Cutaneous pharmacokinetics-based bioequivalence: A clinical dermal open flow microperfusion verification study using lidocaine and prilocaine combination topical products.

BACKGROUND: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established. OBJECTIVE: To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties. METHODS: The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 h. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC0to12h and Cmax using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study. RESULTS: BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible. CONCLUSIONS: dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK-based BE approach for topical lipophilic drugs, including lidocaine and prilocaine.

Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes.

OBJECTIVE: To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). RESEARCH DESIGN AND METHODS: This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. RESULTS: With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. CONCLUSIONS: AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.

Digital algorithm-guided insulin therapy in home healthcare for elderly persons with type 2 diabetes: A proof-of-concept study.

GlucoTab@MobileCare, a digital workflow and decision support system with integrated basal and basal-plus insulin algorithm was investigated for user acceptance, safety and efficacy in persons with type 2 diabetes receiving home health care by nurses. During a three months study nine participants (five female, age 77 ± 10 years, HbA1c 60 ± 13 mmol/mol (study start) vs. 57 ± 12 mmol/mol (study end) received basal or basal-plus insulin therapy as suggested by the digital system. In total 95% of all suggested tasks (blood glucose (BG) measurements, insulin dose calculations, insulin injections) were performed according to the digital system. Mean morning BG was 171 ± 68 mg/dL in the first study month vs. 145 ± 35 mg/dL in the last study month, indicating a reduced glycemic variability of 33 mg/dL (standard deviation). No hypoglycemic episode < 54 mg/dL occurred. User's adherence was high and the digital system supported a safe and effective treatment. Larger scale studies are needed to confirm findings under routine care. German Clinical Trials Register ID: DRKS00015059.

Study protocol for assessing the user acceptance, safety and efficacy of a tablet-based workflow and decision support system with incorporated basal insulin algorithm for glycaemic management in participants with type 2 diabetes receiving home health care: A single-centre, open-label, uncontrolled proof-of-concept study.

INTRODUCTION: Diabetes management can be especially complex for older adults who receive health care at home. Thus, international guidelines recommend basal-insulin regimens due to simpler handling and low hypoglycaemia risk. A basal-insulin algorithm (including basal-plus) was developed to also include participant's health status and subsequently implemented into a tablet-based workflow and decision support system, GlucoTab@MobileCare. This study protocol describes a proof-of-concept study to investigate user acceptance, safety and efficacy of the GlucoTab@MobileCare system in participants receiving home health care. METHODS: The open-label, single-centre, uncontrolled study will recruit a maximum of ten participants with insulin treated type-2-diabetes (age ≥18 years) who receive home health care. During a three month study period participants will receive basal- or basal-plus-insulin therapy once daily as suggested by the GlucoTab@MobileCare system. Statistical analysis will be conducted on an intention-to-treat basis. The primary endpoint is the percentage of tasks (BG measurements, insulin dose calculations, insulin injections) that were performed according to GlucoTab@MobileCare suggestions relative to the total of suggested tasks. Secondary endpoints include user acceptance, safety and efficacy parameters. The study was approved by the ethics committee and regulatory authorities. Before obtaining written informed consent, all participants will receive oral and written information about all aspects of the study. Results will be published in a peer-reviewed journal and at diabetes and geriatric conferences. DISCUSSION: Potential implications may be improved quality and safety of basal-insulin therapy in older adults as well as support for health-care-providers in daily routine including evidence-based knowledge. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00015059).

Feasibility of Blood Glucose Management Using Intra-Arterial Glucose Monitoring in Combination with an Automated Insulin Titration Algorithm in Critically Ill Patients.

Background: This two-center pilot study combined for the first time an intra-arterial glucose sensor with a decision support system for insulin dosing (SGCplus system) in critically ill patients with hyperglycemia. Methods: Twenty-two patients who were equipped with an arterial line and required iv insulin therapy were managed by the SGCplus system during their medical treatment at the intensive care unit. Results: Time to target was 111 ± 195 min (80-150 mg/dL) and 135 ± 267 min (100-160 mg/dL) in the lower and higher glucose target group. Mean blood glucose (BG) was 142 ± 32 mg/dL with seven BG values <70 mg/dL. Mean daily insulin dose was 62 ± 38 U and mean daily carbohydrate intake 148 ± 50 g/day (enteral nutrition) and 102 ± 58 g/day (parenteral nutrition). Acceptance of SGCplus suggestions was high (93%). Conclusions: The SGCplus system can be safely applied in critically ill patients with hyperglycemia and enables good glycemic control.