Mary E. Seger

Pharmacokinetic‐pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis

We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis.

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

OBJECTIVE LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union– and US-approved versions of IGlar. RESEARCH DESIGN AND METHODS These were three single-site, randomized, double-blind, two-treatment, four-period, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ≥7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTS A total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [Cmax]) and PD (maximum glucose infusion rate [Rmax]; total glucose infusion during the clamp [Gtot]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. Adverse events were similar between treatments. CONCLUSIONS These studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

Bioequivalence and comparative pharmacodynamics of insulin lispro 200 U/mL relative to insulin lispro (Humalog®) 100 U/mL

Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog®, IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, open‐label, 2‐sequence, 4‐period crossover, randomized, 8‐hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration‐versus‐time curve from time zero to the time of the last measurable concentration (AUC0–tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter‐ and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20‐U single doses, and PD responses were comparable between formulation strengths.

Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial

BackgroundConsistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use.MethodsThis trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 μg, levonorgestrel [LV] 150 μg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 μg BID from Days 1 through 4 and at 10 μg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period.ResultsExenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial.ConclusionsThe observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection.Trial registrationClinicalTrials.gov: NCT00254800.

Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM).

LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single‐site, randomized, subject‐ and investigator‐blinded, 4‐treatment, 4‐period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty‐four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC0–24] and maximum observed drug concentration [Cmax]) and PD parameters (total amount of glucose infused during the clamp [Gtot] and maximum glucose infusion rate [Rmax]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg.

Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points

Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic’s structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.

Reply to Heise et al.

To the Editor: In a recent article by Heise et al. [1], the pharmacodynamic (PD) and pharmacokinetic (PK) properties of insulin (INS) glulisine and INS lispro were compared. In this randomized four-way, crossover study, 80 lean and obese subjects without diabetes [stratified into four body mass index (BMI) classes] were randomized to receive single injections of glulisine and lispro (0.2 and 0.4 U/kg) on four occasions under glucose clamp conditions. Glucose infusion rates (GIRs) and insulin concentrations were assessed for 10 h after each dose [1]. The abstract’s conclusions, stating that ‘glulisine shows a faster onset of action than lispro, independent of BMI and dose’, deserve clarification and comment. The concluding statement was based on the findings that glulisine was associated with a greater GIR–AUC0–1h and earlier time to 10% of total GIR–AUC (GIR-t10%) at both 0.2 and 0.4 U/kg doses and PK findings suggesting a faster rise in insulin concentrations (which we comment on separately below). However, the PK/PD profiles were not provided and neither were data at 1–10 h. Based on the observation that GIR-Tmax was not statistically different between treatments, this would indicate that the onset of peak insulin activity was equivalent for glulisine and lispro. Instead, the focus is on somewhat arbitrarily selected end-points around the 0to 1-h timeframe and t10%, in contrast to more uniformly selected end-points based on time to achieve a predefined per cent of peak insulin activity. Additionally, the authors mentioned that there were no significant differences in GIR-t20%, GIRmax and GIR–AUC0–10h between glulisine and lispro at either dose and the total metabolic effect was not different between the two insulin analogues. It is also to be noted that the numerical differences in GIR–AUC0–1h/GIR–AUC0–10h between treatments are small and represent less than 10% of the total glucodynamic activity. Furthermore, as the interaction term between BMI and treatment was not significant, partitioning the data according to different BMI classes is not consistent with sound statistical testing. While some PK parameters (INS–AUC0–10h, ratio of INS–AUC0–1h to INS–AUC0–10h, INS-t10% and INSmax) suggest a higher maximum concentration and greater total AUC with glulisine compared with lispro, the authors mentioned that the ‘differences in insulin exposure are considered artefactual and are because of differences in the cross-reactivity to human insulin between the analogue–specific kits used for analysis’ [1]. Thus, comparisons in terms of PK properties between the two insulin analogues have to be guarded. It is also to be noted that while the article discusses much about the PK measurements at 0–1 h, the difference in INS-t20% was not significant and most importantly, neither was the time to maximum insulin concentration. The article also raises speculations about the potential clinical implications of the current findings. However, there is no evidence about the clinical difference between insulin glulisine and insulin lispro. A large study comparing glulisine to lispro in more than 600 patients with type 1 diabetes (using insulin glargine as the basal insulin in both treatment arms) demonstrated no differences in glycosylated haemoglobin or hypoglycaemia [2]. In summary, the conclusion that glulisine has a faster onset of action than lispro has to be qualified as limited to parameters at the 0to 1-h time period or time at which less than10%of the glucodynamicactivityhas occurred in subjects without diabetes. These have to be interpreted cautiously in light of other PK/PD studies [3–6] as well as clinical evidence that showno clinical difference between insulin glulisine compared with insulin lispro [2].

Inhibition of PKC β by Ruboxistaurin Does Not Enhance the Acute Blood Pressure Response to Nitroglycerin

Ruboxistaurin is a selective protein kinase C β inhibitor undergoing clinical investigation for treatment of diabetic microvascular complications. This study assessed a possible blood pressure (BP) interaction between ruboxistaurin and the exogenous nitric oxide donor, glyceryl trinitrate (GTN). Subjects (N=22) with chronic stable angina received placebo or ruboxistaurin 96 mg/day orally to steady state in a crossover design. Graded GTN (0, 5, 10, 20, 40, 80, and 120 μg/min) or 5% dextrose solution was then infused intravenously and BP was measured following each dose. Ruboxistaurin did not alter the slope of change in standing systolic BP (ΔsSBP/1n[GTN dose]) curve (P=0.272 analysis of covariance) or affect the ΔsSBP at the estimated GTN dose producing a 10‐mm Hg reduction in sSBP from baseline on placebo (mean difference −0.9 mm Hg; 95% confidence of interval, −3.3–1.5). In conclusion, ruboxistaurin does not potentiate the acute BP‐lowering effects of GTN.