Brenda Cirincione

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 μg/ml and that less susceptible strains could be treated with prolonged infusions.

Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing.

Background and ObjectivesExenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus.Patients and MethodsPatients with type 2 diabetes participated in either a single-dose trial (n=62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER.ResultsExenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6–7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (−42.7 ±15.7 mg/dL with the 0.8mg dose and −39.0±9.3mg/dL with the 2mg dose; both p<0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC50) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2mg doses of exenatide ER). The 2 mg dose reduced bodyweight (−3.8 ± 1.4kg; p<0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbAlc) levels were reduced with the 0.8 mg dose (−1.4±0.3%; baseline 8.6%) and with the 2mg dose (−1.7 ± 0.3%; baseline 8.3%) [both p<0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity.ConclusionThese 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]

Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment

Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time‐course and cross‐reactivity of anti‐exenatide antibodies and potential effects on efficacy and safety.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

ABSTRACT Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

GLP-1 based therapies: differential effects on fasting and postprandial glucose

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 of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections

ABSTRACT 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.

Population Pharmacokinetic Analysis of Linezolid in Patients With Infectious Disease: Application to Lower Body Weight and Elderly Patients

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1‐compartment PK model with first‐order absorption and first‐order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

Population Pharmacokinetics of Tigecycline in Patients with Complicated Intra-Abdominal or Skin and Skin Structure Infections

ABSTRACT Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (α = 0.05) and backward (α = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC0-12) were generally unbiased (median prediction error, −1.60% to −3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC0-12 in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc. Methods Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. Results Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. Conclusions These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

Population pharmacokinetics of tigecycline in healthy volunteers.

Tigecycline, a novel glycylcycline, possesses broad‐spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5–300 mg) or multiple (25–100 mg) doses every 12 hours for up to 10 days. Three‐compartment models with zero‐order input and first‐order elimination separately described the single‐ or multiple‐dose full‐profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse‐sampling scheme and dosage. A 2‐compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC0–12. This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.