![\"see](\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/12\/PKPD-1-copy.jpg?ssl=1\")
<\/a>When doripenem was developed, one could have simply used the same dosing and be done with it \u2013 after all, the two drugs are from the same antibiotic class, share the same mode of action resulting in cidal activity by blocking the same PBPs, have very similar pharmacokinetics, ADME, and antibacterial spectrum. Both are excellent antipseudomonal drugs. Overall, doripenem MICs for Gram-negative bacteria, esp. non-lactose fermenters, are a tad lower than those for imipenem, a main reason for its development.<\/p>\n
However, since the mid-90ies, PK\/PD and Monte Carlo simulations were used regularly, with attainment ratios predicting reliably an effective dosing regimen. Based on bacterial kinetic data from the Craig mouse thigh model, we learned that (1) beta-lactam antibiotics\u00a0are T>MIC drugs, (2) a %T>MIC of\u00a040-50%% was usually sufficient for penicillins and cephalosporins, but can be a bit lower for penem antibiotics. We also learned later that ignoring dosing predictions from PK\/PD modeling can be very risky and lead to underdosing (see Ambrose et al for examples [2]<\/a>).<\/p>\n Given the predictive accuracy of PK\/PD modeling, a mini-industry developed that specialized in the art of of simulating the likelihood of clinical success based on organism MIC distributions, animal PK\/PD, and human exposure data. We have come to rely on PK\/PD for dose-finding thus avoiding patient exposure to subtherapeutic low or toxic high doses. PK\/PD has become a major pillar in a streamlined drug development program or in situations when a\u00a0standard large-size RCTs cannot be conducted. This is especially true for development of drugs for MDR pathogens which are too rare for NI-based efficacy testing.<\/p>\n Based on Phase 2 clinical data including earlier HAP trials the Institute for Clinical Pharmacodynamics did extensive PK\/PD modeling\u00a0[3]<\/a>. They persuasively argued that doripenem dosed at 1g IV q8h, infused over 4 hours, would lead to target attainment rates of >90% for the pathogens usually encountered in late-onset VAP patients. This regimen also\u00a0provided a >35% T>MIC during the dosing cycle.<\/p>\n However, doripenem efficacy turned out to be sub-par compared to imipenem and the study had to be terminated prematurely as NI (with a CI of -15% margin) was not achieved\u00a0[4]<\/a>. The FDA released a statement summarizing the findings [5]<\/a>:<\/p>\n How could this happen? What went wrong? Why was imipenem superior despite its higher MICs and shorter T>MIC? Where is the editorial that explains to us why PK\/PD failed doripenem?<\/p>\n Across\u00a0various antibiotic classes, PK\/PD modeling is most solid for dose selection of fluoroquinolones, but the beta-lactam class of antibiotic has also been studied extensively.\u00a0 So, this was not \u2018new territory\u2019 for the\u00a0PK experts.<\/p>\n Let’s cut right to the chase: we have not heard any good answers to these questions. Here a\u00a0few explanations that are bandied about which don\u2019t make much sense on closer inspection:<\/p>\n So, we\u00a0remain perplexed and surprised but also a bit annoyed. One\u00a0would have thought our PK\/PD experts would want to reanalyze the data and redo the modeling in order to understand why doripenem ran into trouble. Why are they\u00a0ignoring the doripenem fiasco, isn’t there a lesson to be learned here?<\/p>\n The gods of statistics tell us to expect a false positive result in approx. 1 out of 20 test runs, so doripenem may just have had a \u2018bad VAP day\u2019. I don\u2019t find that a satisfactory explanation\u00a0but hope that you – the reader – may have a better answer. Your comments and insights are appreciated.<\/p>\n Abbreviations <\/p>\n References: When imipenem is dosed at 1 g q8h for serious infections, it is infused over 40-60 min. Its label states that it is indicated for \u201clower RTI\u201d, an old-fashioned term from the days when bronchitis and pneumonias were still lumped together, CAP was not differentiated from HAP, and HAP and Continue reading Why Did PK\/PD Modeling Fail Doripenem in VAP?<\/span><\/a><\/p>\n\n
\nI doubt that because the clinical response curves separate already within the first 10 days, with lower clinical response rates for doripenem at EOT.<\/span><\/li>\n
\nTrue, in the van Wart publication the need of dose adjustment for \u2018severity of illness\u2019 is not being addressed. Patients with very high Clcr certainly did poorly in the doripenem arm.\u00a0 \u00a0However, such changes in drug PK would presumably apply to both drugs in the same direction and magnitude and not unevenly affect only doripenem.<\/span><\/li>\n<\/ul>\n
\n<\/strong>RTI \u00a0 \u00a0 \u00a0 \u00a0 respiratory tract infection
\nHAP \u00a0 \u00a0 \u00a0 hospital-acquired pneumonia
\nVAP \u00a0 \u00a0 \u00a0 ventilator-associated pneumonia
\nNI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 non-inferiority
\nClcr \u00a0 \u00a0 \u00a0 \u00a0clearance creatinine
\nVd \u00a0 \u00a0 \u00a0 \u00a0 \u00a0volume of distribution
\nPK\/PD \u00a0 pharmacokinetic\/pharmacodynamic
\nT>MIC \u00a0 time above MIC
\nPBP \u00a0 \u00a0 \u00a0 penicillin-binding protein
\nADME \u00a0 \u00a0absorption, distribution, metabolism, excretion
\nEOT \u00a0 \u00a0 \u00a0 end-of-therapy
\nRCT \u00a0 \u00a0 \u00a0 randomized controlled trial
\nMITT \u00a0 \u00a0 \u00a0microbiologic intent-to-treat population
\nME \u00a0 \u00a0 \u00a0 \u00a0 microbiologically evaluable population<\/p>\n
\n<\/strong>[1]<\/a> Package Insert Primaxin http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2014\/050587s076lbl.pdf
\n[2]<\/a> Ambrose. Clin Infect Dis 2008; 47; S225
\n[3]<\/a> Van Wart.\u00a0 Diagn Microbiol. Infect. Dis. 2009; 63: 409
\n[4]<\/a> Kollef.\u00a0 Crit Care 2012; 16: R218
\n[5]<\/a> http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm285883.htm<\/p>\n","protected":false},"excerpt":{"rendered":"