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

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

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

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

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 27.2-32.4 66.9-77.5 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) 67:1027-52 16/04/2009

-lactams are time-dependent… but how long do you need them? Andes & Craig Int. J. Antimicrob. Agents 2002, 19: 261-268 various -lactams various pathogens doripenem Van Wart et al., Diagn Microbiol Infect Dis. (2009) 63:409-414 16/04/2009

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 0.125 to 16 mg/L. Kim et al., AAC (2008) 52:2497-2502 16/04/2009

Doripenem: improvement of f T > MIC by means of prolonged infusion dosing interval Bhavnani et al., AAC (2005) 49:3944-47 16/04/2009

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) 49:3944-47 16/04/2009

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) 63:409-414 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

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 = 0.100 mg/mL) Multiple-Dose data from study DORI-NOS-1001. 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

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

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

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

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

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

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

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

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

But are carbapenems sufficiently stable for a 4 h infusion ? Viaene et al., AAC 2002; 46:2327-2332 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

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

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

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

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

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

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

Backup slides 16/04/2009

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 :175-180 16/04/2009

In vitro activity against selected Gram-(-) bacteria Range of MIC90 values organism Nb strains DOR MEM Enterobacter spp 3951 0.06-0.25  0.06-0.5 E. coli 17483  0.015-0.06 ESBL (+) 886  0.06-0.03  0.06 Klebsiella spp 5920  0.06-0.125 K. pneumoniae 1625 0.03-0.25  0.03-0.12 88 0.06-0.12 Proteus mirabilis 2052 0.12-1  0.06-0.25 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) 68:2021-2057 16/04/2009

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) 71:1085-95 16/04/2009

Selection of resistance in vitro (MPC) MPC in Pseudomonas 0.4-1.6 0.8-6.3 frequency of resistance selection: < 2 10-9 ~ 10-8 MIC/Cmin > 6 Tam et al. AAC (2005) 49:4920-7 Sakyo et al., J. Antibiot. (2006) 59:220-228 16/04/2009

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