This double-blind randomized crossover trial is the first to compare the PD and PK properties of two URIs (BCLIS and FIA) and of a conventional analog (ASP). Forty-three patients with type 1 diabetes received a bolus of 0.15 U/kg of BCLIS, FIA or ASP with CSII on top of a 0.01 U/kg/h basal rate under euglycemic clamp conditions (ClampArt®). Compared to ASP, BCLIS had significantly faster-on and -off PD with higher AUCs in the first two hours, lower AUCGIR 2-6h and earlier tearly0.5GIRmax and tlate0.5GIRmax (Table, Figure). Compared to FIA, BCLIS showed similar early GIR excursions and a significantly faster-off PD with earlier tlate0.5GIRmax. PK was aligned with PD and showed higher early (0-1h) and lower late (2-6h) exposures of BCLIS vs. FIA.
Table: Mean±SD PD and PK parameters
| Parameter | Definition | BCLIS | ASP | FIA | p-value BCLIS/ASP | p-value BCLIS/FIA |
| AUCGIR 0-2h [mg/kg] | PD effect in first two hours | 592±275 | 500±244 | 566±276 | 0.0038 | 0.3127 |
| AUCGIR 2-6h [mg/kg] | PD effect 2-6 hours post-dose | 693±329 | 881±387 | 753±268 | 0.0015 | 0.3087 |
| tearly0.5GIRmax [min] | Time to early half-maximum PD | 44±22 | 57±19 | 42±13 | <0.0001 | 0.9020 |
| tlate0.5GIRmax [min] | Time to late half-maximum PD | 210±68 | 232±52 | 228±61 | 0.0020 | 0.0017 |
| AUCINS 0-1h [h.mU/L] | Insulin exposure 0-1 hour post-dose | 68±27 | 43±22 | 59±21 | <0.0001 | 0.0284 |
| AUCINS 2-6h [h.mU/L] | Insulin exposure 2-6 hours post-dose | 81±43 | 95±41 | 93±45 | 0.0006 | 0.0001 |
| tlate0.5INSmax [min] | Time to late half-maximum insulin concentrations | 147±48 | 183±68 | 165±59 | <0.0001 | 0.0028 |
| Parameter | Definition | BCLIS | ASP | FIA | p-value BCLIS/ASP | p-value BCLIS/FIA |
| AUCGIR 0-2h [mg/kg] | PD effect in first two hours | 592±275 | 500±244 | 566±276 | 0.0038 | 0.3127 |
| AUCGIR 2-6h [mg/kg] | PD effect 2-6 hours post-dose | 693±329 | 881±387 | 753±268 | 0.0015 | 0.3087 |
| tearly0.5GIRmax [min] | Time to early half-maximum PD | 44±22 | 57±19 | 42±13 | <0.0001 | 0.9020 |
| tlate0.5GIRmax [min] | Time to late half-maximum PD | 210±68 | 232±52 | 228±61 | 0.0020 | 0.0017 |
| AUCINS 0-1h [h.mU/L] | Insulin exposure 0-1 hour post-dose | 68±27 | 43±22 | 59±21 | <0.0001 | 0.0284 |
| AUCINS 2-6h [h.mU/L] | Insulin exposure 2-6 hours post-dose | 81±43 | 95±41 | 93±45 | 0.0006 | 0.0001 |
| tlate0.5INSmax [min] | Time to late half-maximum insulin concentrations | 147±48 | 183±68 | 165±59 | <0.0001 | 0.0028 |
B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. O. Klein: None. C. Seroussi: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. A. Ranson: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. J. Arrubla: None. J. Correia: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. R. Soula: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Board Member; Self; Cellnovo. B. Alluis: None. G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. S. Glezer: Stock/Shareholder; Self; Sanofi. Stock/Shareholder; Spouse/Partner; Sanofi. Employee; Self; ADOCIA, Novo Nordisk Inc.. Employee; Spouse/Partner; Pfizer Inc., Teva Pharmaceutical Industries Ltd.. Stock/Shareholder; Spouse/Partner; Teva Pharmaceutical Industries Ltd. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi.
