1. Doripenem: pharmacokinetics and pharmacodynamics
Paul M. Tulkens, MD, PhD
Françoise Van Bambeke, PharmD, PhD
Unité de Pharmacologie cellulaire et moléculaire
Louvain Drug Research Institute
Université catholique de Louvain
Brussels, Belgium
16/04/2009

2. Penams and carbapenems
Penicillins N O
COOH C S
greater intrinsic
activity due to larger
instability of the -lactam ring because of C1-C2 double bond and electrocapturing effect of the basic group
basic group N
Carbapenem
imipenem O
COOH
16/04/2009

3. From imipenem to doripenem
C2-(aminomethylideneamino)ethylsulfanyl O N S H 2 C 3
meropenem
1-methyl, C2-pyrrolidylthio-dimethylcarbamoyl
doripenem *
1-methyl, C2-pyrrolidylthio-sulfamoylaminomethyl
16/04/2009

4. From imipenem to doripenem
log P
pKa1
pKa2
-2.78
4.39
10.63
-3.13
4.37
8.34
-3.65
9.39
imipenem
C2-(aminomethylideneamino)ethylsulfanyl O N S H 2 C 3
meropenem
1-methyl, C2-pyrrolidylthio-dimethylcarbamoyl
doripenem *
1-methyl, C2-pyrrolidylthio-sulfamoylaminomethyl
16/04/2009

5. Comparative PK profile in volunteers
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
Elimination of doripenem is primarily via the renal route
Dosage adjustment is necessary in patients with moderate and severe renal impairment; AUCs of doripenem and of the microbiologically inactive ring-opened metabolite are substantially increased in patients who require haemodialysis compared with healthy subjects
the pharmacokinetics of doripenem are not expected to be affected by hepatic impairment.
Zhanel et al., Drugs (2007) 67:
16/04/2009

6. -lactams are time-dependent…
but how long do you need them?
Andes & Craig Int. J. Antimicrob. Agents 2002, 19:
various -lactams
various pathogens
doripenem
Van Wart et al., Diagn Microbiol Infect Dis. (2009) 63:
16/04/2009

7. f Time above MIC to obtain specified decreases of CFUs in an animal model
neutropenic murine thigh infection model against 24 clinical
P. aeruginosa isolates with MICs of to 16 mg/L.
Kim et al., AAC (2008) 52:
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8. Doripenem: improvement of f T > MIC by means of prolonged infusion
dosing interval
Bhavnani et al., AAC (2005) 49:
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9. Doripenem: prolonged infusion allow to cover higher MICs for a f T > MIC of 35 %
dosing interval
dosing interval
35 %
Bhavnani et al., AAC (2005) 49:
16/04/2009

10. Doripenem: Target attainment rate after Monte-Carlo simulation
0.5 h infusion :
MIC90 = 2
4 h infusion :
MIC = 4
Van Wart et al., Diagn Microbiol Infect Dis. (2009) 63:
Patients from clinical trials …
1h infusion :
MIC90 = 1
4 h infusion :
MIC90 = 4
Ikawa et al., Diagn Microbiol Infect Dis. (2008) 62:292-7
Japanese patients after IA surgery…
16/04/2009

11. EUCAST PK/PD evaluation
4. Pharmacokinetics
Dosage
500 mg over 1ha
500 mg over 4hb
Cmax (mg/L)
21.1 (4.63)
8.69 (1.73)
Cmin (mg/L)
BQL
Total body clearance (L/h)
15.3 (3.54)
14.6 (3.17)
T ½ (h)
1.15 (0.287)
1.23 (0.214)
AUClast (mg.h/L)
33.9 (7.40)
35.7 (7.12)
Fraction unbound (%)
Doripenem is approximately 8 % protein boundc
Volume of distribution (L/kg)
16.9 (3.81)
18.0 (4.03)
References
a,b,c
Comments
Mean (SD) presented
BQL – Below Quantifiable Limit (LLOQ = mg/mL)
Multiple-Dose data from study DORI-NOS No accumulation was noted and data similar to that after single-dose administration.
Single-Dose data from study DORI-NOS-1004.
S-4661-B-05-N, R1412, R1414, R1417
In press – not final
16/04/2009

12. EUCAST PK/PD evaluation
5. Pharmacodynamics
As with other carbapenems the animal model studies demonstrated that T>MIC is the best predictor of microbiologic outcome (key pharmacodynamic index) for doripenem.
S. pneumoniae
S. aureus
Gram-negatives
% fT>MIC for bacteriostasisa
12.4+/-6.2
29+/-5.3
% fT>/MIC for 1 log drop
21.1+/-8.9
32.3+/-6.7
36.1+/-7.4
% fT>/MIC for 2 log drop
27.3+/-11.9
35.4+/-5.0
43.3+/-7.1
References
Andes and Craig. ICAAC.2003
Comments
Data from neutropenic mouse thigh infection model: 6 strains of S. pneumoniae, 3 strains of S. aureus, 3 strains of E. coli, 4 strains K. pneumoniae,2 strains of E. cloacae, and 1 strain P. aeruginosa for stasis and 1 log drop (one strain of E.coli and one strain of K. pneumoniae not done for 2 log drop)
1. Andes DR, Craig WA. Presented at: 43rd ICAAC Conference; Chicago, IL; Sept 14-17, 2003; A-308
2. Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 2002;19(4):261-8.
3. Kuti JL, Ong C, Lo M, Melnick D, Soto N, Nicolau DP. Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections. Int J Antimicrob Agents 2006;28(1):62-8.
4. Burgess DS, Frei CR. Comparison of beta-lactam regimens for the treatment of gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics. J Antimicrob Chemother 2005;56(5):893-8.
5. Data on file. Andes D, Craig WA. DORI-M-002: The pharmacodynamic activities of doripenem. Madison, WI; 2002.
In press – not final
16/04/2009

13. EUCAST PK/PD evaluation
In press – not final
16/04/2009

14. EUCAST PK/PD evaluation
Specific target attainment rates for organisms obtained in the phase 3 clinical studies
Dosing regimens used
500 mg, q8h, 1 h infusion
500 mg, q8h, 4 h infusion
Species specific target attainment
25% T>MIC
30% T>MIC
35% T>MIC
Enterobacteriaceae
99.88
99.82
99.72
99.91
99.9
Non-Enterobacteriaceae
92.34
90.13
87.83
93.96
93.69
93.3
Pseudomonas aeruginosa
91.42
88.96
86.41
93.25
92.95
92.51
Acinetobacter spp.
82.13
80.95
78.99
82.26
82.2
82.16
Other gram-negative
99.43
98.01
96.06
100.02
100.01
Haemophilus spp.
100
99.97
Enterococcus faecalis
76.79
62.42
50.79
90.61
89.4
87.18
S. aureus Oxa-S
99.99
Streptococcus pneumoniae
99.7
100.
Streptococcus spp. (other than S. pneumoniae)
99.81
99.66
99.54
99.96
99.93
Other gram-Positive
89.74
89.02
90.08
90.05
90.03
All Anaerobes
97.75
97.26
96.66
98.09 98
97.89
In press – not final
16/04/2009

15. EUCAST PK/PD evaluation
Specific target attainment rates for organisms obtained in the phase 3 clinical studies
Dosing regimens used
500 mg, q8h, 1 h infusion
500 mg, q8h, 4 h infusion
Species specific target attainment
25% T>MIC
30% T>MIC
35% T>MIC
Enterobacteriaceae
99.88
99.82
99.72
99.91
99.9
Non-Enterobacteriaceae
92.34
90.13
87.83
93.96
93.69
93.3
Pseudomonas aeruginosa
91.42
88.96
86.41
93.25
92.95
92.51
Acinetobacter spp.
82.13
80.95
78.99
82.26
82.2
82.16
Other gram-negative
99.43
98.01
96.06
100.02
100.01
Haemophilus spp.
100
99.97
Enterococcus faecalis
76.79
62.42
50.79
90.61
89.4
87.18
S. aureus Oxa-S
99.99
Streptococcus pneumoniae
99.7
100.
Streptococcus spp. (other than S. pneumoniae)
99.81
99.66
99.54
99.96
99.93
Other gram-Positive
89.74
89.02
90.08
90.05
90.03
All Anaerobes
97.75
97.26
96.66
98.09 98
97.89
In press – not final
16/04/2009

16. EUCAST PK/PD evaluation
Specific target attainment rates for organisms obtained in the phase 3 clinical studies
Dosing regimens used
500 mg, q8h, 1 h infusion
500 mg, q8h, 4 h infusion
Species specific target attainment
25% T>MIC
30% T>MIC
35% T>MIC
Enterobacteriaceae
99.88
99.82
99.72
99.91
99.9
Non-Enterobacteriaceae
92.34
90.13
87.83
93.96
93.69
93.3
Pseudomonas aeruginosa
91.42
88.96
86.41
93.25
92.95
92.51
Acinetobacter spp.
82.13
80.95
78.99
82.26
82.2
82.16
Other gram-negative
99.43
98.01
96.06
100.02
100.01
Haemophilus spp.
100
99.97
Enterococcus faecalis
76.79
62.42
50.79
90.61
89.4
87.18
Staphylococcus aureus Oxa-S
99.99
Streptococcus pneumoniae
99.7
100.
Streptococcus spp. (other than S. pneumoniae)
99.81
99.66
99.54
99.96
99.93
Other gram-Positive
89.74
89.02
90.08
90.05
90.03
All Anaerobes
97.75
97.26
96.66
98.09 98
97.89
In press – not final
16/04/2009

17. EUCAST PK/PD evaluation
Specific target attainment rates for organisms obtained in the phase 3 clinical studies
Dosing regimens used
500 mg, q8h, 1 h infusion
500 mg, q8h, 4 h infusion
Species specific target attainment
25% T>MIC
30% T>MIC
35% T>MIC
Enterobacteriaceae
99.88
99.82
99.72
99.91
99.9
Non-Enterobacteriaceae
92.34
90.13
87.83
93.96
93.69
93.3
Pseudomonas aeruginosa
91.42
88.96
86.41
93.25
92.95
92.51
Acinetobacter spp.
82.13
80.95
78.99
82.26
82.2
82.16
Other gram-negative
99.43
98.01
96.06
100.02
100.01
Haemophilus spp.
100
99.97
Enterococcus faecalis
76.79
62.42
50.79
90.61
89.4
87.18
Staphylococcus aureus Oxa-S
99.99
Streptococcus pneumoniae
99.7
100.
Streptococcus spp. (other than S. pneumoniae)
99.81
99.66
99.54
99.96
99.93
Other gram-Positive
89.74
89.02
90.08
90.05
90.03
All Anaerobes
97.75
97.26
96.66
98.09 98
97.89
In press – not final
16/04/2009

18. DORIBAX® Summary or Product Characteristics (EMEA)
EMEA registration
DORIBAX® Summary or Product Characteristics (EMEA)
16/04/2009

19. DORIBAX® Summary or Product Characteristics (EMEA)
EMEA registration *
clinical data are fully taken into account in the EUCAST breakpoint setting ! *
DORIBAX® Summary or Product Characteristics (EMEA)
16/04/2009

20. But are carbapenems sufficiently stable for a 4 h infusion ?
Viaene et al., AAC 2002; 46: N O
COOH C S
basic group
slide 2
because they carry a C2-aminated side chain (nucleophile)
these penems are less stable
than other -lactams !
16/04/2009

21. But how can doripenem still be used in a 4 h infusion (vs. imipenem) ?
1. strong tensions in the bicyclic ring due to the C2-C3 double bond
2. AND fast nucleophilic attack (instability of the amidinium function)
imipenem
1. same strong tensions in the bicyclic ring due to the C2-C3 double bond
doripenem (and also meropenem) O N S H 2
3. BUT slower nucleophilic attack (steric hindrance)
16/04/2009

22. Stability according to EMEA
 0.5 % solution… Intensive Care Units may like to put 500 mg in 48 mL (1.048 %)
DORIBAX® Summary or Product Characteristics (EMEA)
16/04/2009

23. Stability according to EMEA
 0.5 % solution… Intensive Care Units may like to put 500 mg in 48 mL (1.048 %)
glucose is a good nucleophilic attacker (a lot of –OH groups…
DORIBAX® Summary or Product Characteristics (EMEA)
16/04/2009

24. More information about stability…
Your Pharmacist
will love this...
16/04/2009

25. What do we need to do in Belgium ?
check for MIC… (organisms with MIC > 4 mg/L might create problems)
EUCAST full MIC distributions
check for stability under conditions of clinical use… (temperatures > 25°C (often seen in ICU) and concentrated solutions (which clinicians may like) need to be critically assessed)
16/04/2009

26. Belangenconflicten … en dankbetuigingen
Onderzoekstoelagen van Bayer, Pfizer, Wyeth, GSK, …
Vergoedingen voor voordrachten: AstraZeneca, Aventis, Bayer, …
Penninggeld van RIZIV, FOD "Volksgezondheid"
reis kosten van de Europese Unie (EUCAST)
Dankbetuigingen
W. Craig, J.J. Schentag, G. Drusano, K. Drlica (voor concepten en gegevens van PK/PD, MPC, …)
Gunnar Kalhlmeter (voor dias en discussies over EUCAST)
Johan Mouton (voor inleiding tot de populatiefarmacokinetiek, dias, discussies over doripenem, …)
16/04/2009

27. Backup slides
16/04/2009

28. 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 :
16/04/2009

29. 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
Keam, Drugs (2008) 68:
16/04/2009

30. 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:
16/04/2009

31. Selection of resistance in vitro (MPC)
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:
16/04/2009

32. Meropenem : MICs in Belgium vs. EUCAST bkpts
MIC distribution in Enterobacteriaceae Pseudomonas
~ 100 %
~ 85 %
~ 75 %
What about doripenem ?
ICAAC 2008 C1 097
16/04/2009