin Clinical cure at TOC Mouton & Muller Unpublished data Muller et al. 214, AAC,58(5):2512 Impact of APACHE score on microbiological eradication Ceftobiprole, n=251 Impact of APACHE score on clinical outcome Ceftazidime, n=14 AS < 14 AS >14 IMPACT OF ADEQUATE DOSING MORE IMPORTANT IN CIP AS < 14 AS >14 IMPACT OF ADEQUATE DOSING MORE IMPORTANT IN CIP Based on data from Muller et al 214 Based on data from Muller et al 213 Strategies to improve target attainment Probability of cure increases if %ft>mic increases Increase %ft>mic! extended infusion ( continuous infusion) 7

8 Ceftazidime 8h.5h infusion; 2h infusion T>MIC Increases Rat survival 4 days Continuous Infusion vs Q6h Rat survival 4 days Continuous Infusion vs Q6h rat survival % CI Q6h 5% log daily dose mg/kg Regimen PD5 mg/kg CI 1.52 Q6h rat survival % normal Q6h CI log daily dose mg/kg immunocompromised Q6h CI Regimen PD5 mg/kg CI.36 Q6h.35 5% CI 1.52 Q6h neutropenic Mouton & Vinks, Curr Op Crit Care 27, based on data from Roosendaal Mouton & Vinks, Curr Op Crit Care 27, based on data from Roosendaal log1 cfu Kill Kinetics 1 mg/l,125 mg/l 8,5 mg/l 6 1 mg/l 2 mg/l 4 4 mg/l 16 mg/l 2 64 mg/l Time h observed killrate h R² Killrates Max kill Growth Concentration ceftazidim (mg/l) Continuous vs Intermittent infusion : BLISS study No additional killing above 4xMIC Killing is present / absent over short concentration range Mouton et al AAC 27 Abdul-Aziz, Int Care Med 216 PBP 8

9 Dose Optimization - individualized DETERMINE THE PK/PD TARGET MICs TO BE COVERED from the dosing regimen and PK, including population variability and covariates e.g. value of the PK/PD Index (animal studies, clinical studies) ESTIMATE EXPOSURE from PK, including population variability and covariates Estimate exposure How can we predict clearance in critically ill? DOSE (or choice of drug ) Creatinin Clearance In 15 Criticall Ill Patients AIDA on going clinical trial Relation between Creatinin Clearance and Meropenem Clearance In 238 Criticall Ill Patients on 557 occacions during Continuous Infusion Regression= Not significant No model assumptions Paul, Friberg et al. Rohr et al., ECCMID 215 We Need Therapeutic Drug Monitoring for Antibiotics!!!!! - In particular in patients with high/augmented clearance Development of fast methods to measure drug concentrations TDM!! And the MIC part of the Equation? How to use that? For non-continuous infusion, develop and use population models -Analyze covariates 9

10 Gentamicin Wild-type distributions Tobramycin MICs to be covered ECOFF 8 mg/l ECOFF 2 mg/l Pharmacokinetic profile is very similar PK/PD targets similar Mouton et al, MIC-BASED DOSE ADJUSTMENT: FACTS AND FABLES. JAC 217 in press MIC distribution of 14 strains in 5 labs in quaduplicate Linezolid, S.aureus Conclusions PK/PD explains and predicts the effects of antimicrobials For beta lactams, %ft>mic is the most important predictor; for most other drugs it is fauc/mic Increasing %ft>mic to increase target attainment by adjusting the dosing regimens, TDM should be performed if no good prediction can be made Dosing regimens optimal for exposure may select for resistance / adjustments are clearly required Choose the right drug! Mouton et al, Variation of MIC measurements: the contribution of strain and laboratory variability to measurement precision JAC 218, in press 1