Pharmacokinetics study of a single bolus intravenous injection of diclofenac sodium solution administered in male and female healthy volunteers

• Register: ISRCTN
• Last refreshed on: 17 October 2016
• Main ID: ISRCTN20012465
• Date of registration: 15/12/2015
• Prospective Registration: No
• Primary sponsor: IBSA Biochemical Institute (Institut Biochimique) S.A.
• Public title: Pharmacokinetics study of a single bolus intravenous injection of diclofenac sodium solution administered in male and female healthy volunteers
• Scientific title: Pharmacokinetics study of a single bolus intravenous injection of diclofenac sodium solution administered in male and female healthy volunteers: single dose, open-label, four-part pharmacokinetic study.
• Date of first enrolment: 13/04/2015
• Target sample size: 53
• Recruitment status: Completed
• URL: http://isrctn.com/ISRCTN20012465
• Study type: Interventional
• Study design: Single dose open-label randomised cross-over four-part pharmacokinetics study. (Other)
• Phase: Phase I

Countries of recruitment

Switzerland

Contacts

• Name: Milko Radicioni

Key inclusion & exclusion criteria

Inclusion criteria: 1. Informed consent
2. Females and males, 18-55 years old inclusive
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm
5. Females of child-bearing potential using reliable methods of contraception
6. Females of non-child-bearing potential or in post-menopausal status for at least 1 year
7. For all female subjects, pregnancy test result must be negative at screening
Exclusion criteria: 1. ECG 12-leads (supine position): clinically relevant abnormalities
2. Clinically relevant abnormal physical findings
3. Clinically relevant abnormal laboratory values
4. Ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients or other non-steroidal anti-inflammatory drugs (NSAIDs); history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study. History of asthma
5. Relevant history of significant renal, hepatic, gastrointestinal (in particular active or suspected gastrointestinal ulcers or bleeding), genitourinary, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study. History of haemorrhagic diathesis, thalassemia, sickle-cell disease, G6PD deficiency and any other condition that could potentially lead to haemolysis
6. Intake of medications, including over-the-counter (OTC) medications and herbal products for 2 weeks before the start of the study. In particular NSAID or anticoagulant use for 2 weeks before and during the entire study. Hormonal contraceptives for females are allowed
7. Participation in the evaluation of any investigational product in the 3 months before this study
8. Blood donations in the 3 months before this study
9. History of drug, alcohol [> 1 drink/day for females and >2 drinks/day for males, defined according to USDA Dietary Guidelines 2010 (8)], caffeine (>5 cups coffee/tea/day) or tobacco abuse (=10 cigarettes/day)
10. Positive result at the drug test at screening
11. Positive alcohol breath test
12. Abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
13. Positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Exposure (AUC) of diclofenac sodium in healthy adults
Not Applicable

Intervention(s)

Part 0: Each volunteer was assigned to a cohort according to a dose-escalation design (3 subjects to treatment T1, 3 subjects to treatment T2 and 3 subjects to treatment T3) and received one single dose of one of the following test treatments in 1 period per cohort, for a minimum study duration of 11 days, screening visit included:
1. Test treatment T1: Akis, diclofenac sodium 25 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 5 sec
2. Test treatment T2: Akis, diclofenac sodium 50 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 5 sec
3. Test treatment T3: Akis, diclofenac sodium 75 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 5 sec

Part 1: Each volunteer was randomised to receive the following four study treatments in the 4 study periods, according to a computer generated randomisation list, separated by a wash-out interval of at least 7 days, for a minimum study duration of 34 days, screening visit included:
1. Test treatment T3: Akis, diclofenac sodium 75 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 5 sec
2. Test treatment T4: Akis, diclofenac sodium 75 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 15 sec
3. Test treatment T5: Akis, diclofenac sodium 75 mg/1 mL solution for injection in prefilled syringe, IBSA Farmaceutici Italia S.r.l., Italy - injection rate 30 sec
4. Reference formulation R: VOLTAREN, diclofenac sodium 75 mg/3 mL solution for intramuscular injection in ampoules, Novartis Farma S.p.A., Italy

Part 2: Each volunteer was randomised to receive the following four study treatments in the 3 study periods, according to a computer generated randomisation list, separated by a wash-out interval of at least 7 days, for a minimum study duration of 2

Primary Outcome(s)

Part 0 (dose-escalation): to collect safety and tolerability data of T1, T2 and T3; to confirm the safety and tolerability of T3.
Part 1 (rate of administration): to evaluate the PK profile of T3, T4 and T5 and determine the injection rate to be used in study Part 2 and 3 based on PK results and AEs occurrence; to evaluate the PK profile of R.
Part 2 (comparative bioavailability): Primary end-point: to compare the bioavailability of Akis diclofenac sodium 75mg/1 mL administered as a single i.v. bolus injection at the rate selected in Part 1, of the R2 and of the R3, in terms of extent of exposure.
Part 3 (descriptive pharmacokinetics): to further evaluate the PK profile of Akis 75mg/1 mL administered as a single i.v. bolus injection at the rate selected in Part 1.

Part 0:
1. Treatment emergent adverse events (TEAEs);
2. Thrombophlebitis assessment at the i.v. injection site, using a 6-point scale;
3. ECG, vital signs, body weight, laboratory parameters (haematology, biochemistry, immunohaematology).

Part 1:
1. Diclofenamic acid plasma Cmax, Tmax, AUC0-t, AUC0-8, MRT, Vz and t1/2 for T3, T4, T5 and R, C0 only for T3, T4 and T5;
2. Treatment emergent adverse events (TEAEs);
3. Thrombophlebitis assessment at the i.v. injection site, using a 6-point scale;
4. ECG, vital signs, body weight, laboratory parameters (haematology, biochemistry, immunohaematology).

Part 2:
1. Diclofenamic acid plasma AUC0-t and AUC0-8 (if feasible) for T3 or T4 or T5, as selected in Part 1, and for R2 and R3;
2. Treatment emergent adverse events (TEAEs);
3. Thrombophlebitis assessment at the i.v. injection site, using a 6-point scale;
4. ECG, vital signs, body weight, laboratory parameters (haematology, biochemistry, immunohaematology).

Part 3 (if needed):
1. Diclofenamic acid plasma C0, Cmax, Tmax, MRT, Vz and t1/2 for T3 or T4 or T5, as selected in Part 1.

In each period of study parts 1, 2 and 3, venous blood samples (8 mL) were collected at the following times: pre-dose (0), 3, 6, 10, 20, 30, 40, 50 min, 1, 1.25, 1.5, 2, 3, 4, 6 and 8 h post-dose.

Secondary ID(s)

Study CRO-PK-14-290 - Sponsor code 14CH-DCiv11

Source(s) of Monetary Support

IBSA Biochemical Institute SA