PHARMACOKINETIC & PHARMACODYNAMIC OF ANTIBIOTICS SITI HIR HURAIZAH MD TAHIR Bpharm (UKM), MSc (Clinical Microbiology) (UoN) CLINICAL PHARMACIST HOSPITAL MELAKA
WHY STUDY PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD)? Individualize patient drug therapy Monitor medications with a narrow therapeutic index Decrease the risk of adverse effects while maximizing pharmacologic response of medications Evaluate PK/PD as a diagnostic tool for underlying disease state
WHAT IS PHARMACOKINETIC? Derived from the ancient Greek: - Pharmakon: Drug - Kinetikos: to do with motion The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism and elimination of medications. What the body does to the drug?
WHAT IS PHARMACODYNAMIC? The study of the action or effects of drugs on living organism Relationship between drug concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects. What the drug does to the body?
Pharmacokinetics Pharmacodynamics A D M E
PKPD Pharmacokinetics Pharmacodynamics Time course of drug concentration in the body Concentration-effect relationship Dose Drug concentration in blood Effect Drug concentration at target site Clinical Outcomes Pharmacokinetics/Pharmacodynamics (PK/PD) Dose-effect relationship Varghese, J.M. et al. Crit Care Clin 27 (2011) 19 34
Pharmacokinetics Parameters PK Parameter Definition Description Clearance (CL) Volume of distribution (Vd) Half-life (t1/2) The volume of blood cleared of drug per unit time Apparent volume of fluid that contains the total drug dose administered at the same concentration as in the plasma Time required for the plasma drug concentration to decrease by half CL measures the irreversible elimination of a drug from the body by excretion or metabolism Vd is the parameter that relates the total amount of drug in the body to the plasma concentration Half-life is dependent on CL and Vd; half-life is increased with a decrease in CL or an increase in Vd Cmax Peak drug concentration during a dosing interval Cmin AUC0 24 Minimum drug concentration during a dosing interval Area under the concentrationt-time curve from 0 to 24 h Varghese, J.M. et al. Crit Care Clin 27 (2011) 19 34
SEPSIS Increased cardiac output Leaky capillaries &/altered protein binding Normal organ function End organ Dysfunction (eg renal /hepatic) Increased CI Increased Vd Unchanged Vd Decreased CI Low Plasma Concentration Normal Plasma Concentration High Plasma Concentration Roberts, JA. et al. Crit Care Med 2009 Vol. 37, No. 3
Variability In PK Different CI Supranormal (sepsis, stress response) Impaired (ARF) Different Vd Increased (obesity, burns, sepsis, pregnancy) Different VD Different CI Different VD
Volume of Distribution and Fluid Shifts in Sepsis Sepsis release of endotoxins and exotoxins from pathogens. Toxins endothelial damage and thus increased capillary permeability. Capillary leak fluid shifting from the intravascular space into the interstitial space increase the Vd for hydrophilic antimicrobials lower plasma and tissue concentrations. Lipophilic drugs greater extent intracellularly & into adipose tissue not greatly influenced by fluid shifts. Bochud PY and Calandra, BMJ 2003;326:262 6.
Hydrophilic & Lipophilic Hydrophilic antibiotics General PK Vd Low Vd Altered PK in Critically Ill CL Predominantly renal or depending on renal function Distribution Poor intracellular penetration Interstitial penetration Lipophilic antibiotics Examples Beta-lactams, carbapenems, aminoglycosides, glycopeptides, linezolid and Colistin Vd High Unchanged CL Predominantly hepatic or depending on hepatic function Distribution Examples Good intracellular penetration Varghese, J.M. et al. Crit Care Clin 27 (2011) 19 34 Unchanged interstitial penetration fluoroquinolones, macrolides and tigecycline
Dosing should accounts for these changes to prevent suboptimal therapy and suboptimal outcome. Roberts, JA. et al. Crit Care Med 2009 Vol. 37, No. 3
Inappropriate dosing may cause treatment failure
Important Factors to Emphasis - Sufficient spectrum - Given as soon as clinical symptoms of infection emerge - Give effective dose that meets the specific requirements of the patient
Antibiotics & its PKPD Different antimicrobial classes have different PK/PD Dosing should take into consideration the different in PK/PD characteristic of prescribed antimicrobial & susceptibility of the organism to achieve optimal efficacy
PK/PD indices correlated with optimal antimicrobial activity Antibiotic Classification PK/PD Index Definition of PK/PD Index Examples of Antibiotics Timedependent T>MIC Percentage time for which the concentration of a drug remains more than the minimum inhibitory Concentration (MIC) during a dosing interval Beta-lactams Carbapenems Clindamycin Erythromycin Linezolid Concentration dependent Concentration dependent with time dependence Cmax/MIC AUC0 24/MIC Ratio of the peak drug concentration to the MIC of the pathogen Ratio of the area under the concentration time curve (AUC) during a 24-h period to the MIC of the pathogen Aminoglycosides Fluoroquinolones Glycopeptides Tigecycline Azithromycin Colistin Varghese, J.M. et al. Crit Care Clin 27 (2011) 19 34 Michalopoullos A. S. & M. E. Ann Intensive Care 1 (2011)
Concentration dependent vs Time dependent Concentration dependent Maximum killing = Cmax above 8-10x MIC (AMG) AUC above MIC by 80% (Quinolones) Dose to achieve highest peak value/auc Time dependent Maximum killing = Drug concentrations 3-4x MIC Dose to achieve longer time of drug concentrations > 3-4x MIC (60-70%) Burgess, Use of Pharmacokinetics and Pharmacodynamics to Optimize Antimicrobial Treatment of Pseudomonas aeruginosa Infections, CID 2005:40(Suppl 2) S99-104
Concentration (μg/ml) Pharmacodynamic optimization : time-dependant antibiotic Continuous infusion to maintain drug concentrations above the MIC for the entire 24-hour interval Loading dose Continuous infusion MIC Time (hour)
Concentration (μg/ml) Extended infusion administer the same dose at the same frequency of administration but to extend the infusion time Rapid infusion (30 min) Meropenem 500 mg Extended infusion (3 hours) MIC Time (hour) Dandekar PK et al. 2003. Pharmacotherapy. 23: 988-991
Effect of extended infusion of carbapenem antibiotics on the bactericidal cumulative fraction of response against multidrug-resistant Pseudomonas aeruginosa Antibiotic regimen Bactericidal cumulative reaction of response (%) 30-minute infusion 3-hour infusion Change (%) Imipenem 1g q8h 69.3 72.0 +2.7 Meropenem 1g q8h 77.1 83.8 +6.7 Meropenem 2g q8h 84.1 88.1 +4.0 Ludwig E et al., 2006. Int. J. Antimicrob. Agents. 28: 433-438
Suggested Dosing Adjustment for Critically Ill Patients Roberts JA et alcrit Care Med 2009 Vol. 37, No. 3 Antibiotic Class Normal Renal Function Moderate to Severe Renal Dysfunction Comments Aminoglycosides Carbapenems Glycopeptides Fluoroquinolones Use high doses (e.g., gentamicin 7 mg/kg) where possible to target Cmax:MIC ratio of 10; monitor Cmin and aim for undetectable plasma concentrationsa Consider extended or continuous infusion or more frequent dosing to ensure T MIC; therapeutic drug monitoring may be useful if available Dosing at 30 40 mg/kg/day (vancomycin),which can be increased according to Cmin plasma concentrations (aim for 15 20 mg/l); continuous infusions should be used when difficulty obtaining therapeutic Cmin Doses that achieve high Cmax:MIC ratio should be targeted (e.g. ciprofloxacin 1200 mg/day); levofloxacin may require 500 mg 12-hourly in some patients with high creatinine clearance; where high doses used, monitor for toxicity (seizures) Use high doses where possible and monitor Cmin thereafter (36 to 48 hourly extended interval dosing acceptable); dosing can be guided by MIC data If intermitted dosing used, dosing can occur at reduced dose or frequency (not both); toward larger doses as beta lactams have large therapeutic window High dosing on day 1 may be required to ensure adequate distribution; dose adjustments should occur according to Cmin concentrations Dose adjustment is probably only required in renal impairment for levofloxacin, gatifloxacin, and ciprofloxacin; where possible reduce frequency and maintain dose Tigecycline Use 100 mg loading dose then 50 mg 12 hourly No dose adjustment required in renal failure Linezolid Use 600 mg 12 hourly or dialysis Colistin Use 5 mg/kg/day of colistin base (75,000 international units/kg/day colistimethate sodium)c intravenously in 3 divided doses Reduce dose or frequency (not both)
CONCLUSION Understanding the PK and PD of antibiotics helps achieve maximum benefit with less side effects. Dose and dosing frequency of antibiotics are determined based on the PK and PD properties. Evidence-based dosing is necessary to achieve pharmacodynamic targets and to prevent resistance as well as optimizing patient outcomes in facilities without TDM services.