Pharmacokinetics, Pharmacodynamics
Conditions
Keywords
insulin aspart
Brief summary
This study is a randomized, double-blinded, two-treatment, two-period, two-sequence crossover pivotal Biosimilar study. The purpose of this study is to establish pharmacokinetic (PK) and pharmacodynamics (PD) biosimilarity of proposed biosimilar I004 and the US-approved NovoLog.
Interventions
DRUGI004
Drug will be administered via subcutaneous injection into the abdominal wall of the peri-umbilical area with a dose of 0.2 units/kg based on the body weight measured at Treatment Period 1 under fasting condition.
DRUGNovoLog
Drug will be administered via subcutaneous injection into the abdominal wall of the peri-umbilical area with a dose of 0.2 units/kg based on the body weight measured at Treatment Period 1 under fasting condition.
Sponsors
Amphastar Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Upon review, agree to participate and sign informed consent. * Healthy male and female subjects ≥ 18 to ≤ 65 years of age. * Body mass index (BMI) ≥ 18.5 to ≤ 29.9 kg/m2 * Weight ≥ 50 kg. * Fasting plasma glucose of \< 100 mg/dL (5.5 mmol/L) measured with YSI at site; one repeat test is allowed. * HbA1c \< 5.7%. * Non-smoker for ≥ 3 months prior to Screening. * Female candidates must be \> 1 year post-menopausal, surgically sterile, or practicing a clinically acceptable form of birth control and confirmed by negative serum pregnancy test at Screening.
Exclusion criteria
* History of diabetes mellitus. * Resting blood pressure (BP) \> 140/90 mmHg or \< 90/60 mmHg. Subjects BP may be re-checked. * Participation in an investigational drug/device study within 30 days or 5 half-lives within the last dose of any study drug, whichever is longer. * History of any serious adverse reaction or hypersensitivity to any of the investigational product components. * Have significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders or abnormalities, or other major systemic disease that, according to the investigator, would unduly risk the subject's safety or may impact the conduct of the study. * Subject shows evidence of significant active neuropsychiatric disease, including taking prescription medication for such diseases (including anti-depressant/anti-anxiety medication). * Presence of clinically significant physical, laboratory, or ECG findings at Screening that, in the opinion of the Investigator, may interfere with any aspect of study conduct or interpretation of results, or may present a safety issue to that particular subject (laboratory results may be re-checked once on a separate day per Investigator discretion). * Long QT syndrome or family history of long QT syndrome or corrected QT interval (QTcF) \> 450 ms in men, \> 470 ms in women at Screening. * Liver function test results of AST and/or ALT ≥ 2.5 upper normal limit (ULN) * Subject has a history of syncope. * History of any major surgery within 6 months. * History of any active infection, other than mild viral illness within 30 days prior to dosing. * History of blood clots (e.g., deep vein thrombosis or embolism) or a frequent appearance in 1st degree relatives as judged by the Investigator. * Known history or positive test of hepatitis B surface antigen (HBsAG), hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-1) or 2 (HIV-2) antibody. * History of alcohol abuse as judged by the Investigator within approximately 1 year. Average weekly alcohol intake \> 21 units/week (males) and \> 14 units/week (females) or are unwilling to stop alcohol consumption from 24 hours prior to each dosing until discharged from the clinical research unit (CRU). Positive alcohol test at Screening. (One unit of alcohol equals about 250 mL of beer or lager, one glass of wine, or 20 mL of spirits). * History of illicit drug abuse, including marijuana, within approximately 1 year or evidence of current use as judged by the Investigator. Positive drug test at Screening. * Donation or loss of \> 500 mL of blood within 56 days. * Chronic use of over-the-counter or prescription medication within 7 or 14 days prior to dosing (apart from vitamin/mineral supplements, occasional paracetamol, or birth control methods \[Desogestrel is not allowed\]). * Unable to comply with the safety monitoring requirements of this clinical study or is considered by the investigator to be an unsuitable candidate for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Insulin Aspart Concentration, CIAmax | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. |
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From Time 0 to 12 Hours Post-dose, AUCIA(0-12h) | 0 to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(0-12h) will be calculated from the concentration curves. Only AUC from 0 to 12 hours (AUCIA(0-12h)) is reported. |
| Maximum Glucose Infusion Rate, Gmax | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Area Under the Curve (AUC) for Glucose Infusion Rate From Time 0 to 12 Hours Post-dose, AUCG(0-12h) | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(0-12h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From Time 0 to Infinity, AUCIA(0-∞) | 0 to infinity (extrapolated; concentrations measured through 12 hours post-dose) | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(0-∞) will be calculated from the concentration curves. AUCIA(0-∞) is derived using standard extrapolation beyond the last measurable concentration. |
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From Time 0 to 1 Hour Post-dose, AUCIA(0-1h) | 0 to 1 hour post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(0-1h) will be calculated from the concentration curves. Only AUC from 0 to 1 hour (AUCIA(0-1h)) is reported. |
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From Time 0 to 2 Hours Post-dose, AUCIA(0-2h) | 0 to 2 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(0-2h) will be calculated from the concentration curves. Only AUC from 0 to 2 hours (AUCIA(0-2h)) is reported. |
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From Time 0 to 4 Hours Post-dose, AUCIA(0-4h) | 0 to 4 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(0-4h) will be calculated from the concentration curves. Only AUC from 0 to 4 hours (AUCIA(0-4h)) is reported. |
| Area Under the Curve (AUC) of Insulin Aspart Serum Concentration From 4 to 12 Hours Post-dose, AUCIA(4-12h) | 4 to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. AUCIA(4-12h) will be calculated from the concentration curves. Only AUC from 4 to 12 hours (AUCIA(4-12h)) is reported. |
| Time of Maximum Insulin Aspart Serum Concentration, tIAmax | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. |
| Apparent Clearance of Insulin Aspart, CL/F | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. |
| Apparent Volume of Distribution of Insulin Aspart, Vz/F | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. |
| Half-life of Insulin Aspart, t1/2 | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Insulin Aspart. |
| Maximum Serum Human Insulin Concentration, CHImax | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Human Insulin |
| Area Under the Curve (AUC) of Human Insulin Serum Concentration From Time 0 to 12 Hours Post-dose, AUCHI(0-12h) | 0 to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Human Insulin. AUCHI(0-12h) will be calculated from the concentration curves. Only AUC from 0 to 12 hours (AUCHI(0-12h)) is reported. |
| Time of Maximum Human Insulin Serum Concentration, tHImax | Baseline (Time 0) to 12 hours post-dose | Pharmacokinetic (PK) blood samples will be collected from 60 minutes before dose through 12 hours post-dose. Serum will be isolated for analyzing the concentrations of Human Insulin. |
| Area Under the Curve (AUC) for Glucose Infusion Rate Due to Insulin Aspart From Time 0 to 12 Hours Post-dose, AUCGA(0-12h) | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCGA(0-12h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Maximum Glucose Infusion Rate Due to Insulin Aspart, GAmax | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Area Under the Curve (AUC) for Glucose Infusion Rate (GIR) From Time 0 to the Time of Last Measurable GIR, AUCG(0-last) | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(0-last) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Area Under the Curve (AUC) for Glucose Infusion Rate From Time 0 to 1 Hour Post-dose, AUCG(0-1h) | From drug administration to 1 hour post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(0-1h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Area Under the Curve (AUC) for Glucose Infusion Rate From Time 0 to 2 Hours Post-dose, AUCG(0-2h) | From drug administration to 2 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(0-2h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Area Under the Curve (AUC) for Glucose Infusion Rate From Time 0 to 4 Hours Post-dose, AUCG(0-4h) | From drug administration to 4 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(0-4h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Area Under the Curve (AUC) for Glucose Infusion Rate From Time 4 to 12 Hours Post-dose, AUCG(4-12h) | From 4 hours post-dose to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. AUCG(4-12h) will be calculated from the glucose infusion rate curves. Because GIR is recorded in mg/kg/min, the area under the GIR-time curve has units mg/kg. |
| Last Measurable Glucose Infusion Rate, Glast | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Time of Maximum Glucose Infusion Rate, tGmax | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Time of Glucose Infusion Start, tGonset | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Time of Last Measurable Glucose Infusion Rate, tGlast | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Time to Half of Maximum Glucose Infusion Rate (Gmax) Before Gmax Is Reached, tG50%Early | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
| Time to Half of Maximum Glucose Infusion Rate (Gmax) After Gmax Is Reached, tG50%Late | From drug administration to 12 hours post-dose | Participants will undergo a euglycemic clamp, where blood glucose concentration will be held at a constant target level by adjusting exogenous glucose infusion rate (GIR) following drug administration. GIR will be recorded for the duration of the euglycemic clamp and used to evaluate the Pharmacodynamic (PD) response. |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized to receive all 2 treatments over 2 treatment periods in a crossover design.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 11.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants |
| Race/Ethnicity, Customized Black or African-American | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 43 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 66 |
| other Total, other adverse events | 7 / 65 | 10 / 66 |
| serious Total, serious adverse events | 0 / 65 | 0 / 66 |
Outcome results
None listed