William Lyness

An evaluation of patient preference for an alternative insulin delivery system compared to standard vial and syringe.

ABSTRACT Background: Diabetes mellitus (DM) affects over 18.2 million Americans and diabetes-related medical costs exceed 132 billion dollars per year, totaling more than 12% of the United States healthcare budget. The Diabetes Control and Complications Clinical Trial demonstrated that intensive insulin therapy and the control of plasma glucose can significantly reduce the incidence of late diabetic complications and delay the progression of existing conditions in type 1 diabetes. Optimal glycemic control often requires intensive insulin therapy to maintain a hemoglobin A1C (A1C) of less than 7% as recommended by the American Diabetes Association. It is estimated that more than half of the approximately 7 million Americans using insulin do so with suboptimal treatment and while administering one or two insulin injections per day. Non-adherence may be a contributing factor in suboptimal treatment. For a variety of reasons, many patients diagnosed with diabetes and treated with insulin are non-adherent. Scope: The primary objective of this study was to evaluate preference for an insulin delivery system comparing a disposable doser (InnoLet) to the standard vial/syringe. In a prospective, randomized, open-label, two-period, crossover study, 260 patients were enrolled (age ≥ 18 years, with type 1 or 2 diabetes, and receiving NPH or regular or 70/30 insulin for at least 6-months). A total of 162 patients completed both treatment arms. Excluded were those unable to read/write English or administer their own injections, pregnant/lactating women, those using antipsychotics, and those with a history of alcohol abuse or cognitive impairment. Patients completed the eight-item Diabetes Fear of Self-Injection Questionnaire at baseline, week 12 and week 24. Items were rated on a 4-point Likert scale (1 = almost never; 4 = almost always) with a maximum fear score of 32. At week 24, patients completed a preference survey. Findings: Of the 162 patients completing both treatment arms, 89 (55.0%) were in the vial/syringe to disposable doser treatment arm, 50% were female and mean age was 60 ± 11 years. Patients in both treatment arms displayed little significant differences in baseline characteristics. Patients reported significantly lower fear of self-injection after using the disposable doser compared to vial/syringe (mean ± SEM: 9.5 ± 0.2 vs. 11.2 ± 0.4; p < 0.0001). Most patients (71.5%) indicated a preference for the disposable doser compared to the vial/syringe method ( p < 0.0001). Conclusion: The majority of patients preferred the disposable doser, and reported significantly less fear of self-injection using this delivery system. There are some potential limitations to consider. A randomization bias may have been present, patients who enrolled in this study were those who were actively seeking medical treatment for diabetes, insulin pens and cartridges are not available for all types of insulin regimens, pre-filled pens and cartridges may not be altered and, in general, alternative insulin delivery systems tend to be more costly than insulin sold in traditional vials. However, insulin may have greater patient acceptance and less psychological distress when administered via an alternative delivery system.

Similarity of insulin detemir pharmacokinetics, safety, and tolerability profiles in healthy caucasian and Japanese american subjects.

The objective of this study was to compare the pharmacokinetics of insulin detemir in three ascending doses in healthy Japanese and Caucasian subjects. This was an open‐label, single‐center, parallel‐group design evaluating 30 subjects (15 Japanese and 15 Caucasians). Subjects received a total of three subcutaneous injections (one injection per visit) of insulin detemir (0.19, 0.38, 0.75 U/kg [1 U = 24 nmol]) in ascending order. Following drug administration, subjects received intravenous glucose in 0.5‐mg/kg/min increments every 30 minutes, followed by a constant rate of 2.0 mg/kg/min for up to 12 hours. For pharmacokinetic evaluations, serial blood sampling was performed over a period of 30 hours after dosing. Of the subjects, 36 were enrolled, and 30 completed the study. There was a linear dose‐response relationship between the three ascending insulin detemir doses and serum insulin detemir AUC values for both the Japanese and Caucasian subjects. The two dose‐response regression lines had equivalent slopes but slightly different intercepts (although not statistically significant). This difference may be due to variation in AUC, body weight differences, or chance. Six subjects discontinued the study, 2 as a result of adverse events (blood draw–related ecchymosis and hypoglycemia). The most frequent treatment‐emergent adverse events (TEAE) were headache, dizziness, and reactions related to blood draws/infusion sites. All TEAEs were mild to moderate in severity. The results show that an increase in insulin detemir dose will result in a similar increase in insulin detemir concentration in the two ethnic groups. Therefore, therapeutic dosing of insulin detemir is expected to be similar in both ethnic groups, with no special dose adjustment or algorithm based on race. Insulin detemir at 0.19, 0.38, and 0.75 U/kg was generally well tolerated in both Japanese and Caucasian subjects.

Tolerability and Pharmacokinetics of Monotherapy Felbamate Doses of 1,200–6,000 mg/day in Subjects with Epilepsy

: Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200–6,000 mg/day were assessed in two open‐label studies with similar designs.

Coadministration of Phenytoin and Felbamate: Evidence of Additional Phenytoin Dose-Reduction Requirements Based on Pharmacokinetics and Tolerability with Increasing Doses of Felbamate

Summary: Purpose: This open‐label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM).

Evaluation of the Potential Interaction Between Felbamate and Erythromycin in Patients with Epilepsy

Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence the metabolism of many therapeutic agents. An open‐label, randomized, two‐period, crossover study was therefore conducted to evaluate the pharmacokinetics of felbamate before and after a concurrent 10‐day regimen (333 mg three times daily) of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate monotherapy for treatment of epilepsy. Mean dose‐normalized values for maximum concentration (Cmax) and area under the concentration—time curve (AUCr) of felbamate were not statistically different in patients taking felbamate as monotherapy than in patients after erythromycin coadministration. Estimates of time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg), average concentration (Cav), and degree of fluctuation (DFss) were likewise unchanged. The incidence of mild and moderate adverse events increased during coadministration of the two drugs. Because patients with epilepsy can not be treated with erythromycin alone, it could not be determined whether the adverse events were attributable to erythromycin or to the combination of the two drugs. Steady‐state pharmacokinetic parameters of felbamate were not influenced by erythromycin coadministration.

Fixed-dose combination tablet of repaglinide and metformin is bioequivalent to concomitantly administered individual tablets of repaglinide and metformin : randomized, single-blind, three-period crossover study in healthy subjects.

AbstractBackground and objective: Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. Methods: Healthy subjects (n = 93, age 18–5 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. Results: Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the prespecified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed end-points. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. Conclusion: An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

Patient Perception and Use of an Insulin Injector/Glucose Monitor Combined Device

PURPOSE This clinical trial assessed patient preference, satisfaction, and use of an insulin injector/glucose monitor combination device versus syringes and a separate glucose monitor. METHODS In a randomized, multicenter, 2-period crossover study, 15 patients with type 1 diabetes were randomized to use either a combined injector/monitor device or syringes, a vial, and a separate glucose monitor, then switched to the alternate treatment. Efficacy, safety, preference, satisfaction, and actual use (via meter download) of the 2 systems were compared. RESULTS Most of the patients preferred using the combination device to syringes and a separate meter. Results from the Handling of Delivery Systems questionnaire given at the end of the study indicated that 49% of patients felt they tested their blood glucose more often with the combination device than with a separate meter. A higher frequency of daily monitoring was reported with the combination device in patients overall (approximately 1 more reading per week). However, a large subset of patients (32%) showed substantial increases in their frequency of daily glucose monitoring (an average of 1 additional reading per day). CONCLUSIONS Use of the combination device was associated with significant improvements in patient treatment satisfaction.