PK/PD: new insights for antibacterial and antiviral applications.

The path of new compounds from discovery to bedside is long and costly and a large majority of compounds never make it to the market. To improve drug development, better tools are needed to assess efficacy and safety early in the process. One approach that has been suggested by the FDA to help streamlining the drug development process is pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. In this approach, a model-based link between PK profiles and corresponding PD is established. Once a suitable model is identified and validated, predictions about efficacy and safety of different dosing regimens can be made. The goal of this review is to examine the current state of PK, PD, and PK/PD in antibiotic and antiviral research and development.

[1]  J. Bilello,et al.  In Vitro-In Vivo Model for Evaluating the Antiviral Activity of Amprenavir in Combination with Ritonavir Administered at 600 and 100 Milligrams, Respectively, Every 12 Hours , 2003, Antimicrobial Agents and Chemotherapy.

[2]  O. Cars,et al.  Tissue concentrations: do we ever learn? , 2007, The Journal of antimicrobial chemotherapy.

[3]  J. Bilello,et al.  A 24-week open-label Phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir) , 1996, AIDS.

[4]  W. Craig,et al.  In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin , 2007, Antimicrobial Agents and Chemotherapy.

[5]  M. Bergeron,et al.  Difference in blister fluid penetration after single and multiple doses of ceftriaxone , 1985, Antimicrobial Agents and Chemotherapy.

[6]  G. Drusano,et al.  Mathematical Modeling of the Interrelationship of CD4 Lymphocyte Count and Viral Load Changes Induced by the Protease Inhibitor Indinavir , 1998, Antimicrobial Agents and Chemotherapy.

[7]  J. Bilello,et al.  Use of Drug Effect Interaction Modeling with Monte Carlo Simulation To Examine the Impact of Dosing Interval on the Projected Antiviral Activity of the Combination of Abacavir and Amprenavir , 2000, Antimicrobial Agents and Chemotherapy.

[8]  Hartmut Derendorf,et al.  Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC , 2004, Antimicrobial Agents and Chemotherapy.

[9]  E. Schuck,et al.  Integration of pharmacokinetic/pharmacodynamic modeling and simulation in the development of new anti-infective agents – minimum inhibitory concentration versus time-kill curves , 2007, Expert opinion on drug discovery.

[10]  P. Toutain,et al.  The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics. , 2002, Research in veterinary science.

[11]  O. Cars,et al.  Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. , 2005, The Journal of antimicrobial chemotherapy.

[12]  A. Dasgupta Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[13]  H. Eichler,et al.  Surgery and intensive care procedures affect the target site distribution of piperacillin , 2000, Critical care medicine.

[14]  A. MacGowan,et al.  Elements of design: the knowledge on which we build. , 2004, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[15]  Mats O. Karlsson,et al.  Semimechanistic Pharmacokinetic/Pharmacodynamic Model for Assessment of Activity of Antibacterial Agents from Time-Kill Curve Experiments , 2006, Antimicrobial Agents and Chemotherapy.

[16]  A. Ding,et al.  Assessing antiviral potency of anti-HIV therapies in vivo by comparing viral decay rates in viral dynamic models. , 2001, Biostatistics.

[17]  H. Derendorf,et al.  Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue , 2004, Antimicrobial Agents and Chemotherapy.

[18]  E. Tschernko,et al.  In vivo microdialysis to measure antibiotic penetration into soft tissue during cardiac surgery. , 2007, Annals of Thoracic Surgery.

[19]  B. Corrigan,et al.  How Modeling and Simulation Have Enhanced Decision Making in New Drug Development , 2005, Journal of Pharmacokinetics and Pharmacodynamics.

[20]  Hartmut Derendorf,et al.  Pharmacokinetic/ pharmacodynamic evaluation of anti-infective agents , 2005, Expert review of anti-infective therapy.

[21]  A. Perelson,et al.  Complex patterns of viral load decay under antiretroviral therapy: influence of pharmacokinetics and intracellular delay. , 2004, Journal of theoretical biology.

[22]  F. Legat,et al.  Penetration of Fosfomycin into Inflammatory Lesions in Patients with Cellulitis or Diabetic Foot Syndrome , 2003, Antimicrobial Agents and Chemotherapy.

[23]  Jianguo Zhi,et al.  Microbial pharmacodynamics of piperacillin in neutropenic mice of systematic infection due toPseudomonas aeruginosa , 1988, Journal of Pharmacokinetics and Biopharmaceutics.

[24]  R. Owens,et al.  Assessment of pharmacokinetic-pharmacodynamic target attainment of gemifloxacin against Streptococcus pneumoniae. , 2005, Diagnostic microbiology and infectious disease.

[25]  P. Friedmann,et al.  The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water‐soluble drugs investigated by microdialysis , 2003, The British journal of dermatology.

[26]  David E. Martin,et al.  Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3′,3′-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection , 2007, Antimicrobial Agents and Chemotherapy.

[27]  A. Klimowicz,et al.  Acyclovir concentrations in the skin of humans after a single oral dose assessed by in vivo cutaneous microdialysis , 2006, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[28]  R. Schinazi,et al.  Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. , 2002, Antiviral research.

[29]  Nnis System National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003. , 2003, American journal of infection control.

[30]  J J Schentag,et al.  Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients , 1993, Antimicrobial Agents and Chemotherapy.

[31]  M. Grant,et al.  Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis. , 2006, The Journal of antimicrobial chemotherapy.

[32]  M. Müller,et al.  Microdialysis in clinical drug delivery studies. , 2000, Advanced drug delivery reviews.

[33]  J. Powers Antimicrobial drug development--the past, the present, and the future. , 2004, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[34]  W. Craig Pharmacodynamics of Antimicrobials: General Concepts and Applications , 2001 .

[35]  J. Blaser,et al.  Interface-area-to-volume ratio of interstitial fluid in humans determined by pharmacokinetic analysis of netilmicin in small and large skin blisters , 1991, Antimicrobial Agents and Chemotherapy.

[36]  S. Sarafianos,et al.  Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. , 2004, Current opinion in structural biology.

[37]  U. Ungerstedt,et al.  AAPS‐FDA Workshop White Paper: Microdialysis Principles, Application, and Regulatory Perspectives , 2007 .

[38]  R. Schinazi,et al.  Antiviral methods and protocols , 1999 .

[39]  U. Theuretzbacher Tissue penetration of antibacterial agents: how should this be incorporated into pharmacodynamic analyses? , 2007, Current opinion in pharmacology.

[40]  J. Bilello,et al.  Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable. , 2001, The Journal of infectious diseases.

[41]  H. Derendorf,et al.  Clinical Microdialysis in Skin and Soft Tissues: An Update , 2008, Journal of clinical pharmacology.

[42]  L. Ståhle,et al.  Distribution to the skin of penciclovir after oral famciclovir administration in healthy volunteers: comparison of the suction blister technique and cutaneous microdialysis. , 1999, Acta dermato-venereologica.

[43]  W. Craig Does the dose matter? , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  D. Bernstein,et al.  A model of human cytomegalovirus infection in severe combined immunodeficient mice. , 2007, Antiviral research.

[45]  G. Drusano,et al.  Antimicrobial Pharmacodynamics in Theory and Clinical Practice , 2007 .

[46]  E. Schuck,et al.  Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Once-Daily Treatment Using Ciprofloxacin in an Extended-Release Dosage Form* , 2005, Infection.