Vancomycin Pharmacokinetics. Myrna Y. Munar, Pharm.D., BCPS Associate Professor of Pharmacy

Transcription

1 Vancomycin Pharmacokinetics Myrna Y. Munar, Pharm.D., BCPS Associate Professor of Pharmacy

2 Goals Review the PK properties of vancomycin Compare and contrast methods of dosage regimen design for vancomycin Apply the PK model to develop and adjust individualized dosing regimens for patients

3 Objectives Through the preparation for and participation in this lecture, a successful student should be able to: Identify the appropriate PK model and equations commonly used to dose vancomycin Describe the PK highlights of vancomycin, and identify the normal population PK parameters Identify absorption characteristics of vancomycin List the distribution characteristics and protein binding of vancomycin

4 Objectives Discuss when peak and trough serum vancomycin concentrations should be obtained Describe the elimination and excretion of vancomycin Identify the normal population PK parameters and the suggested dosage recommendations for vancomycin Determine appropriate target vancomycin concentrations for a given patient Discuss adverse effects of vancomycin and relate to serum concentrations Identify those disease states known to influence the PK of vancomycin

5 Objectives Discuss the effect of various diseases or physiologic states on the disposition of vancomycin Evaluate the advantages and limitations of dosing nomograms for vancomycin Compare and contrast the use of a one- vs two-compartment model to dose vancomycin

6 Objectives Given a patient history and therapeutic goal, develop a loading dose and maintenance dose regimen for vancomycin using dosing nomograms and an appropriate PK model Given a patient history, therapeutic goal and serum concentration data, calculate k and V D and use to adjust the patient s maintenance dose regimen Identify indications for monitoring serum vancomycin concentrations Develop a PK monitoring plan for a given patient receiving vancomycin

7 Introduction Obtained from Streptomyces orientalis MOA: Glycopeptide antibiotic with bactericidal activity by blocking cell wall synthesis at a site different from penicillins Secondary damage to cytoplasmic membrane Bactericidal against most gram + organisms (except Enterococci) Slow-killing activity Synergism with gentamicin against gram positive organisms

8 Bacteria MIC Range (mcg/ml) MIC Median (mcg/ml) MBC (mcg/ml) Staphylococcus aureus Methicillin susceptible Methicillin resistant Staph epidermidis Staph pneumonia Strep viridans > 50 Strep faecalis > > 100 Strep bovis Clostridia spp > 10 Clostridum difficile <

9 Concern for Resistance Promote appropriate use Glycopeptide-resistant enterococci (GRE) Aka vancomycin-resistant enterococci (VRE) Multiply resistant organism High-level resistance; vanco MIC > 64 Organisms resistant to vancomycin may have no alternative therapy

10 Vancomycin OHSU Formulary Restriction Approved uses at OHSU Documented infection caused by gram-positive organisms not susceptible to other agents (i.e. penicillins, cephalosporins, and clindamycin) Documented infection caused by susceptible organism in patients with a documented, lifethreatening allergy to beta-lactam antimicrobials ( i.e. penicillins and cephalosporins) Oral treatment of antibiotic-associated colitis which is severe and potentially life-threatening or has failed to respond to 3 days of oral metronidazole or oral bacitracin

11 Vancomycin OHSU Formulary Restriction Approved uses at OHSU continued Three days or less of empiric therapy when there is reasonable suspicion of oxacillin resistant S. aureus, S. epidermidis (coagulase-negative staph), or ampicillinresistant enterococcus Surgical prophylaxis in patients with documented cefazolin allergy; or documented, severe penicillin allergies and no recent history of tolerating a cephalosporin Lists approved and non-approved uses at OHSU

12 PK Highlights Primarily excreted unchanged by glomerular filtration Two-compartment drug dosed with a one-compartment model Evolving approach to PK dosing

13 Absorption Oral: F < 0.05 May be significantly absorbed Patients who are functionally anephric Patients who have GI bleeds/ulcerations Concentrations up to 30 mcg/ml have been reported IV: F = 1.0; IM: very painful Intraperitoneal: F = with a 6 hour dwell time Intrathecal/Intraventricular : CNS infections require intrathecal instillation Dose = 5 20 mg q 24 h Get your clicker ready

14 Please make your selection Choose the FALSE statement A) Vancomycin cannot be given orally because of poor oral bioavailability, F < 0.05 B) Vancomycin is active against Clostridium difficile, therefore it can be given orally to treat antibioticassociated colitis aka pseudomembranous colitis C) According to OHSU guidelines, vancomycin can be given for oral treatment of antibiotic-associated colitis which is severe and potentially lifethreatening or has failed to respond to 3 days of oral metronidazole or oral bacitracin D) Vancomycin is not the first line agent for antibioticassociated colitis because of changing or increasing resistance patterns

15 Distribution Distributes into pleural, pericardial, ascitic, bile, and synovial fluids Crosses placenta Excreted in breast milk CSF concentrations in n=9 children with bacterial meningitis were 14 28% of serum concentrations

16 Two-Compartment Model Alpha (distribution) phase = hrs Beta (elimination) phase = 3 9 hrs Average terminal phase t 1/2 = 7hrs Terminal t 1/2 & CL correlated with CrCl

17 Vancomycin Infusion Guidelines Dose (mg) < > > 1500 Infusion Duration (min) Time to draw C peak (min after start of infusion) All trough values should be drawn immediately prior to next dose (within 30 min of next dose). All serum levels should be drawn from an IV site other than the IV site utilized for infusion of the drug.

18 Peak Concentrations (C peak ) When to draw peak concentrations: To assure that distribution is complete, peaks should be drawn at 5 alpha-half-lives after administration (2.5 5 hours ) However, most obtain peaks as follows: Normal renal function: draw 1 hour after a 1 hour infusion Impaired renal function (CrCl < 50 ml/min): draw 2 hours after a 1 hour infusion

19 PK- Distribution Serum Concentration alpha beta true PK extrap PK measured PK Time (hrs)

20 Get your clicker ready

21 Drawing peaks in the distributive phase will lead to errors in calculating: A) Volume of distribution B) Clearance C) Elimination rate constant (k) D) Half-life (t 1/2 ) E) C and D

22 Distribution V D,ss = 0.8 L/kg (range: L/kg) V c = 0.2 = 0.6 L/kg Protein binding 50 60% in healthy volunteers 30 40% in infected patients 0 31% (mean = 18.5%) in end-stage renal disease (ESRD)

23 Elimination Route: primarily excreted (80 90%) unchanged by glomerular filtration May have some tubular secretion or reabsorption Some evidence of non-renal clearance CL NR = 6 ml/min in normal renal function CL NR = 4 6 ml/min in ESRD

24 Renal Function k (hr -1 ) y=mx + b k= hr -1 (CrCl ml/min) Matzke CrCl ml/min

25 Half-life (t 1/2 ) & Clearance (CL) T 1/2 = 7 hours in normal renal function T 1/2 = 5 7 days in anephrics Vancomycin CL (ml/min/kg) = (CrCl in ml/min/kg) Anephric CL = 5 7 ml/min

26 Vancomycin Serum Concentrations Generally accepted guidelines Peaks mcg/ml = mg/l Troughs 5-15 mcg/ml = mg/l Depends on type, severity of infection Trough 20 mcg/ml targeted in certain clinical situations Rationale based on average MIC for Staph aureus of 5 mg/l; therefore, a peak of 6 8 x MIC (30 40 mg/l) and a trough 1 2 x MIC (5 15 mg/l) would be effective Get your clicker ready

27 Please make your selection A) Vancomycin exhibits concentrationdependent bactericidal activity B) Vancomycin exhibits time-dependent bactericidal activity C) Neither D) Both

28 PD Properties of Antimicrobials Pattern of Activity Antibiotics Goal of Therapy Type I Concentration-dependent killing and Prolonged persistent effects AG Daptomycin FQ Ketolides Maximize concentrations PK/PD Parameter 24h-AUC/MIC Peak/MIC Type II Time-dependent killing and Minimal persistent effects Carbapenems Cephalosporin Erythromycin Linezolid Penicillins Maximize duration of exposure T>MIC Type III Time-dependent killing and Moderate to prolonged persistent effects. Azithromycin Clindamycin Oxazolidinones Tetracyclines Vancomycin Maximize amount of drug 24h-AUC/MIC

29 Pharmacodynamics PK/PD predictors of outcome Time > MIC Goal: exceed MIC for entire dosing interval AUIC AUIC; AUC 24 /MIC > 125 (? > 400) proposed to correlate w/ bacterial eradication and prevent resistance development Schentag JJ. Crit Care Med 2001;29(4):N100-7.

30 Pharmacodynamics Unlike aminoglycosides, vancomycin does not exhibit peak-associated (concentrationdependent) killing Vancomycin exhibits time-dependent bacterial killing usually best achieved at troughs 3 5 x MIC Troughs are monitored Peaks are important primarily from a toxicity standpoint

31 Ototoxicity Incidence: < 2%; damage to 8 th cranial nerve Deafness, vertigo, dizziness, tinnitus May be reversible or permanent Reported with peak vancomycin concentration > 80 mg/l or rapid infusions Commonly associated with vancomycin given with erythromycin or aminoglycosides Associated with earlier, less pure vancomycin

32 Ototoxicity Patients at risk: renal impairment receiving high IV doses for prolonged periods of time receiving other ototoxic drugs

33 Nephrotoxicity Associated with earlier, less pure vancomycin Very low, rare reports with newer formulations Rarely, acute interstitial nephritis has been reported Nephrotoxicity associated with combined therapy with furosemide, aminoglycosides, or amphotericin B has been reported

34 Get your clicker ready

35 True or False Way back when Dr. Munar was going to pharmacy school, vancomycin was referred to as Missisippi mud.

36 Nephrotoxicity Patients at risk: Neutropenia Peritonitis Elderly Liver disease Male patients

37 Red Neck Syndrome Histamine-like reaction with rapid administration of vancomycin (>500 mg over 30 minutes) Recommend administration rates of < 15 mg/min (eg 1 g over 1 hour) Central development of erythema and rash at base of neck, flushing, pruritis, hypotension, chills, tachycardia, and headache; rarely cardiac arrest and seizures

38 Red Neck Syndrome Usual onset a few minutes after start of infusion, but may not occur until after infusion has ended Usually resolves spontaneously over several hours after d/c infusion Reaction may necessitate use of antihistamines, corticosteroids, or IV fluids Lengthening time of infusion to 2 hours or pretreatment w/antihistamine may decrease future reactions

39 Other Neutropenia Rash Phlebitis

40 Factors Affecting PK of Vancomycin

41 Obesity Evidence suggests V D and CL in obese patients correlates best with ACTUAL vs IBW (Blouin) Use an adjusted body weight in morbidly obese patients

42 Pediatrics Neonates Infants Children V D,ss (L/kg) CL (ml/min/ m 2 ) Rodvold, 1997

43 Burn Patients V D,ss = L/kg CL = ml/min Ref: Pleasants

44 Dosage Regimen Design

45 Patient Database Demographic data: age, weight, height, gender Vital signs Disease states present Renal function Concurrent drug therapy Organism and site of infection Pertinent labs

46 Therapeutic Objective Decide on target serum concentrations Identify monitoring parameters for efficacy and toxicity (BUN, SCr, I/O, WBC w/diff, C & S, x-rays, temperature)

47 Usual Range of Doses Adults (normal renal fxn) mg q 6-12 h About 25 mg/kg/day Eg 500 mg q 6 h or 1 g q 12 h Anephrics 7.5 mg/kg q 7-10 days Usually 1 g every week Exception: pt undergoing high-flux hemodialysis Use these guidelines for comparative purposes after performing calculations

48 Monitoring: Is it Justified? Efficacy Lack of clear correlation between levels and clinical outcome Considerations MIC for pathogens PK/PD properties assoc. w/ efficacy (e.g., time above MIC, AUIC, AUC/MIC) Safety Risk of toxicity based predominantly on animal models/case reports Correlation with serum concentrations not clear May augment oto-, nephrotoxicity of AG

49 Monitoring Practice varies Recommend trough every 5-7 days, unless change in PK parameters dictates more frequently May consider peak concentrations in certain circumstances (next slide) Increasing data for monitoring AUC/AUIC

50 Considerations for checking peak/ trough or more frequent monitoring Critically ill pts Site of infection (endocarditis, osteomyelitis ) Poor therapeutic response Suspected unusual PK Concurrent oto- or nephrotoxic agents Unusually high MIC values Severe renal impairment

51 Approach Begin patients on usual doses Obtain steady-state serum concentrations Adjust dose Nomograms are available for patients with impaired renal function

52 Path to follow for starting dose

53 Determine CrCl For this exercise, use Cockroft & Gault We will discuss the various methods for calculating glomerular filtration rate (GFR) or creatinine clearance (CrCl) in the renal PK topics

54 Cockroft & Gault ( 140 age) ( 72 Scr) CrCl(ml / min) = IBW( 0. 85females) M: IBW (kg) = 50 kg (Ht. Inches > 5 ) F: IBW (kg) = 45.4 kg (Ht. Inches > 5 ) Features: For patients Scr < 4.5 mg/dl; within 30% of IBW; age > 18 years Requires steady-state Scr values Ref: Nephron 1976;16:31-41

55 Renal Function k (hr -1 ) y=mx + b k= hr -1 (CrCl ml/min) Matzke CrCl ml/min

56 Population PK Equations Determine k (Matzke) k (hr -1 ) = (CrCl) CrCl in ml/min Determine t1/2 (hrs) = 0.693/k Determine Vd (L) = 0.8 L/kg Range L/kg Use actual body weight Use adjusted body weight if morbidly obese

57 Optimum Dosing Interval (tau) tau = 1 k ln C C min, desired max, desired + t Tau = dosing interval Small t = infusion time

58 Short IV Infusions C max1 Tau-t C C C C max1 min1 max, ss min, ss = = C dose / t V k D max1 e max, ss kt dose / t kt ( 1 e ) OR ( 1 e ) k ( Tau t) dose / t = CL = C e kt ( 1 e ) k ( Tau t) CL 1 1 e ktau C min1 small t = t = infusion time tau = dosing interval

59 Short IV Infusions C C C C rate in over rate out max1 min1 max, ss min, ss dose / t = VD * k = C e max1 max, ss ( kt 1 e ) k ( Tau t) dose / t = VD * k = C e ( kt 1 e ) k ( Tau t) R ac 1 1 e ktau Recall, dose/t = rate of drug infusion 1 e -kt = fraction of SS achieved by time t OR fraction of drug lost during time t e -k(tau-t) = fraction of drug remaining at end of dosing interval = time tau minus t R ac = accumulation factor, allows you to fast forward to steady-state (SS)

60 ( ) = = kt ktau desired D ktau kt D e e C k V t dose e e k V t dose C 1 1 * * / * / max, max Optimum Dose Solve for dose/t

61 Double check Use optimal dosing regimen suggested to determine expected C min and C max

62 Short IV Infusions Tau-t C C max, ss min, ss dose / t = VDk = C max, ss e kt ( 1 e ) k ( Tau t) 1 1 e ktau small t = t = infusion time tau = dosing interval

63 Path to follow for working from known concentrations

64 Mechanics of Obtaining Serum Concentrations Peak After Distribution Log C p Delta time! = tau minus t Dose Infused IV Trough Before Dose Dose Infused IV Time At SS, assume trough Dose Infused IV

65 Example MI was prescribed vancomycin 1 g over 1 hour every 24 hours (0800). Vancomycin concentrations were obtained around the 4 th dose, given at The concentrations are as follows: Time 0800; Vancomycin 12 mcg/ml Time 1000; Vancomycin 30 mcg/ml

66 Mechanics of Obtaining Serum Concentrations Peak After Distribution 1000 Log C p Delta time! Dose Infused IV Trough Before Dose 0800 Dose Infused IV Time At SS, assume trough 0800 next day Dose Infused IV

67 Get your clicker ready

68 In order to calculate k, we assume that delta t is: A) The difference between 0800 and 1000, which is 2 hours B) The difference between 1000 and 0800 the following day, which is 22 hours C) I can t tell from the graph

69 Elimination Rate Constant (k) k or k = = ln C C ln C Δt ln C Δt 1 This equation will give you a negative value. -k = negative number, therefore + k = positive number

70 Example MI was prescribed vancomycin 1 g over 1 hour every 24 hours (0800). Vancomycin concentrations were obtained around the 4 th dose, given at The concentrations are as follows: Time 0800; Vancomycin 12 mcg/ml Time 1000; Vancomycin 30 mcg/ml

71 Get your clicker ready

72 Calculate k & t 1/2 A) k = 0.46; t 1/2 = 1.5 hrs B) k = 0.042; t 1/2 approx. 17 hrs C) I can t tell.

73 PK- Distribution Serum Concentration alpha beta true PK extrap PK measured PK Time (hrs)

74 Determine patient C max & C min C t or C = max C = max C e e t kt kt

75 If C max & C min acceptable, continue dosing. If not, determine new regimen.

76 Volume of Distribution (V D) V D = dose k / t C max 1 e kt ( kt ) C e min Small t = infusion time

77 Optimum Dosing Interval (tau) tau = 1 k ln C C min, desired max, desired + t Tau = dosing interval Small t = infusion time

78 ( ) = = kt ktau desired D ktau kt D e e C k V t dose e e k V t dose C 1 1 * * / * / max, max Optimum Dose Solve for dose/t

79 Short IV Infusions C max1 Tau-t C C C C max1 min1 max, ss min, ss = = C dose / t V k D max1 e max, ss kt dose / t kt ( 1 e ) OR ( 1 e ) k ( Tau t) dose / t = CL = C e kt ( 1 e ) k ( Tau t) CL 1 1 e ktau C min1 small t = t = infusion time tau = dosing interval

80 Short IV Infusions C C C C rate in over rate out max1 min1 max, ss min, ss dose / t = VD * k = C e max1 max, ss ( kt 1 e ) k ( Tau t) dose / t = VD * k = C e ( kt 1 e ) k ( Tau t) R ac 1 1 e ktau Recall, dose/t = rate of drug infusion 1 e -kt = fraction of SS achieved by time t OR fraction of drug lost during time t e -k(tau-t) = fraction of drug remaining at end of dosing interval = time tau minus t R ac = accumulation factor, allows you to fast forward to steady-state (SS)

81 Short IV Infusions Tau-t C C max, ss min, ss = = C dose / t CL max, ss e kt ( 1 e ) k ( Tau t) 1 1 e ktau small t = t = infusion time tau = dosing interval