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

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

3. 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

4. What’s The Problem??!!

5. 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 Le Normand Y, Int J Biomed Comput. 1994

6. Vancomycin

7. 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

8. 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

9. 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

10. Going back to cancer patients

11. 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

12. Why vancomycin ?!

13. 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

14. Objectives

15. 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

16. 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

17. Methodology

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

19. Methodology

20. 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

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

22. Results

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

24. 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.

25. Type of Cancer
Cancer group

26. Chemotherapy
Cancer group

27. 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.

28. 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.

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

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

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

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

33. 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
2.02
0.052
Lower
Upper
SD, Standard Deviation. CI, Confidence Interval.

34. 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.

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

36. 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
0.061
Lower
Upper
PK, Pharmacokinetics. Vd, Volume of Distribution. TBW, Total Body Weight. SD, Standard Deviation.
CI, Confidence Interval.

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

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

39. 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

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

41. 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.

42. 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

43. 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

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

45. 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)

46. 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

47. 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

48. 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

49. 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

50. Thank you for your listening