Use of Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Phase 2 and 3 Dosing Strategies for Doripenem

Abstract

A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 g/ml and that less susceptible strains could be treated with prolonged infusions.There has been a growing appreciation of the value of incorporating knowledge from nonclinical models of infection into the early stages of clinical drug development. As described by Drusano et al., the integration of pharmacokinetic-pharmacodynamic (PK-PD) targets derived from nonclinical exposure-response data with phase 1 pharmacokinetic data can be used to optimize antimicrobial dosing regimens for phase 2 and 3 studies (2). Recently, the Food and Drug Administration has implemented end-of-phase-2a meetings with sponsors to review the pharmacokinetics and PK-PD of investigational agents and discuss data supporting dose selection in order to increase the likelihood of regulatory success (4). Doripenem, a parenteral carbapenem currently in clinical development, demonstrates a broad spectrum of in vitro and in vivo microbiological activity against most clinically relevant gram-negative and -positive pathogens, including commonly occurring extended-spectrum beta-lactamase and AmpC producing strains (3; H. Huynh, P. R. Rhomberg, and R. N. Jones, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-528, 2003). Like previous studies with beta-lactams in neutropenic mouse-thigh infection models (1), a study by Craig and Andes found the proportion of the dosing interval for which drug concentrations exceed the MIC of the targeted microorganism (TϾMIC, in percent) for doripenem to be the PK-PD measure that correlated best with change in bacterial count (log 10 CFU/thigh) for Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae (D. R. Andes and W. A. Craig, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-308, 2003). The mean (SD) TϾMIC associated with 1-and 2-log reductions were 21.1% (8.9%) and 27.3% (11.9%) for S. pneumoniae, 32.3% (6.7%) and 35.4% (5.0%) for S. aureus, and 36.1% (7.4%) and 43.3% (7.1%) for gram-negative bacilli, respectively. Using the above-described PK-PD targets and phase 1 pharmacokinetic data, we carried out the analyses described herein in order to (i) develop a population pharmacokinetic model to describe the disposition of doripenem; (ii) assess the performance of various doripenem dosing regimens in attaining PK-PD targets over a range of MICs using a Monte Carlo simulation; and (iii) identify potential dosing regimens for phase 2 and 3 studies.Phase 1 data were obtained from a double-blind dose escalation study of intravenous doripenem in 24 healthy subjects between 18 and 65 years of age who received one of four regimens for 7 days, 500 or 1,000 mg given every 12 or 8 h (D. Thye, T. Kilfoil, A. Leighton, and M. Wikler, Abstr. Intersci. Conf. Antimicrob. ...

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

“…As per local antibiotic guidelines, patients receiving doripenem in a Malaysian intensive care unit (ICU) typically receive a standard dose of 500 mg every 8 h as a 1-h intravenous (IV) infusion. However, the appropriateness of this dosing regimen is disputable, as it is based on PK/PD data derived from earlier studies which mostly recruited heterogeneous cohorts of healthy volunteers and noncritically ill Caucasian patients (3)(4)(5)(6). Importantly, results of subsequent PK/PD studies suggest that current recommendations may be grossly flawed in critically ill patients and that optimal dosing requirements may significantly differ from that initially proposed (7)(8)(9).…”

“…In this context, it is imperative to consider regional antibiotic susceptibility data whereby, in the Asia-Pacific region, the MIC required to inhibit the growth of 90% of organisms (MIC 90 ) for doripenem against P. aeruginosa was reported as 8 mg/liter (15,16). However, a typical dose of 500 mg every 8 h as a 1-h infusion is reported to be effective only against pathogens with an MIC of Յ2 mg/liter; its application, therefore, is likely to fail in such a scenario (4,6).…”

Population Pharmacokinetics of Doripenem Based on Data from Phase 1 Studies with Healthy Volunteers and Phase 2 and 3 Studies with Critically Ill Patients

“…It is approved for complicated intra-abdominal and complicated urinary tract infections (UTI) in the United States and in Europe, where it is also approved for nosocomial pneumonia (15). All carbapenems (except for ertapenem) have very similar pharmacokinetics, including halflife (1 h), protein binding (2 to 20%), distribution properties (0.23 to 0.35 liters/kg of body weight), and temporal plasma profiles (3,29).…”

“…Using doripenem dosing regimens intended for clinical use, Bhavnani et al developed a population pharmacokinetic model from limited intensively sampled data from a phase 1 study of 24 healthy volunteers with normal renal function (3). Simulation results based on this model predicted that 500 mg of doripenem infused over 1 h, administered every 8 h, would be effective against bacterial strains with MICs up to 2 g/ml and that less susceptible strains could be treated with a more prolonged infusion.…”

Prediction of Pharmacokinetics of Antibiotics in Patients with End-Stage Renal Disease

“…8) In particular, this kind of methodology is informative for the development of antibiotic agents, since there is clear evidence that the pharmacological effect is well correlated to some PK/PD parameters. 9,10) Hemodialysis is a physical process that can be described by a mathematical model. 3,11) There are many factors affecting drug removal during hemodialysis, including molecular weight, lipid and water solubility, surface area, porosity of the dialysis membrane, blood and dialysate flow rates, protein binding and red blood cell partitioning.…”