- Email: [email protected]
The author responds
Clinical Therapeutics/Volume 30, Number 10, 2008
Letter to the Editor Dear Dr. Walson:
I recently read with interest the study by Lucasti et al in the May 2008 issue of Clinical Therapeutics comparing the safety and efficacy of doripenem versus meropenem in the treatment of complicated intra-abdominal infection.1 The authors concluded that doripenem was similar to meropenem in both safety and efficacy, which was supported by their statistical analysis. I agree that the 2 regimens compared were similar in outcomes, but question whether the drug regimens were equivalent. In this study, doripenem (500 mg q8h) was infused over 1 hour versus a 3- to 5-minute bolus injection of meropenem (1 g q8h). The stability of meropenem is somewhat limited, but has been shown stable for up to 4 hours at room temperature depending on diluent.2 While a bolus injection of meropenem is an FDA-approved administration regimen, I would argue that it is not optimal from a pharmacokinetic/pharmacodynamic standpoint. I would also contend that a regimen of meropenem 1 g q8h infused over 1 hour could have been utilized and would have resulted in more clinically useful data. Similar pharmacodynamic optimization bias was utilized in a comparison of doripenem versus imipenem in the treatment of ventilator-associated pneumonia.3 In this previous study, Chastre et al utilized a 4-hour infusion of doripenem (500 mg q8h) compared with a 30- to 60-minute infusion of imipenem (500 mg q6h). Similar to the recent investigation by Lucasti et al, this previous study resulted in the authors’ conclusion of clinical and statistical noninferiority to the comparator regimen. It is again arguable whether the regimens compared were indeed equivalent. There is a growing body of evidence supporting the pharmacodynamic optimization of carbapenem and other β-lactam antibiotics.4 It is important for the practicing clinician to balance the benefits of extended infusion strategies in treating resistant organisms with the reality of nursing ratios, concurrent medications, and stability issues. In reviewing the literature, clinicians should also carefully consider pharmacodynamic optimization as a possible bias in clinical trials. Adam D. Porath, PharmD, BCPS Department of Pharmacy Renown Regional Medical Center Reno, Nevada
ACKNOWLEDGMENT Dr. Porath has received a research grant from Merck & Co., Inc.
REFERENCES 1. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868–883. 2. Merrem (Meropenem) [package insert]. Wilmington, DE: AstraZeneca; 2007. 3. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study. Crit Care Med. 2008;36:1089–1096. 4. Nicolau DP. Pharmacodynamic optimization of β-lactams in the patient care setting. Crit Care. 2008;12(Suppl 4):S2.
The author responds: We appreciate the opportunity to reply to the comments by Dr. Porath regarding our recent publication of complicated intra-abdominal infection (cIAI) clinical trial data for doripenem.1 Dr. Porath raised the important issue of choosing appropriate comparator regimens in clinical trials, and we are pleased to provide additional details regarding the justification for the regimens used in the doripenem clinical trials. 1934
Volume 30 Number 10
Letter to the Editor The choice of comparator and dosing regimen are considered very carefully in registration trials, incorporating advice from experts and various health authorities. Because the studies described in the recent publication were intended to support new drug registration in different regions, we were bound by what is approved in the various countries where the studies were to be conducted. Although there may be published data on “off-label” use of the comparator therapies, these are unlikely to meet the approval of health authorities who are ultimately responsible for approval of new drugs. For example, in the United States, the approved methods of administering meropenem are either intravenous infusion over approximately 15 to 30 minutes or intravenous bolus injection over approximately 3 to 5 minutes.2 Intravenous infusion of meropenem in excess of 30 minutes, as suggested by Dr. Porath, would constitute off-label use and would limit use of the data for registration purposes. Second, because the cIAI studies were blinded, a double-dummy drug infusion design was used. For each dose, two infusions were given in sequence, one containing active drug and one containing placebo. To ensure patients received active study drug as soon as possible, active meropenem (or matching placebo) was administered as a bolus followed by active doripenem (or placebo). Although other designs were considered, this was thought to be the simplest and safest way for patients to rapidly receive active study drug. Third, based on published pharmacokinetic studies of meropenem bolus dosing, this regimen was predicted to be highly effective. Following bolus injection of meropenem 1 g, mean (SD) time above minimum inhibitory concentration (T>MIC) values exceed 4 μg/mL for 42.5% (6.2%) of an 8-hour dosing interval.3 T>MIC values for carbapenems that exceed 40% of the dosing interval are widely considered to predict clinical efficacy.4 In the cIAI studies, pathogens with meropenem MICs >4 μg/mL were exceedingly rare. Thus, the meropenem dosing regimen in the cIAI studies was deemed to provide more than adequate coverage against the pathogens isolated. Furthermore, patients infected with pathogens resistant to meropenem (ie, with MICs >8 μg/mL) were excluded from the primary analyses, thus reducing any bias due to exposure to potentially less effective comparator therapy. Dr. Porath cited the ventilator-associated pneumonia study conducted by Chastre et al5 as an additional example of “pharmacodynamic optimization bias” and again questioned the “equivalence” of the treatment regimens. In this large study, Chastre et al utilized a 4-hour infusion of doripenem (500 mg q8h) compared with imipenem 500 mg q6h infused over 30 minutes or 1 g q8h infused over 60 minutes. Of note, imipenem is not labeled for infusions beyond 60 minutes and has limited stability in solution, therefore restricting the potential for extended-duration infusions with this agent.6 Nevertheless, both regimens of imipenem allowed in the study have been shown to provide T>MIC values exceeding 40% of the dosing interval for imipenem-susceptible pathogens.4 As in the cIAI studies, patients with imipenem-resistant infections were excluded from the primary analysis. Data from pharmacokinetic/pharmacodynamic analyses support the comparator dosing regimens used in the doripenem studies, and the authors believe that comparisons with these regimens provide stringent affirmations of the efficacy of doripenem 500 mg q8h therapy. We agree with Dr. Porath that the growing body of evidence supporting the pharmacodynamic optimization of β-lactams, including the carbapenems, is an important concept in drug development. Although, as discussed above, approved dosing regimens may constrain options for dosing comparators in registration drug trials, demonstrably inferior regimens would not be scientifically or ethically justifiable. The noninferiority results of the cIAI study confirm the equivalence of the dosing comparators used in this instance. Christopher Lucasti, MD South Jersey Infectious Disease Somers Point, New Jersey
REFERENCES 1. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868–883. 2. Merrem IV (Meropenem) [package insert]. Wilmington, DE: AstraZeneca; 2007. 3. Jaruratanasirikul S, Sriwiriyajan S. Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection. J Antimicrob Chemother. 2003;52:518–521.
October 2008
1935
Clinical Therapeutics 4. Sun HK, Kuti JL, Nicolau DP. Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: A report from the OPTAMA program. Crit Care Med. 2005;33:2222–2227. 5. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study. Crit Care Med. 2008;36:1089–1096. 6. Primaxin IV (imipenem/cilastatin) [package insert]. Whitehouse Station, NJ: Merck; 2007.
doi:10.1016/j.clinthera.2008.10.015
1936
Volume 30 Number 10
Letter to the Editor Dear Dr. Walson:
I recently read with interest the study by Lucasti et al in the May 2008 issue of Clinical Therapeutics comparing the safety and efficacy of doripenem versus meropenem in the treatment of complicated intra-abdominal infection.1 The authors concluded that doripenem was similar to meropenem in both safety and efficacy, which was supported by their statistical analysis. I agree that the 2 regimens compared were similar in outcomes, but question whether the drug regimens were equivalent. In this study, doripenem (500 mg q8h) was infused over 1 hour versus a 3- to 5-minute bolus injection of meropenem (1 g q8h). The stability of meropenem is somewhat limited, but has been shown stable for up to 4 hours at room temperature depending on diluent.2 While a bolus injection of meropenem is an FDA-approved administration regimen, I would argue that it is not optimal from a pharmacokinetic/pharmacodynamic standpoint. I would also contend that a regimen of meropenem 1 g q8h infused over 1 hour could have been utilized and would have resulted in more clinically useful data. Similar pharmacodynamic optimization bias was utilized in a comparison of doripenem versus imipenem in the treatment of ventilator-associated pneumonia.3 In this previous study, Chastre et al utilized a 4-hour infusion of doripenem (500 mg q8h) compared with a 30- to 60-minute infusion of imipenem (500 mg q6h). Similar to the recent investigation by Lucasti et al, this previous study resulted in the authors’ conclusion of clinical and statistical noninferiority to the comparator regimen. It is again arguable whether the regimens compared were indeed equivalent. There is a growing body of evidence supporting the pharmacodynamic optimization of carbapenem and other β-lactam antibiotics.4 It is important for the practicing clinician to balance the benefits of extended infusion strategies in treating resistant organisms with the reality of nursing ratios, concurrent medications, and stability issues. In reviewing the literature, clinicians should also carefully consider pharmacodynamic optimization as a possible bias in clinical trials. Adam D. Porath, PharmD, BCPS Department of Pharmacy Renown Regional Medical Center Reno, Nevada
ACKNOWLEDGMENT Dr. Porath has received a research grant from Merck & Co., Inc.
REFERENCES 1. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868–883. 2. Merrem (Meropenem) [package insert]. Wilmington, DE: AstraZeneca; 2007. 3. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study. Crit Care Med. 2008;36:1089–1096. 4. Nicolau DP. Pharmacodynamic optimization of β-lactams in the patient care setting. Crit Care. 2008;12(Suppl 4):S2.
The author responds: We appreciate the opportunity to reply to the comments by Dr. Porath regarding our recent publication of complicated intra-abdominal infection (cIAI) clinical trial data for doripenem.1 Dr. Porath raised the important issue of choosing appropriate comparator regimens in clinical trials, and we are pleased to provide additional details regarding the justification for the regimens used in the doripenem clinical trials. 1934
Volume 30 Number 10
Letter to the Editor The choice of comparator and dosing regimen are considered very carefully in registration trials, incorporating advice from experts and various health authorities. Because the studies described in the recent publication were intended to support new drug registration in different regions, we were bound by what is approved in the various countries where the studies were to be conducted. Although there may be published data on “off-label” use of the comparator therapies, these are unlikely to meet the approval of health authorities who are ultimately responsible for approval of new drugs. For example, in the United States, the approved methods of administering meropenem are either intravenous infusion over approximately 15 to 30 minutes or intravenous bolus injection over approximately 3 to 5 minutes.2 Intravenous infusion of meropenem in excess of 30 minutes, as suggested by Dr. Porath, would constitute off-label use and would limit use of the data for registration purposes. Second, because the cIAI studies were blinded, a double-dummy drug infusion design was used. For each dose, two infusions were given in sequence, one containing active drug and one containing placebo. To ensure patients received active study drug as soon as possible, active meropenem (or matching placebo) was administered as a bolus followed by active doripenem (or placebo). Although other designs were considered, this was thought to be the simplest and safest way for patients to rapidly receive active study drug. Third, based on published pharmacokinetic studies of meropenem bolus dosing, this regimen was predicted to be highly effective. Following bolus injection of meropenem 1 g, mean (SD) time above minimum inhibitory concentration (T>MIC) values exceed 4 μg/mL for 42.5% (6.2%) of an 8-hour dosing interval.3 T>MIC values for carbapenems that exceed 40% of the dosing interval are widely considered to predict clinical efficacy.4 In the cIAI studies, pathogens with meropenem MICs >4 μg/mL were exceedingly rare. Thus, the meropenem dosing regimen in the cIAI studies was deemed to provide more than adequate coverage against the pathogens isolated. Furthermore, patients infected with pathogens resistant to meropenem (ie, with MICs >8 μg/mL) were excluded from the primary analyses, thus reducing any bias due to exposure to potentially less effective comparator therapy. Dr. Porath cited the ventilator-associated pneumonia study conducted by Chastre et al5 as an additional example of “pharmacodynamic optimization bias” and again questioned the “equivalence” of the treatment regimens. In this large study, Chastre et al utilized a 4-hour infusion of doripenem (500 mg q8h) compared with imipenem 500 mg q6h infused over 30 minutes or 1 g q8h infused over 60 minutes. Of note, imipenem is not labeled for infusions beyond 60 minutes and has limited stability in solution, therefore restricting the potential for extended-duration infusions with this agent.6 Nevertheless, both regimens of imipenem allowed in the study have been shown to provide T>MIC values exceeding 40% of the dosing interval for imipenem-susceptible pathogens.4 As in the cIAI studies, patients with imipenem-resistant infections were excluded from the primary analysis. Data from pharmacokinetic/pharmacodynamic analyses support the comparator dosing regimens used in the doripenem studies, and the authors believe that comparisons with these regimens provide stringent affirmations of the efficacy of doripenem 500 mg q8h therapy. We agree with Dr. Porath that the growing body of evidence supporting the pharmacodynamic optimization of β-lactams, including the carbapenems, is an important concept in drug development. Although, as discussed above, approved dosing regimens may constrain options for dosing comparators in registration drug trials, demonstrably inferior regimens would not be scientifically or ethically justifiable. The noninferiority results of the cIAI study confirm the equivalence of the dosing comparators used in this instance. Christopher Lucasti, MD South Jersey Infectious Disease Somers Point, New Jersey
REFERENCES 1. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868–883. 2. Merrem IV (Meropenem) [package insert]. Wilmington, DE: AstraZeneca; 2007. 3. Jaruratanasirikul S, Sriwiriyajan S. Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection. J Antimicrob Chemother. 2003;52:518–521.
October 2008
1935
Clinical Therapeutics 4. Sun HK, Kuti JL, Nicolau DP. Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: A report from the OPTAMA program. Crit Care Med. 2005;33:2222–2227. 5. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study. Crit Care Med. 2008;36:1089–1096. 6. Primaxin IV (imipenem/cilastatin) [package insert]. Whitehouse Station, NJ: Merck; 2007.
doi:10.1016/j.clinthera.2008.10.015
1936
Volume 30 Number 10