1. Doripenem vs Meropenem: a summary of International and Belgian published data
Françoise Van Bambeke,
Unité de Pharmacologie cellulaire et moléculaire
Louvain Drug Research Institute
Université catholique de Louvain
Brussels, Belgium
Advisory Board AstraZeneca, Brussels – 02/02/2009
02/02/2009
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2. Classification of parenteral carbapenems
Group 1
Limited activity on non-fermentative Gram(-)
Ertapenem
Panipenem
Group 2
Active on non-fermentative Gram(-)
Impinem
Meropenem
Biapenem
Doripenem
Group 3
Group 2 + MRSA
CS-023 (investigational)
Shah et al. CMI (2008) 14 suppl. 1 :
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3. Structure of the molecules
no lateral chain methyl subst.
 Resistance to -lactamases
No endocyclic S
 Strong binding to PBP
 VERY broad spectrum
Zwitterion
Penetration in Gram(-),
including Pseudomonas
meropenem
doripenem
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4. AstraZenaca-Advisory Board
In vitro activity
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5. In vitro activity against selected Gram-(-) bacteria
Range of MIC90 values
organism
Nb strains
DOR
MEM
Enterobacter spp
3951 
E. coli
17483 
ESBL (+)
886 
 0.06
Klebsiella spp
5920 
K. pneumoniae
1625  88
Proteus mirabilis
2052
0.12-1  40
0.25
0.12
Serratia spp
619
Acinetobacter spp
2974
 8-32
> 8-32
Pseudomonas aeruginosa
11990
0.5->8
1-16
non -S
937
16-64
1 (to 2) dilutions
difference in MIC,
most often
in advantage
to MEM !
Keam, Drugs (2008) 68:
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6. Susceptibility to resistance mechanisms
Influence of resistance mechanisms in Pseudomonas
carbapenem
MexAB
MexEF
OprD
metallo -lactamase
imipenem S
r / R R
meropenem r
doripenem nd
R : MIC > 8 mg/L
r : MIC < 8 mg/L
Dalhoff et al., Biochem. Pharmacol. (2006) 71:
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7. Selection of resistance in vitro
MPC in Pseudomonas
frequency of resistance selection:
<
~ 10-8
MIC/Cmin > 6
Tam et al. AAC (2005) 49:4920-7
Sakyo et al., J. Antibiot. (2006) 59:
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8. Pharmacokinetics / Pharmacodynamics
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9. Comparative PK profile
Single dose PK
parameter
DOR
MEM
(500 mg)
(1g)
Cmax (mg/L)
20.2 26
50-60
Prot. binding (%)
8.9 2
AUC (mg.h/L) – 8 h
44.1
T ½ (h)
0.93 1
Zhanel et al., Drugs (2007) 67:
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10. Comparative PK profile
Bolus vs Prolonged infusion
parameter
DOR (500 mg)
MEM (1g)
(Bol)
(Prol)
Cmax (mg/L) 23 8
112 30
AUC (mg.h/L) – 8 h 36 17
136
186
T > CMI 1 55 80 75 98
T > CMI 4
27.5 57 73
T > CMI 8
17.5 - 46 58
Kim et al., AAC (2008) 52:
Jaruratanasirikul et al., AAC (2005) 49:
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11. Doripenem : PK/PD modeling
PK/PD in support to dosing : t > MIC ~ 35 %
500 mg ; q 8 h
4 h infusion :
MIC = 8
MPC
33 %
70 %
1 h infusion :
MIC = 2
Bhavnani et al., AAC (2005) 49:
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12. Meropenem: PK/PD modeling
PK/PD in support to dosing : t > MIC ~ 35 %
1 g ; q 8 h
3 h infusion :
MIC = 18
0.5 h infusion :
MIC = 8
MPC
40 %
65 %
Li et al. J Clin Pharmacol. (2006) 46:1171-8
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13. Doripenem : PK/PD modeling
Probability of target attainment rate based on Monte Carlo simulation
0.5 h infusion :
MIC = 2
4 h infusion :
MIC = 4
Ikawa et al., Diagn Microbiol Infect Dis. (2008) 62:292-7
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14. Meropenem : PK/PD modeling
Probability of target attainment rate based on Monte Carlo simulation
0.5 h infusion :
MIC = 1.5
1 g ; q 8 h
3 h infusion :
MIC = 4
Li et al., J. Clin. Pharmacol (2006) 46:
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15. Meropenem vs Doripenem: PD vs EUCAST bkpts
(500 mg 3 x)
MEM
(1 g 3 x)
EUCAST
enterobacteriaceae
1 / 4
2 / 8
Pseudomonas
PD short infusion 2
PD prolonged infusion 4
Li et al., J. Clin. Pharmacol (2006) 46:
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16. Meropenem vs Doripenem: stability for prolonged infusion
% of intact molecule remaining after the indicated time of incubation at room T°
DOR
MEM
End of infusion
95-97 % (4h)
~ 95 % (3h)
12 h
93-95 %
~70 %
Time > 90 % (literature)
> 12 h
5.15 h
(SmPC)
8 h
Psathas et al., Clin Ther. (2008) 30:
Viaene et al., AAC (2002) 46:
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17. Meropenem vs Doripenem: MICs vs EUCAST bkpts
MIC distribution in enterobacteriacae (USA strains)
Pillar et al., Antimicrob Agents Chemother :
02/02/2009
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18. Meropenem vs Doripenem: MICs vs EUCAST bkpts
MIC distribution in Pseudomonas (USA strains)
Pillar et al., Antimicrob Agents Chemother :
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19. Meropenem vs Doripenem: MICs vs EUCAST bkpts
MIC distribution in Pseudomonas (Canada)
ICAAC 2008 C
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20. Meropenem vs Doripenem: MICs vs EUCAST bkpts
MIC distribution in Pseudomonas (Europe)
~ 90 %
~ 90 %
~ 90 %
~ 90 %
~ 80 %
~ 75 %
~ 80 %
~ 80 %
ECCMID 2008 P1168; 2007 P1664; 2087
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21. Meropenem : MICs in Belgium vs EUCAST bkpts
MIC distribution in Enterobacteriaceae and Pseudomonas
~ 100 %
~ 85 %
~ 75 %
What about doripenem ?
ICAAC 2008 C1 097
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22. AstraZenaca-Advisory Board
Clinical efficacy
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23. Respiratory tract infections
doripenem
Keam, Drugs (2008) 68:
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24. Respiratory tract infections
meropenem; ~ 20 % of Pseudomonas
study
Nb patients
randomized
Treatment regimen
Response rate (clinical)
Response rate (bacterio)
HAP
211
MEM 1 g q8h
89 /87 *
89 / 91 *
(Cefta 2g + Tob 1mg/kg) q8h
72 / 72 *
67 / 69 * 84 81 73
Cefta 2 g q8h + AMK 15 mg/kg 72 76
VAP
140
MEM 1 g q8hv b
82.5
74.5
66.1
53.3
* ventilated patients (70 %)
Sieger et al., Crit Care Med. (1997) 25:
Mouton et al., J Antimicrob Chemother. (1995) 36 Suppl A:145-56
Alvarez Lerna et al., J. Chemother. (2001) 13:70-81
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25. Respiratory tract infections: DOR vs IMI
Microbiological success
Chastre et al., Crit. Care Med. (2008) 36:
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26. ICU infections: MEM vs IMI (Belgian study)
Patient characteristics
Verwaest et al., Clin. Microbiol. Infect. (2001) 6:
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27. ICU infections: MEM vs IMI (Belgian study)
Clinical/microbiological response
Verwaest et al., Clin. Microbiol. Infect. (2001) 6:
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28. ICU infections: MEM vs IMI (Belgian study)
microbiological response
Verwaest et al., Clin. Microbiol. Infect. (2001) 6:
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29. Intra-abdominal infections : DOR vs MEM
Design
Patients with IAI, surgical intervention < 24 h + AB needed
exclusion : uncomplicated infections
APACHE II > 30
life-threatening illness
necrotizing pancreatitis / pancreatic abcess
infection by pathogen R to one of the studied drugs
Patients profile
91 % APACHE II < 10
60 % appendix; 20 % colon
10 % post-operative
Treatment
DOR 500 mg x 3; 1h vs MEM 1 g x 3 ; 5 minutes
Lucasti et al., Clin. Ther (2008) 30:868-83
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30. Intra-abdominal infections: DOR vs MEM
Microbiology
Lucasti et al., Clin. Ther (2008) 30:868-83
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31. Intra-abdominal infections: DOR vs MEM
Clinical success
Lucasti et al., Clin. Ther (2008) 30:868-83
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32. Intra-abdominal infections: DOR vs MEM
Microbiological evaluation
Lucasti et al., Clin. Ther (2008) 30:868-83
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33. AstraZenaca-Advisory Board
Safety profile
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34. Safety - Intra-abdominal infections
Lucasti et al., Clin. Ther (2008) 30:868-83
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35. Comparative safety profile
Lucasti et al., Clin. Ther (2008) 30:868-83
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36. Meropenem safety profile
Linden, Drug Saf. (2007) 30:657-68
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37. AstraZenaca-Advisory Board
Neurotoxicity
binding affinity for GABA receptors
depending of (+) charge
of the side chain
drug
IC 50 (mM)
imipenem
0.5
meropenem
27.6
doripenem
50.0
X 55
X 1.8
Dalhoff et al., Biochem. Pharmacol. (2006) 71:
02/02/2009
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38. Meropenem safety profile
Linden, Drug Saf. (2007) 30:657-68
02/02/2009
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