history of pk-pd: 1970s- 2008: from the formative years to mainstream use

MN Dudley, Craig PK-PD Symposium 2008 1

MN Dudley

Efflux Pump Inhibitors: A Viable Option?

Michael N. Dudley, Pharm.D., FCCP

Vice President, Pharmacology and MicrobiologyEssential Therapeutics, Mountain View, CA & Waltham, MA

Michael N. Dudley, Pharm.D., FCCP

Vice President, Pharmacology and MicrobiologyEssential Therapeutics, Mountain View, CA & Waltham, MA

History of PK-PD:

1970s- 2008: From the Formative Years to Mainstream Use

Michael N. Dudley, Pharm. D, FIDSA

Senior Vice President, Research and Development and Chief Scientific Officer

San Diego, CA


Four Decades of PK-PD: 1970-2008

What were the key tools? Analytical Models Drugs

Applications How evolved did this evolve? Who cares? Now vs. Then

The Future


Four Decades of Antibiotic PK-PD" Those who cannot remember the past are condemned to

repeat it”. George Santanaya in The Life of Reason, Volume 1, 1905;

US (Spanish-born) philosopher (1863 - 1952)


Billy Craig:Guitar Player or PK-PD Expert?


1970’s: Understanding Antibiotic PK

Pharmacokinetic analysis tools Aminoglycoside antibiotics Protein binding of antimicrobials


1970s: Importance of Individualizing Dose

Kinetic model for gentamicin dosing with the use of individual patient parameters.

Sawchuk RJ, Zaske DE, Cipolle RJ, Wargin WA, Strate RG. Clin Pharmacol Ther. 1977 Mar;21(3):362-9.

Multiple-infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level-time data obtained after a single infusion were used to determine the patient's gentamicin half-life (t 1/2) and distribution volume. Patients with serum creatinine (Cr) less than 1.2 mg per 100 ml had t 1/2 (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr greater than or equal to 1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patient's kinetic parameters and desired steady-state peaks and nadirs, assumed a one-compartment model with first-order elimination and 1-hr constant-rate input at fixed intervals. Follow-up steady-state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged --0.05 mug/ml with 60% of the measured values falling within 1 mug/ml of that predicted. Predicted-measured nadir differences averaged --0.62 mug/ml (significantly different from zero) indicating slight bias in the model. Fifty-six percent of these nadirs were within 1 mug/ml of that predicted.


1970s: A Mechanistic Understanding

Gentamicin tissue accumulation and nephrotoxic reactions.

Schentag JJ, Cubmo, TJ, Jusko, WJ, Plaut ME. JAMA. 1978 Nov 3;240(19):2067-9.

In 64 adults treated with gentamicin sulfate, peak and trough serum concentrations rose gradually and declined in two phases after the final dose. Seventeen patients experienced renal damage. The 17 patients had greater amounts of gentamicin in tissues even after the first dose and before any renal effects were noted. This pharmacokinetics analysis provided evidence that patients who experience gentamicin-related nephrotoxic effects while receiving recommended doses of gentamicin could be distinguished from patients with no toxic effects because they experienced abnormal tissue accumulation before detectable changes in renal function occurred.


1970s: Considering the PD Opportunities

Persistent effect of antibiotics on Staphylococcus aureus after exposure for limited periods of time. J Infect Dis. 1977 Feb;135(2):217-23.

McDonald PJ, Craig WA, Kunin CM.

Persistent suppression of bacterial growth by certain antibiotics was tested by periodic counts of viable organisms in a culture of Staphylococcus aureus that had been incubated in media containing drugs for limited periods of time and then removed by centrifugation. During short (2 hr) periods of exposure of test cultures to penicillin G, cephalothin, erythromycin, clindamycin, vancomycin, and tetracyline, effects on the growth of S. aureus were produced that persisted after removal of the drug for periods of 1.7-4.1 hr. A persistent antibiotic effect was not observed with gentamicin. The persistent effects of penicillin G and erythromycin were directly related to duration of exposure and concentration of drug, up to a point of maximal response. The maximal durations of bacterial suppression after exposure to penicillin G and erythromycin were approximately 2 and 5 hr, respectively. These effects were observed over a wide range of inocula.


1980’s: Identifying the Paradigm Model Development Insights into Classes of Antibiotics

Beta-lactams Fluoroquinolones Aminoglycosides

Microcomputers


1980s: An Integration?Integration of selected pharmacologic and microbiologic properties of

three new beta-lactam antibiotics: a hypothesis for rational comparison. Rev Infect Dis. 1984 May-Jun;6(3):357-63

Drusano GL, Ryan PA, Standiford HC, Moody MR, Schimpff SC.To enable the comparison of antibiotics in a standardized, meaningful manner, a system that

integrates the pharmacologic and microbiologic properties of beta-lactam antibiotics has been developed. The system compares the duration of time that concentrations of both total and free drug exceed the 90% minimal inhibitory concentration ( MIC90 ) of various pathogens as well as the area under the concentration-time curve for both total and free drug, the latter measurement being an indication of potential for antibiotic diffusion to the periphery. Of the three cephalosporin(-like) compounds evaluated, moxalactam produced the longest duration of free drug above the MIC90 for the Enterobacteriaceae as well as the largest free-drug area under the concentration-time curve following a standardized 2-g intravenous infusion. Both the duration of time cefotaxime was above the MIC90 for the Enterobacteriaceae and the area under the concentration-time curve were significantly less because of its short elimination half-life, results indicating the need for more frequent dosing with cefotaxime than with moxalactam. Cefoperazone, because of its high degree of protein binding and higher MIC90, develops the least duration of time above the MIC90 for most pathogens. None of these new agents provides free-drug concentrations above the MIC90 for Pseudomonas aeruginosa for longer than 0.6 hr, which suggests that they may be inadequate as single-agent therapy for many serious infections due to this pathogen. Because promotion of comparisons by this method relies on in vitro data for analysis, the conclusions relating to expected clinical efficacy are proffered and should be interpreted with caution.(ABSTRACT TRUNCATED AT 250 WORDS)SOME THINGS NEVER CHANGE!!


or an Individualization? Role for dual individualization with cefmenoxime.Schentag JJ, Smith IL, Swanson DJ, DeAngelis C, Fracasso JE, Vari A,

Vance JW. Am J Med. 1984 Dec 21;77(6A):43-50.

Cefmenoxime concentration/effect relationships were retrospectively explored for gram-negative bacteria isolated from 14 critical care patients treated for nosocomial pneumonia. The effects of cefmenoxime concentrations on in vitro growth kinetics of 21 isolated pathogens were studied using the Abbott MS-2 Research System, from which a dynamic response concentration was derived. Serum pharmacokinetic profiles were obtained in each patient. These data were used to calculate the in vivo total area under the curve over dynamic response concentration and the time that cefmenoxime concentrations exceeded the dynamic response concentration for each bacteria. The same determinations were made in 18 patients prospectively treated, except that dosage was optimized on the basis of previous mathematical relations to achieve bacterial eradication in four days. This method of dosage optimization is termed dual individualization. Serial cultures of infected tissues were evaluated to determine the number of days to the eradication of bacteria, and the pharmacokinetic and pharmacodynamic variables were used to describe the bacteriologic response of the original pathogen isolated in pretreatment culture. Bacterial eradication rates could be described from cefmenoxime pharmacokinetics in the patient and from the relation between concentration and bacterial inhibition. Patients who were prospectively treated using these retrospectively derived relationships had a predictable day of bacterial eradication. This, in turn, was associated with a shorter duration of treatment (p less than 0.05). The success of prospective dual individualization is encouraging and suggests that more precise optimization of antibiotic dosage can yield a predictable rate of bacterial eradication from the infection site.


A PK-PD Target of Aminoglycosides

Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987 Jan;155(1):93-9.

Moore RD, Lietman PS, Smith CR.

In an examination of the relationships among plasma aminoglycoside concentrations, the minimal inhibitory concentration (MIC) for the infecting organism, and therapeutic outcome, data were analyzed from 236 patients with gram-negative bacterial infections who were participants in four clinical trials of gentamicin, tobramycin, and amikacin. Clinical response to therapy occurred in 188 (80%) patients. Elevated maximal and mean peak aminoglycoside concentration/MIC ratios were strongly associated with clinical response (P less than .00001 and P less than .0001, respectively). A graded dose-response effect was found between an increasing maximal peak concentration/MIC ratio and clinical response. By logistic regression the peak concentration/MIC ratios were associated significantly with clinical response after adjustment for underlying severity of illness and other factors correlated with response. These results demonstrate that a high peak concentration relative to the MIC for the infecting organism is a major determinant of the clinical response to aminoglycoside therapy.


1983


1980s: An Important Tool is IntroducedImpact of dosing intervals on activity of gentamicin and ticarcillin against

Pseudomonas aeruginosa in granulocytopenic mice. J Infct Dis. 1983 May;147(5):910-7

Gerber AU, Craig WA, Brugger HP, Feller C, Vastola AP, Brandel J.

The influence of dosing intervals on the activity of gentamicin and ticarcillin against Pseudomonas aeruginosa was studied in vivo. Granulocytopenic mice infected with P. aeruginosa in the thigh muscle were treated with 1-hr or 3-hr injections of gentamicin, ticarcillin, or gentamicin-ticarcillin. Plasma pharmacokinetics of the drugs were correlated with antibacterial activity. Gentamicin injected every 1 hr tended to be less active than gentamicin injected at longer intervals. In contrast, ticarcillin given every 1 hr was significantly more efficacious than equivalent total doses injected every 3 hr. The dosing schedule of gentamicin-ticarcillin was again important for ticarcillin but did not appreciably affect the antibacterial activity of gentamicin. Thus, antimicrobial chemotherapy of P. aeruginosa infections in the granulocytopenic host might be improved by administering ticarcillin rather than gentamicin as a constant infusion.

“I have a very bad feeling about this..its going to be a very long decade”


Population Analysis in the Mouse Thigh Model

Gerber, Vestola, Brandel, and Craig, JID 1982


In Vitro PK-PD Models

An in vitro model for the study of antibacterial dosage regimen design.

Toothaker RD, Welling PG, Craig WA. J Pharm Sci. 1982 Aug;71(8):861-4.

A model was developed that is capable of simulating antibacterial agent concentration versus time profiles commonly observed following intravenous and intramuscular bolus injections, intravenous infusions, and oral doses, administered as single or multiple doses. The model consisted of two physical compartments separated by a membrane of a commercial hemodialyzer. The 1.08 m2 membrane surface area allowed rapid transmembrane passage of drugs and other small molecules, while membrane pore size prevented bacterial passage. These characteristics allowed bacteria in one of the two compartments of the model to be exposed to time-variant drug concentrations without affecting the number or concentration of bacteria. The model was used to study the effects of a multiple intravenous bolus dosage regimen of ampicillin on Escherichia coli ATCC 12407.


In Vitro Hollow Fiber Pharmacodynamic Model

For Study of Antibacterial, Antiviral Pharmacodynamics

In Vitro Hollow Fiber Pharmacodynamic Model

For Study of Antibacterial, Antiviral Pharmacodynamics

Zinner, Blaser, Dudley, Am J Med, 1986


Blaser et. al., AAC 1987


Approach for Identifying Optimal Dosage Regimens for Antiinfectives is

Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988 Oct;158(4):831-47

Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA.

Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

Current antimicrobial dosing regimens are designed to maintain active drug levels for most of the dosing interval and are based on 40-y-old observations. With use of numerous multiple-dosing regimens in an animal model, this study is the first to successfully minimize the interdependence between pharmacokinetic parameters and thereby determine, by stepwise multivariate regression analysis, that the time that serum levels exceeded the minimum inhibitory concentration (MIC) was the most significant parameter determining efficacy for beta-lactams and erythromycin against various pathogens, whereas the log area under the curve was the major parameter for aminoglycosides. Optimal dosing intervals were no greater than the time that serum levels exceeded the MIC plus the duration of the postantibiotic effect. Careful application of these concepts should allow other investigators to use more optimally dosed regimens than those previously used in preclinical trials and to design studies to improve on current dosing regimens for humans.


Key summary of the “state of the art” and prospectus for the future


1990s: Wide Application of PK-PD

PK-PD studies become widely implemented in preclinical models for new drugs

Early use acceptance by the FDA as part of planning for clinical trials, analysis of data (Carl Peck, MD)

Internet Better microcomputers Population pharmacokinetics


Phase II Trial of IV Ciprofloxacin in Lower Respiratory Infections

50 Patients with LRTI, 50% Failed Previous Rx Ciprofloxacin 200-300 mg IV q 12 h. All Isolates Intially Susc. to Ciprofloxacin (MIC < 1) Pharmacokinetic Measurements Results

Good Result for Pathogens w/ MICs < 0.25 mg/L Poor Results with Infections due to Ps. aeruginosa

69% of Isolates Persisting in Sputum were Resistant to Ciprofloxacin.

Peloquin et. al. Arch Intern Med 1989;149:2269


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Days of treatment

0 20 2 4 6 8 10 12 14 4 6 8 10 12 1400

100100

7575

5050

2525AUC:MIC 125-250AUC:MIC 125-250

AUC:MIC > 250AUC:MIC > 250

AUC:MIC < 125AUC:MIC < 125

Ciprofloxacin: Bacterial Eradication from Sputum and AUC:MIC24 in Hospitalized Patients

Forrest A et al. Antimicrobial Agents Chemother 37:1073–1081, 1993.


Observed Total CFU

Resistant Subpop Susc. Subpop

Sum of Susc. + Resist

Dudley & Zinner, ICAAC 1987; Jumbe et.al, 2003

Modeling Bacterial Subpopulations for Fluoroquinolones and Ps. aeruginosa


Memorable and Historic Battles

George Drusano Jerry Schentag John Powers Others?


Comparison of Serum Levels of Amoxicillin (7mg/kg Human Dose) in Humans and Mice With Uranyl Nitrate-Induced Renal Failure

Andes & Craig, AAC 1997

MN Dudley, Craig PK-PD Symposium 2008 30IDSA, San Diego 2003

MN Dudley

Effect of Amoxicillin 7mg/kg q8h on Str. pneumoniae With Varying Levels of Penicillin Susceptibility in the

Neutropenic Mouse Thigh Model Using Human PK

Andes & Craig, AAC 1997


Landmark paper showing full integration of information from animal model studies, population PK and MC simulation to identify dosing

Breakpoints for MIC testing Monte Carlo simulation becomes an important tool for drug

development as well as consensus work in setting breakpoints in CLSI, EUCAST


William Craig, MD

Tireless researcher Teacher and mentor Enthusiastic investigator Creative Encourager to young investigators Visionary Organizer and “peacemaker” Highly respected by peers, students


The Duke or The Dean of PK-PD??


MN Dudley

Efflux Pump Inhibitors: A Viable Option?

-5

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-1

0

1

2

3

10 100 1000

AUC:MIC

Cha

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in L

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U/th

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nfxC strains (N = 8)

Emax model of nfxC strains

Non-nfxC strains (N = 14)

Emax model of non-nfxC strains

Emax = 4.8EC50 = 29.6

R2 = 0.87Gamma = 3.8

Emax = 4.2EC50 = 68.8

R2 = 0.86Gamma = 3.2

MouseThigh Infection Model

Strains with MexEF-OprN overexpression are more susceptible to levofloxacin in vivo than strains without MexEF-OprN overexpression

MIC = 0.125- 7.2 ug/ml

MIC = 0.015 -2.2 ug/ml

Griffith et. al. AAC 2006


Prospective Evaluation of a Mathematical Model Predicted

Levofloxacin Regimen for Suppression of Resistant

Subpopulations in Mouse Thigh Model

AUC:MIC= 52

Resistance Predicted

Validation of Mathematical Model Predicted AUC:MIC= 157 to Prevent Selection of Resistance

Monte Carlo Simulation of Levofloxacin 750 mg QD for 10,000 Patients

Jumbe et. al. J Clin Invest 2003;112:275.

history of pk-pd: 1970s- 2008: from the formative years to mainstream use

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