Doripenem: pharmacokinetics and pharmacodynamics. Paul M. Tulkens, MD, PhD Françoise Van Bambeke, PharmD, PhD

Transcription

1 16/04/ 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

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

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

4 16/04/ S S S From imipenem to doripenem C 3 C 3 S 2 imipenem meropenem doripenem * log P pka 1 pka C2-(aminomethylideneamino)ethylsulfanyl methyl, C2-pyrrolidylthio-dimethylcarbamoyl methyl, C2-pyrrolidylthio-sulfamoylaminomethyl

5 Comparative PK profile in volunteers Single dose PK parameter DR MEM (500 mg) (500 mg) (1g) C max (mg/l) Prot. binding (%) AUC (mg.h/l) 8 h T ½ (h) 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: /04/2009 5

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

7 16/04/ 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:

8 16/04/ Doripenem: improvement of f T > MIC by means of prolonged infusion dosing interval Bhavnani et al., AAC (2005) 49:

9 16/04/ 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:

10 16/04/ Doripenem: Target attainment rate after Monte-Carlo simulation 0.5 h infusion : MIC 90 = 2 4 h infusion : MIC = 4 Van Wart et al., Diagn Microbiol Infect Dis. (2009) 63: Patients from clinical trials 1h infusion : MIC 90 = 1 4 h infusion : MIC 90 = 4 Ikawa et al., Diagn Microbiol Infect Dis. (2008) 62:292-7 Japanese patients after IA surgery

11 16/04/ EUCAST PK/PD evaluation 4. Pharmacokinetics Dosage 500 mg over 1h a 500 mg over 4h b Cmax (mg/l) 21.1 (4.63) 8.69 (1.73) Cmin (mg/l) BQL 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 bound c Volume of distribution (L/kg) 16.9 (3.81) 18.0 (4.03) References Comments a,b,c Mean (SD) presented BQL Below Quantifiable Limit (LLQ = mg/ml) References (a)multiple-dose data from study DRI-S o accumulation was noted and data similar to that after single-dose administration. (b)single-dose data from study DRI-S (c)s-4661-b-05-, R1412, R1414, R1417 In press not final

12 16/04/ EUCAST PK/PD evaluation 5. Pharmacodynamics As with other carbapenems the animal model studies demonstrated that is the best predictor of microbiologic outcome (key pharmacodynamic index) for doripenem. S. pneumoniae S. aureus Gram-negatives % f for bacteriostasis a 12.4+/ / /-5.3 % ft>/mic for 1 log drop 21.1+/ / /-7.4 % ft>/mic for 2 log drop 27.3+/ / /-7.1 References Andes and Craig. ICAAC.2003 Andes and Craig. ICAAC.2003 Andes and Craig. ICAAC.2003 Comments a.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) References 1. Andes DR, Craig WA. Presented at: 43rd ICAAC Conference; Chicago, IL; Sept 14-17, 2003; A Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 2002;19(4): Kuti JL, ng C, Lo M, Melnick D, Soto, icolau 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): 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): Data on file. Andes D, Craig WA. DRI-M-002: The pharmacodynamic activities of doripenem. Madison, WI; In press not final

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

14 16/04/ EUCAST PK/PD evaluation Specific target attainment rates for organisms obtained in the phase 3 clinical studies Dosing regimens used Species specific target attainment 500 mg, q8h, 1 h infusion 500 mg, q8h, 4 h infusion 25% 30% 35% 25% 30% 35% Enterobacteriaceae on-enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp ther gram-negative aemophilus spp Enterococcus faecalis S. aureus xa-s Streptococcus pneumoniae Streptococcus spp. (other than S. pneumoniae) ther gram-positive All Anaerobes In press not final

15 16/04/ EUCAST PK/PD evaluation Specific target attainment rates for organisms obtained in the phase 3 clinical studies Dosing regimens used Species specific target attainment 500 mg, q8h, 1 h infusion 500 mg, q8h, 4 h infusion 25% 30% 35% 25% 30% 35% Enterobacteriaceae on-enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp ther gram-negative aemophilus spp Enterococcus faecalis S. aureus xa-s Streptococcus pneumoniae Streptococcus spp. (other than S. pneumoniae) ther gram-positive All Anaerobes In press not final

16 16/04/ EUCAST PK/PD evaluation Specific target attainment rates for organisms obtained in the phase 3 clinical studies Dosing regimens used Species specific target attainment 500 mg, q8h, 1 h infusion 500 mg, q8h, 4 h infusion 25% 30% 35% 25% 30% 35% Enterobacteriaceae on-enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp ther gram-negative aemophilus spp Enterococcus faecalis Staphylococcus aureus xa-s Streptococcus pneumoniae Streptococcus spp. (other than S. pneumoniae) ther gram-positive All Anaerobes In press not final

17 16/04/ EUCAST PK/PD evaluation Specific target attainment rates for organisms obtained in the phase 3 clinical studies Dosing regimens used Species specific target attainment 500 mg, q8h, 1 h infusion 500 mg, q8h, 4 h infusion 25% 30% 35% 25% 30% 35% Enterobacteriaceae on-enterobacteriaceae Pseudomonas aeruginosa Acinetobacter spp ther gram-negative aemophilus spp Enterococcus faecalis Staphylococcus aureus xa-s Streptococcus pneumoniae Streptococcus spp. (other than S. pneumoniae) ther gram-positive All Anaerobes In press not final

18 16/04/ EMEA registration DRIBAX Summary or Product Characteristics (EMEA)

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

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

21 16/04/ 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 S 2 imipenem 2. AD fast nucleophilic attack (instability of the amidinium function) 1. same strong tensions in the bicyclic ring due to the C2-C3 double bond S 2 S 2 3. BUT slower nucleophilic attack (steric hindrance) doripenem (and also meropenem)

22 16/04/ Stability according to EMEA 0.5 % solution Intensive Care Units may like to put 500 mg in 48 ml (1.048 %) DRIBAX Summary or Product Characteristics (EMEA)

23 16/04/ 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 groups DRIBAX Summary or Product Characteristics (EMEA)

24 More information about stability 16/04/

25 16/04/ 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)

26 16/04/ Belangenconflicten en dankbetuigingen Belangenconflicten nderzoekstoelagen van Bayer, Pfizer, Wyeth, GSK, Vergoedingen voor voordrachten: AstraZeneca, Aventis, Bayer, Penninggeld van RIZIV, FD "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, )

27 Backup slides 16/04/

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 : /04/

29 In vitro activity against selected Gram-(-) bacteria Range of MIC 90 values organism b strains DR MEM Enterobacter spp E. coli ESBL (+) Klebsiella spp K. pneumoniae ESBL (+) Proteus mirabilis ESBL (+) Serratia spp Acinetobacter spp > 8-32 Pseudomonas aeruginosa > Keam, Drugs (2008) 68: /04/

30 Susceptibility to resistance mechanisms Influence of resistance mechanisms in Pseudomonas carbapenem MexAB MexEF prd metallo -lactamase imipenem S r / R R R meropenem R R r R doripenem R nd r R R : MIC > 8 mg/l r : MIC < 8 mg/l Dalhoff et al., Biochem. Pharmacol. (2006) 71: /04/

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: Sakyo et al., J. Antibiot. (2006) 59: /04/

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