Pharmacokinetics of Vancomycin in Adult Oncology Patients Prepared by: Hadeel Al-Kofide Supervised By: Dr. Iman Zaghloul Dr. Lamya AlNaim

Do you remember what went between the clinical pharmacist & the intern ??

Cancer & Infection Gram positive infections, causes up to 70% of confirmed cancer infections Methicillin-resistance Staphylcoccus aureus (MRSA) account for up to 50% of S.aureus infection Vancomycin is the only antibiotic studied for the treatment of febrile neutropenia in cancer patients when MRSA is suspected Jackson A, Pharmacotherapy Self-Assessment Program, 4th Edition, Infections in Patients With Cancer

What’s The Problem??!!

Volume of Distribution Literature Review Studies have shown a sub-therapeutic levels of vancomycin in cancer patients Therefore, higher dosages have been proposed to ensure optimal drug concentrations Clearance Volume of Distribution Pea F et al, Clin Drug Invest. 2000; Buelga D et al, Antimicrob Agents Chemother. 2005. Le Normand Y, Int J Biomed Comput. 1994

Vancomycin

Therapeutic Levels Vancomycin normal levels are: Peak=20 -40 mg/L Trough=10-15 mg/L Cantú T et al, Antimicrob Agents Chemother. 1990; Begg E et al, J Clin Pharmacol. 2001

Pharmacokinetics Oral bioavailability <5 % Renal Elimination ≈ 85-90% Non-renal elimination ≈ 10-15% Cl = 0.65 x CrCl Cl, Clearance. CrCl, Creatinine Clearance Begg E et al, J Clin Pharmacol. 2001; Pea F et al, J Antimicrob Chemother. 2000; Aldaz A et al, Ther Drug Monit. 2000

Pharmacokinetics Vd = 0.7 L/TBW kg t ½ ≈ 6 hours Protein binding ≈ 50 % Bound to albumin & α1 acid glycoprotein Vd, Volume of Distribution. TBW, Total Body Weight. t1/2, Half-Life Begg E et al, J Clin Pharmacol. 2001; Pea F et al, J Antimicrob Chemother. 2000

Going back to cancer patients

Literature Review Population PK * Patients with hematological malignancies ** Patients with different types of cancer *** Cl 0.65 x CrCl 1.08 x CrCl 1.12 x CrCl Vd 0.7 L/kg 0.98 L/kg t1/2 6 hr 3 hr * Begg E et al, J Clin Pharmacol. 2001; ** Bulge D et al, Antimicrob Agents Chemother. 2005 *** Le Normand Y, Int J Biomed Comput. 1994

Why vancomycin ?!

Because its Vancomycin! Vancomycin is an integral part of the management of febrile neutropenia in cancer patients for several reasons: Emergence of MRSA Absence of an alternative in these patients MRSA, Methicillin-resistance Staphylcoccus aureus

Objectives

Objectives Assess the pharmacokinetics of vancomycin in adult oncology patients in order to: Evaluate the effects of several clinical factors on the disposition kinetics of vancomycin Find potential predictive factors for dosage individualization

Objectives Assess the pharmacokinetics of vancomycin in adult patients (without cancer) in order to: Compare them to cancer patients Obtain vancomycin pharmacokinetic parameters in Saudi population

Methodology

Methodology A retrospective observational study Adult (≥15 year-old) inpatients admitted to King Khalid University Hospital from 2005-2006 on vancomycin for suspected or documented gram-positive bacteria were chosen for analysis Two groups of patients were assigned for eligibility

Methodology

Methodology Patients were excluded based on two criteria: 1) The lack of necessary data concerning the patients’ demographic, clinical status, and vancomycin blood levels 2) Any patient with either acute or chronic renal failure

Methodology Measurement of the peak & trough levels were conducted after the third dose of the initial dosing regimen Vancomycin pharmacokinetic parameters were calculated

Results

Number of Patients Groups Study Control Cancer 18 patients Non-Cancer

Demographic Data Characteristics Study Group Control Group P-value Age, mean (SD) 43.4 (22.1) 48.5 (20.2) 0.526 Height cm, mean (SD) 161.1 (11.7) 164.9 (10.1) 0.349 TBW kg, mean (SD) 66.8 (17.1) 68.9 (14) 0.714 IBW kg, mean (SD) 55.9 (12.5) 58.4 (10.6) 0.56 BSA, mean (SD) 1.7 (0.25) 1.7 (0.19) 0.5 SD, Standard Deviation. TBW, Total Body Weight. IBW, Ideal Body Weight. BSA, Body Surface Area.

Type of Cancer Cancer group

Chemotherapy Cancer group

Clinical Data Characteristics Study Group Control Group P-value Albumin g/L, mean (SD) 26.1 (6.0) 29.5 (6.7) 0.155 Total Protein g/L, mean (SD) 62.4 (6.2) 66.1 (9.5) 0.206 Serum Creatinine umol/L, mean (SD) 64.2 (21.4) 83.1 (35.2) 0.073 Creatinine Clearance ml/min, mean (SD) 105.5 (62.2) 87.2 (27.5) 0.331 SD, Standard Deviation.

Vancomycin Regimen Characteristics Study Group Control Group Dose mg, mean (SD) 986.1 (159.8) 1000 (353.6) Frequency hr, mean (SD) 13.3 (3.9) 11.5 (1.7) Peak mg/L, mean (SD) 19.1 (6.3) 27.2 (10.9) Trough mg/L, mean (SD) 7.1 (5.5) 8.5 (4.5) SD, Standard Deviation.

Vancomycin Pharmacokinetics K Elimination hrˉ¹ Group Mean SD Cancer 0.14 0.1 Non- Cancer 3.9 95% CI t P-value -6.3E-02 6.7 E-2 0.068 0.947 Lower Upper SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Half-Life hr Group Mean SD Cancer 8.6 7.1 Non- Cancer 5.4 1.9 95% CI t P-value -0.7 7.1 1.7 0.111 Lower Upper SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Volume of Distribution L Group Mean SD Cancer 70 45 Non- Cancer 31.1 8.3 95% CI t P-value 16 61.5 3.5 0.002 Lower Upper SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Clearance ml/min Group Mean SD Cancer 110.1 42 Non- Cancer 71.2 22.4 95% CI t P-value 12.8 64.8 3.05 0.005 Lower Upper SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Clearance/Creatinine Clearance Group Mean SD Cancer 1.15 0.47 Non- Cancer 0.86 0.26 95% CI t P-value -3.3E-03 0.58 2.02 0.052 Lower Upper SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Literature Vancomycin PK Vd = 0.7 * TBW Cl = 0.65 * CrCl Vd/TBW = 0.7 Cl/CrCl = 0.65 PK, Pharmacokinetics. Vd, Volume of Distribution. TBW, Total Body Weight. Cl, Clearance. CrCl, Creatinine Clearance.

Vancomycin Pharmacokinetics Literature PK vs. Cancer Patients PK Parameter Mean SD 95% CI t P-value Cl/CrCl 1.15 0.47 0.27 0.73 4.57 0.000 Lower Upper PK, Pharmacokinetics. Cl, Clearance. CrCl, Creatinine Clearance. SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Literature PK vs. Cancer Patients PK Parameter Mean SD 95% CI t P-value Vd/TBW 1.1 0.8 -1.8E-2 0.77 2 0.061 Lower Upper PK, Pharmacokinetics. Vd, Volume of Distribution. TBW, Total Body Weight. SD, Standard Deviation. CI, Confidence Interval.

Vancomycin Pharmacokinetics Cl, Clearance. CrCl, Creatinine Clearance. Vd, Volume of Distribution. TBW, Total Body Weight.

Vancomycin Cl vs. CrCl Linear regression analysis Cancer patients Non-Cancer patients Cl, Clearance. CrCl, Creatinine Clearance.

Correlation Correlation between vancomycin disposition and clinical and demographic data was done on cancer patients No significant correlation was observed with any clinical data except for vancomycin clearance and creatinine clearance

Vancomycin Cl & CrCl Vancomycin CrCl Clearance ml/min ml/min P-value 0.010 * * Using Pearson Correlation Cl, Clearance. CrCl, Creatinine Clearance.

Discussion Despite the frequent administration of vancomycin in oncology patients, standard dosage regimens continue to be used, although they may often be suboptimal owing to the greater Cl & Vd found in this target population Cl, Clearance. Vd, Volume of Distribution.

Discussion There was about 80% increase in vancomycin clearance in patients with cancer compared to literature on general population When comparing with our control there was a 50% increase in vancomycin clearance Vancomycin clearance in the control Saudi group was increased by 32% when compared to published literature

Discussion Population PK * Patients with hematological malignancies ** Patients with different types of cancer *** Cancer Group 0.65 x CrCl 1.08 x CrCl 1.12 x CrCl Vd 0.7 L/kg 0.98 L/kg 1.1 L/kg Cl * Begg E et al, J Clin Pharmacol. 2001; ** Bulge D et al, Antimicrob Agents Chemother. 2005 *** Le Normand Y, Int J Biomed Comput. 1994

Discussion Cl, Clearance. CrCl, Creatinine Clearance. Vd, Volume of Distribution. TBW, Total Body Weight.

Discussion When the vancomycin dose was calculated for cancer patients based on their PK parameters it was double the regular dose (about 60 mg/kg/day)

Discussion Critical characteristics of patients with cancer such as diagnosis, and the existence of neutropenia among other clinical parameters analyzed, had no significant correlation with or effect on vancomycin disposition Except for creatinine clearance which would be expected in a drug eliminated mainly through renal excretion

Discussion The absence of correlation for high creatinine clearance values may be explained by the fact that glomerular filtration is not the only mechanism for vancomycin clearance. Tubular secretion is a possible mechanism for vancomycin renal elimination The measurement of tubular secretion is not possible for now

Limitations Inability to find cancer patients on vancomycin through the study period made it difficult to conduct a prospective study Poor documentation in patient files Small sample size specially in control group which may not represent the Saudi population truly

Limitations Limited sample acquisition in the clinical setting permitted only one-compartment model for PK analysis, although it is well accepted that vancomycin PK characteristics are more realistically described by a two-compartment model

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