Essential Science: The State of the Art of Pharmacokinetics and Pharmacodynamics for Antimicrobial Drug Development

Transcription

1 Essential Science: The State of the Art of Pharmacokinetics and Pharmacodynamics for Antimicrobial Drug Development 7 September 2018 Nikolas J Onufrak, Pharm.D. Institute for Clinical Pharmacodynamics, Inc. Schenectady, New York

2 Outline The Premise The Reality The Future The Point 2

3 Outline The Premise The path to regulatory approval is clear and well-tread The Reality The Future The Point 3

4 The path to regulatory approval is clear and well-tread Preclinical Clinical In vitro In vivo, animal In vivo, human SCTK 1CM HFIM DRS DFS P1 P2 P3 What do we learn?

5 in vitro PK-PD Analyses Static Concentration Time-Kill Studies One-Compartment Infection Model MIC distribution(s) of target pathogen(s) Killing capacity Resistance emergence, suppression thereof Extract basic properties of agent Hollow-Fiber Infection Model Institute for Clinical Pharmacodynamics, Inc.

6 Animal PK-PD Analyses Dose-Ranging Studies in vivo E max Determination of PK-PD driver Magnitude of driver for various degrees of effect Dose-Fractionation Studies Establish exposureresponse correlates Institute for Clinical Pharmacodynamics, Inc.

7 Human PK-PD Analyses Phase 1 Studies Phase 2 Studies Factors affecting drug disposition and response Extent of variability between and within individuals Probability of PK-PD target attainment Phase 3 Studies Ensure safe and effective dose Institute for Clinical Pharmacodynamics, Inc.

8 Outline The Premise The Reality PK-PD target determination is predicated on careful experimental design Establishment of an agent s efficacy is relative to when the endpoint is observed Assuming a single, absolute PK-PD target exists is naïve The Future The Point 8

9 PK-PD target determination is predicated on careful experimental design 9

10 (K. pneumoniae) PK-PD target determination is predicated on careful experimental design What is the impact of dosing interval on dose-response? With shorter dosing intervals, required dose remains constant cefazolin imipenem ceftazidime gentamicin netilmicin Why? Aminoglycoside murine t 1/2 ~ 20 min + Varying extent of PAE AUC:MIC selected as PK-PD driver With longer dosing intervals, required dose steadily increases t>mic selected as PK-PD driver At intervals beyond the effect duration, only t>mic able to be correlated with response Leggett JID 1989 Craig Clin Microbiol Newsl

11 PK-PD target determination is predicated on careful experimental design Cefazolin What is the impact of dose range on dose-response? The sigmoidicity of life: there are thresholds for initiation of effect, there are thresholds for maximization of effect Experiments conducted solely at the extremes of response cannot determine the PK-PD driver Vogelmann JID

12 Establishment of an agent s efficacy is relative to when the endpoint is observed 12

13 Polymyxin B vs. MDR K. pneumoniae Establishment of an agent s efficacy is relative to when the endpoint is observed KPC-K. pneumoniae isolate 1 KPC-K. pneumoniae isolate 2 Extensive initial killing by polymyxin B-containing regimens: how to interpret? Bulman AAC

14 Polymyxin B vs. MDR K. pneumoniae Establishment of an agent s efficacy is relative to when the endpoint is observed KPC-K. pneumoniae isolate 1 KPC-K. pneumoniae isolate 2 Extensive initial killing by polymyxin B-containing regimens: how to interpret? Different conclusion if only 24-hour timepoint considered: when do we measure MICs? Bulman AAC

15 Polymyxin B vs. MDR K. pneumoniae Establishment of an agent s efficacy is relative to when the endpoint is observed KPC-K. pneumoniae isolate 1 KPC-K. pneumoniae isolate 2 Extensive initial killing by polymyxin B-containing regimens: how to interpret? Different conclusion if only 24-hour timepoint considered: when do we measure MICs? Assessment at later timepoints reveals inadequacy of combination: how long do we treat patients? Bulman AAC

16 Linezolid vs. NRP M. tuberculosis Establishment of an agent s efficacy is relative to when the endpoint is observed Regimens ineffective in first few days of therapy: does this matter? Eradication possible by staying the course Efficacy determination must consider goal of therapy Drusano AAC

17 Assuming a single, absolute PK-PD target exists is naïve 15

18 Assuming a single, absolute PK-PD target exists is naïve PK-PD relationship for six S. aureus isolates discerned r 2 = fauc:mic targets based on fitted Hill model: Stasis ~10 1-log ~ 30 2-log ~ 1000 Figure courtesy Dr. Sujata Bhavnani Bulik AAC

19 Assuming a single, absolute PK-PD target exists is naïve PK-PD relationship for six S. aureus isolates discerned fauc:mic targets based on fitted Hill model: Stasis ~10 1-log ~ 30 2-log ~ 1000 r 2 = What if we only encounter this isolate? Stasis ~ 5? 1-log ~ 15? 2-log ~ 100? Risk underdosing the agent Figure courtesy Dr. Sujata Bhavnani Bulik AACA

20 Assuming a single, absolute PK-PD target exists is naïve PK-PD relationship for six S. aureus isolates discerned r 2 = What if we only encounter this isolate? fauc:mic targets based on fitted Hill model: Stasis ~ 5? 1-log ~ 15? 2-log ~ 90? Stasis ~10 1-log ~ 30 Risk underdosing the agent 2-log ~ 1000 What if we only encounter this isolate? Stasis ~ 30? 1-log ~ 100? 2-log ~ 1000? Figure courtesy Dr. Sujata Bhavnani Risk overdosing the agent Bulik AAC

21 Assuming a single, absolute PK-PD target exists is naïve Practical Solution: recognize the variability! Study enough isolates to produce a normal distribution of PK-PD target values Leverage random sampling to provide a more realistic appraisal of PK-PD target attainment Figure courtesy Dr. Sujata Bhavnani Bhavnani ASM Microbe 2018 Andes Curr Opin Pharmacol 2017 Trang Curr Opin Pharmacol

22 Assuming a single, absolute PK-PD target exists is naïve Clinical context dictates what extent of drug kill is required PK-PD targets are guides, not absolutes Ambrose EMA Workshop Nov 2015 Trang Curr Opin Pharmacol

23 Outline The Premise The Reality The Future Leveraging existing approaches to observe unbound tissue concentrations Conduct integrated PK-PD analyses accounting for multiple endpoints over time Proposition of indication-specific dosing The Point 21

24 Leveraging existing approaches to observe unbound tissue concentrations 22

25 Leveraging existing approaches to observe unbound tissue concentrations Equilibration with ISF Measurement at the biophase Serial quantification of tissue free-drug concentrations Azeredo Clin Pharmacokinet

26 Leveraging existing approaches to observe unbound tissue concentrations Typical animal PK study Naïve pooled approach by necessity; large number of animals required Animal PK study using µd Allows for use of population analysis methods; reduction in animal use Garrison Eur J Pharm Sci

27 Leveraging existing approaches to observe unbound tissue concentrations First dose Steady-state 16 tissue concentrations in 8 hours Lag in tissue exposure fauc plasma not proportional to AUC tissue 21 tissue concentrations in 8 hours Approximately proportional plasma and tissue profiles Traunmuller AAC

28 Leveraging existing approaches to observe unbound tissue concentrations Plasma Infected lung Normal lung Plasma PK as one might expect but PK in infected lung tells a different story as does the PK from an unaffected region of the lung As microdialysis evolves, certainty of the exposure-response relationship increases Lindenmann JAC

29 Conduct integrated PK-PD analyses accounting for multiple endpoints over time 27

30 Conduct integrated PK-PD analyses accounting for multiple endpoints over time Murine PK-PD model developed Excellent fits achieved Model prospectively validated Levofloxacin AUC:MIC = 52 CFU s CFU r Central [Drug] CFU total Peripheral AUC:MIC = 157 CFU total = CFU s + CFU r CFUr PK-PD target for resistance suppression Jumbe J Clin Invest

31 Initial inoculum Conduct integrated PK-PD analyses accounting for multiple endpoints over time ΔCFU in immunocompetent mice observed Neutrophil effect modelled Saturable killing function Excellent fits achieved P. aeruginosa in lung CFU P. aeruginosa S. aureus Kill max (h -1 ) S. aureus in thigh K m (CFU/g) 2.15 x x 10 6 Neutrophil contribution to cell killing Drusano AAC 2010 Drusano AAC

32 Proposition of indication-specific dosing 30

33 Proposition of indication-specific dosing Tigecycline EMA- and FDA-approved for the treatment of csssis, ciais, and CABP (FDA only) Dosing Regimen: 100 mg x 1, then 50 mg q12h Failed Phase 3 trials for the treatment of HABP and VABP Dosing Regimen? 100mg x 1, then 50 mg q12h In HABP patients, suboptimal probability of attaining 1-log exposure target In VABP patients, vast majority unlikely to attain 1-log exposure target Would pushing the dose help? Data courtesy Dr. William Craig Figure courtesy Dr. Sujata Bhavnani Rubino AAC 2007 Bhavnani AAC 2012 Ambrose Curr Opin Pharmacol

34 Outline The Premise The Reality The Future The Point A thorough understanding of PK and PD provides a roadmap to risk reduction 32

35 An informed view is a rational one Institute for Clinical Pharmacodynamics, Inc.

36 A thorough understanding of PK and PD provides a roadmap to risk reduction FDA regulatory approvals for CABP/HABP/VABP from Failures: 0% - daptomycin, lung surfactant 100% - garenoxacin, safety (hypotension) There are no guarantees, but can at least come to the table well-equipped Bulik 53 rd ICAAC

37 Acknowledgments GEORGE L. DRUSANO, M.D. University of Florida ALASDAIR MACGOWAN, M.D., FRCP University of Bristol ALAN FORREST, PHARM.D. University of North Carolina at Chapel Hill Institute for Clinical Pharmacodynamics PAUL G. AMBROSE, PHARM.D, FIDSA JUSTIN C. BADER, PHARM.D. SUJATA M. BHAVNANI, PHARM.D., M.S. ELIZABETH A. LAKOTA, PHARM.D., M.S. CHRISTOPHER M. RUBINO, PHARM.D. BRIAN VANSCOY, B.SC. Thank you for your attention. 36