Pharmacokinetic Study to Compare the Blood Levels of Abatacept Manufactured at Lonza Biologics to the Blood Levels of Abatacept Manufactured at the Devens, Massachusetts (MA) Facility of Bristol-Myers Squibb

Phase 1

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Biological: Abatacept (BMS-188667)

• Registration Number: NCT01439204
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

The purpose of this study is to determine whether the blood levels of Abatacept (BMS-188667) drug product manufactured at Lonza Biologics and the Devens, MA facility of Bristol-Myers Squibb are comparable in healthy subjects

Detailed Description

Primary Purpose of this study is to compare the pharmacokinetic (PK) of Abatacept (BMS-188667) manufactured at Lonza relative to Abatacept (BMS-188667) manufactured at Devens, MA facility following a single intravenous infusion of 750 mg in healthy subjects

Study Timeline

• Study First Submitted: 2011-09-21
• Study First Submitted QC: 2011-09-22
• Study First Posted: 2011-09-23
• Study Start: 2011-10
• Primary Completion: 2012-02
• Study Completion: 2012-02
• Results First Submitted: 2013-11-04
• Results First Submitted QC: 2013-12-30
• Status Verified: 2014-02
• Results First Posted: 2014-02-04
• Last Update Submitted: 2014-02-21
• Last Update Posted: 2014-03-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 223

Inclusion Criteria

• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations
• Body weight will be between 60 and 100 kg, inclusive

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Exclusion Criteria

• Any significant acute or chronic medical illness
• Any major surgery within 4 weeks of study drug administration
• Smoking more than 10 cigarettes per day
• Recent (within 6 months of study drug administration) drug or alcohol abuse.
• Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or Human Immunodeficiency Virus-1, Human Immunodeficiency Virus-2 antibody
• History of any significant drug allergy or asthma
• Women who are pregnant or breastfeeding and/or unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Abatacept (BMS-188667) manufactured at Lonza, NH facility	Abatacept (BMS-188667)	-
Abatacept (BMS-188667) manufactured at Devens, MA facility	Abatacept (BMS-188667)	-

Primary Outcome Measures

Name	Time	Method
Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Days 1 to 71	Cmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Cmax was measured in micro grams per milliliter (µg/mL).
Time to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	Tmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Tmax was measured in hours (h).
Area Under the Concentration-time Curve (AUC) From Time Zero to 28 Days [AUC(0-28 Days)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	AUC (0 - 28) was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - 28) was measured in micro grams\*hours per milliliter (µg\*h/mL).
Area Under the Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration [AUC(0-T)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	AUC (0 - T) was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - T) was measured in micro grams\*hour per milliliter (µg\*h/mL).
Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(0 - INF)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	AUC (0 - INF) was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - INF) was measured in µg\*h/mL.
Terminal Phase Elimination Half-life (T-HALF) of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	T-HALF was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). T-HALF was measured in hours (h).
Total Body Clearance (CLT) of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	CLT was the volume of abatacept cleared by the system, normalized by baseline body weight. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). CLT was measured in milliliters per hours per kilogram of body weight (mL/h/kg).
Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population	Day 1 to Day 71	Vss was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Vss was measured in liters per kg body weight (L/kg).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Positive Abatacept-induced Immunogenicity Response	Days 29, 57, 71	Immunogenicity determination was based on titers of anti-abatacept and anti- cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4-T) antibodies in serum over time. A participant had a positive abatacept-induced immunogenicity if 1 of the following criteria were met: missing baseline measurement and a positive response after baseline; negative baseline response and positive response after baseline; a baseline response and a positive response after baseline that has a titer value strictly greater than the baseline titer value. A validated, sensitive, electrochemiluminescence assay (ECL) method was used to analyze the antibodies in serum. Samples confirmed positive with ECL and with abatacept serum concentrations of less than equal to 1 µg/mL were further analyzed with a validated, in vitro, cell-based bioassay to analyze the sera containing the abatacept neutralizing activity. Samples obtained on Days 29, 57 and 71 post dose of abatacept on Day 1 (baseline).
Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population	Day 2 to Day 71	Blood samples obtained: Days 1, 2, 4, 8, 15, 22, 29, 43, 57 and 71. International Units per liter (U/L); milligram per deciliter (mg/dL); Male(M); Female (F). Reference ranges (low/high) for laboratories for which participants were identified with marked abnormalities during the study: Blood Urea Nitrogen (M/F) 10-20mg/dL ; Creatine Kinase (F) 21-21 U/L,(M) 32-294 U/L; Direct Bilirubin (M/F) 0.1-0.4 mg/dL ; Fasting Glucose (M/F) 70-110 mg/dL; Lactate Dehydrogenase (M/F) 110-209 U/L.
Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population	Day 2 to Day 72	Blood samples obtained: Days 2, 4, 8, 15, 22, 29, 43, 57 and 71. Male(M); Female (F). Reference ranges (low/high) for laboratory parameters for which participants were identified with marked abnormalities during the study: Leukocytes (quantitative White blood cells) (M/F) 4-11\*10\^3/microliters (µL); Neutrophils (absolute)(M/F) 1.4- 8.2\*10\^3/µL.
Change From Baseline in Systolic Blood Pressure - Safety Population	Day 1 to Day 71	Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71.
Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population	Day 1 to Day 71	Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71.
Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population	Day 1 to Day 71	12-lead electrocardiograms were performed on a supine participant (5 minutes supine) at baseline (baseline = screening; Days -21 to -2) and at Day 71. QT interval and QTc were measured in mille seconds (msec). A change from baseline QT and QTc (corrected for heart rate by Fridericia formula) greater than (\>) 30 msec or less than (\<) 60 msec were presented, as well as values over 450 and 500 msec. QT interval on ECG image defined as: time from the beginning of the QRS (complex consisting of Q, R and S waves) to the end of the T wave.

Trial Locations

Locations (1)

Icon Clinical Pharmacology Unit, Llc; 🇺🇸 Omaha, Nebraska, United States