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History of PK-PD: 1970s- 2008: From the Formative Years to Mainstream Use

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

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History of PK-PD: 1970s- 2008: From the Formative Years to Mainstream Use

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  1. MN Dudley 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

  2. 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

  3. 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)

  4. Billy Craig:Guitar Player or PK-PD Expert?

  5. 1970’s: Understanding Antibiotic PK • Pharmacokinetic analysis tools • Aminoglycoside antibiotics • Protein binding of antimicrobials

  6. 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.

  7. 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.

  8. 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.

  9. 1980’s: Identifying the Paradigm • Model Development • Insights into Classes of Antibiotics • Beta-lactams • Fluoroquinolones • Aminoglycosides • Microcomputers

  10. 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!!

  11. 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.

  12. 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.

  13. 1983

  14. 1980s: An Important Tool is Introduced Impact 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”

  15. Population Analysis in the Mouse Thigh Model Gerber, Vestola, Brandel, and Craig, JID 1982

  16. 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.

  17. In Vitro Hollow Fiber Pharmacodynamic Model For Study of Antibacterial, Antiviral Pharmacodynamics Zinner, Blaser, Dudley, Am J Med, 1986

  18. Blaser et. al., AAC 1987

  19. 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.

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

  21. 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

  22. 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

  23. Ciprofloxacin: Bacterial Eradication from Sputum and AUC:MIC24 in Hospitalized Patients 100 Forrest A et al. Antimicrobial Agents Chemother 37:1073–1081, 1993. 75 AUC:MIC < 125 % of patients remaining culture-positive 50 AUC:MIC 125-250 25 AUC:MIC > 250 0 0 2 4 6 8 10 12 14 Days of treatment

  24. Sum of Susc. + Resist Observed Total CFU Resistant Subpop Susc. Subpop Modeling Bacterial Subpopulations for Fluoroquinolones and Ps. aeruginosa Dudley & Zinner, ICAAC 1987; Jumbe et.al, 2003

  25. Memorable and Historic Battles • George Drusano • Jerry Schentag • John Powers • Others?

  26. Comparison of Serum Levels of Amoxicillin (7mg/kg Human Dose) in Humans and Mice With Uranyl Nitrate-Induced Renal Failure Andes & Craig, AAC 1997

  27. 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

  28. 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

  29. William Craig, MD • Tireless researcher • Teacher and mentor • Enthusiastic investigator • Creative • Encourager to young investigators • Visionary • Organizer and “peacemaker” • Highly respected by peers, students

  30. The Duke or The Dean of PK-PD??

  31. MN Dudley MouseThigh Infection Model Strains with MexEF-OprN overexpression are more susceptible to levofloxacin in vivo than strains without MexEF-OprN overexpression MIC = 0.015 -2.2 ug/ml MIC = 0.125- 7.2 ug/ml Griffith et. al. AAC 2006

  32. Monte Carlo Simulation of Levofloxacin 750 mg QD for 10,000 Patients Prospective Evaluation of a Mathematical Model Predicted Levofloxacin Regimen for Suppression of Resistant Subpopulations in Mouse Thigh Model AUC:MIC= 52 Resistance Predicted Jumbe et. al. J Clin Invest 2003;112:275. Validation of Mathematical Model Predicted AUC:MIC= 157 to Prevent Selection of Resistance

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