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Pharmacokinetic-Pharmacodynamic (PK/PD) of Anti-infective Agents

The pharmacokinetics (time course of concentration in the body) of a drug when combined with its pharmacodynamics (onset, intensity, duration of pharmacological effect of the drug) determines the therapeutic potential of a drug (1).

In anti-infective pharmacology, specifically for bacteria, the primary determinants of pharmacological activity are:

  1. The Minimum Inhibitory Concentration (MIC): the minimum concentration of the drug that yields ninety percent inhibition of bacterial growth in vitro.
  2. The Minimum Inhibitory Concentration (MIC): the minimum concentration of the drug which causes ninety nine percent killing of bacteria in vitro.
  3. Killing Kinetics: the relationship between concentration and the killing of bacteria over time at different concentrations;
    a) Concentration dependent killing – the bacterial killing increases with concentration over a wide concentration range (e.g. fluoroquinolones, Aminoglycosides)(2);
    b) Time dependent (Minimum concentration dependent) killing- the bacterial killing increases over a narrow range of concentration and reaches saturation in killing. The killing effect is more related to time than concentration (e.g. Penicillins, beta- lactams, Tetracycline)(2).

The three main PK/PD parameters that determine the therapeutic efficacy of anti-bacterial drugs in preclinical models of infection and in the clinic are

  1. a) The ratio of area under the free drug concentration time cure to the MIC (fAUC/MIC);
  2. b) The ratio of peak free drug concentration to the MIC (fC max /MIC);
  3. c) The time of free drug concentration above the MIC (T>MIC)(3,4,5).

Preclinical models of infection, such as the neutropenic thigh and lung infection models in mice, have predicted the clinical efficacy of different classes of antibiotics with acceptable accuracy (3, 6, 7, 8).

This has led to the routine use of the neutropenic mouse thigh infection model for evaluating the PK/PD of anti-bacterial agents in drug discovery programs. The major objective in the nonclinical phase is to determine the PK/PD parameter that best describes the efficacy of the clinical candidate in the animal model of infection. The rationale for this is to set PK/PD targets in the clinic to achieve clinical efficacy in patients with infections. Indeed the US FDA has issued a guidance document emphasizing the requirement for characterizing the PK/PD of an anti-bacterial drug in nonclinical models of infection and the identification of the PK/PD index that best describes its efficacy (9).

In the lead identification stage of in anti-bacterial drug discovery, proof of concept studies are done to validate the in vitro observations (target potency, MIC, MBC, kill kinetics) in in vivo models of infection (e.g. neutropenic thigh infection model). Proof of concept is demonstrated when the in vivo efficacy is consistent with the in vitro properties and PK of the lead compound. When the clinical candidate is identified following the lead optimization program, the PK/PD index for efficacy is identified in more complex studies.

TheraIndx Lifesciences has validated models for determining the PK/PD properties of anti- infective agents. PK/PD models include in vitro and in vivo PK/PD models for dose- response-time and dose fractionation studies (thigh, lung, urinary tract, sepsis infection models in neutropenic mice and rats) against a variety of Gram positive and Gram negative bacterial pathogens (ESKAPE)(10,11).



    References:
  • 1. Gabrielsson, J.; Green, A.R.; Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J Pharmacol Exp Ther., 2009, 331(3), 767-74.

  • 2. Craig, W.A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis., 1998, 26 (1), 1-10

  • 3. Ambrose, P.G.; Bhavnani, S.M.; Rubino, C.M.; Louie, A.; Gumbo, T.; Forrest, A.; Drusano, G.L. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis., 2007, 44 (1), 79-8

  • 4. Andes, D.; Craig, W.A. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents., 2002, 19 (4), 261-8.

  • 5. Drusano, G.L. Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'. Nat Rev Microbiol. 2004, 2(4), 289-300.

  • 6. Andes, D.R.; Lepak, A.J. In vivo infection models in the pre-clinical pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Curr Opin Pharmacol., 2017, 36, 94-99.

  • 7. Forrest,A.; Nix, D.E.; Ballow, C.H.; Goss, T.F.; Birmingham, M,C.; Schentag. J.J. Pharmacodynamics of intravenous Ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother., 1993, 37(5), 1073-81.

  • 8. Preston, S.L.; Drusano, G.L.; Berman, A.L.; Fowler, C.L.; Chow, A.T, Dornseif, B.; Reichl, V.; Natarajan, J.; Corrado, M. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA, 1998, 279 (2), 125-9.

  • 9. Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases: Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) August 2017. Clinical/Antimicrobial.

  • 10. Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa, Somashekharayya Hiremath, Avinash Pawar, Mahesh Nanjundappa, Ramesh Jayaraman . Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice. Curr Drug Metab. 2020;21(2):132-139. doi: 10.2174/1389200221666200310105227.

  • 11. The Neutropenic Rat Thigh Infection Model is Ideal for Characterisation of Pharmacokinetics/Pharmacodynamics (PK/PD) of Anti-infectives Following Intravenous Infusion Administration. 2019. Ramesh Jayaraman, Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa, Parameshwar Palmate, Avinash Pawar, Somashekharayya Hiremath, Mahesh Nanjundappa. 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Amsterdam, Netherlands, 2019 (Abstract number 1024)

  • Author : Ramesh Jayaraman-Chief Scientific Officer, TheraIndx Lifesciences.