These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935].

Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.

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. ...

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes.

Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono-or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/ MIC ratio was also borderline predictive of microbiological response (P ‫؍‬ 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.Evaluating exposure-response relationships by use of clinical trial data is an essential component of optimizing antimicrobial treatment, yet it is often quite challenging. A single dosing regimen is often used, thus limiting the range of observed drug exposure, and it is difficult to collect on an individual-patient basis the three integral pieces of information required to perform such analyses: pharmacokinetic (PK), clinical, and microbiological outcome data. The value of such analyses, however, has become increasingly important in quantifying drug efficacy and in contributing to the establishment of appropriate in vitro MIC susceptibility breakpoints by regulatory and clinical agencies (e.g., the Clinical and Laboratory Standards Institute [CLSI] and the European Committee on Antimicrobial Susceptibility Testing [EUCAST]) (5). Utilizing results from PKpharmacodynamic (PK-PD) analyses may allow a better understanding of the causes of variability in responses among subgroup...