Rheumatoid Arthritis
Conditions
Brief summary
This open-label, randomized, cross-over study evaluated the effect of tocilizumab (TCZ) on the pharmacokinetics and pharmacodynamics of a common oral contraceptive (OC) in female patients with active rheumatoid arthritis (RA) and in healthy female volunteers of child bearing age. The RA patients received OC in combination with TCZ, whereas the healthy volunteers received OC only. The RA patients received OC in 3 cycles of 21 days each; TCZ 8 mg/kg was administered once as an intravenous infusion on the first day of Cycle 2. The healthy volunteers received OC for only one 21-day cycle.
Interventions
DRUGTocilizumab
Tocilizumab 8 mg/kg was administered in a single 1-hour infusion on Day 1 of Cycle 2.
DRUGOrtho-Novum® 1/35
Each Ortho-Novum® 1/35 tablet contained 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 44 Years
Healthy volunteers
Yes
Inclusion criteria
* Adult patients with child bearing potential, 18-44 years of age. * Rheumatoid arthritis (RA) for over 6 months duration. * On oral contraceptive without interruption for at least 3 months with normal cycle control. * Treatment with disease-modifying anth-rheumatic drugs (DMARD) for at least 12 weeks prior to study start. * Body weight \< 150 kg.
Exclusion criteria
* Functional class IV rheumatoid arthritis (American College of Rheumatology \[ACR\] classification). * History of amenorrhea (unrelated to pregnancy). * History or current inflammatory joint disease other than RA. * Rheumatic autoimmune disease other than RA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Progesterone Level | Day 21 of Cycles 1-3 for Group 1 and Day 21 of Cycle 1 for Group 2 | Blood samples were collected prior to the administration of Ortho-Novum® 1/35 on Day 21 of each cycle. Serum levels of progesterone were quantitatively determined using the ADVIA Centaur and ADVIA Centaur XP systems (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA). The assay was a competitive immunoassay using direct chemiluminescent technology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Serum Concentration (Tmax) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The time to reach maximum serum concentration was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The time to reach the maximum plasma concentration (Tmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule with the software WinNonlin Enterprise version 5.2 (or above). |
| Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The terminal half-life (t½) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The apparent oral clearance (CL/F) was derived from the plasma concentrations using a non-compartmental method and computed as dose/AUC0-24 with the software WinNonlin Enterprise version 5.2 (or above). |
| Maximum Observed Serum Concentration (Cmax) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated enzyme-linked immunosorbent assay (ELISA). The maximum observed plasma concentration (Cmax) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2 | Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The maximum observed plasma concentration (Cmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Terminal Half-life (t½) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The terminal half-life (t½) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Clearance (CL) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. Clearance (CL), computed as dose/AUCinf, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Apparent Volume of Distribution (Vz) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The apparent volume of distribution (Vz), computed as CL/Kel where CL is clearance and Kel is the apparent elimination rate, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). |
| Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. Serum levels of soluble interleukin-6 receptor were analyzed using a validated ELISA. |
| Serum C-reactive Protein (CRP) Level | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose of tocilizumab infusion on Day 1 of Cycle 2 and on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and on Days 1, 7, and 21 of Cycle 3. Serum levels of C-reactive protein were measured by the Tina-quant CRP (latex) high-sensitivity Roche Immunoturbidimetric method. |
| Area Under the Serum Concentration-time Curve From 0 to Infinity (AUCinf) of Tocilizumab | From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1 | Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The area under the serum concentration-time curve from 0 to infinity (AUCinf) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). AUCinf was computed using the linear trapezoidal rule to tlast plus Clast/Kel, where tlast is the time of the last measurable concentration, Clast is the last measurable concentration, and Kel is the apparent elimination rate, computed as the magnitude of the slope from the log-linear regression of the apparent terminal elimination phase of the serum concentration-versus-time curve. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) Patients with rheumatoid arthritis received Ortho-Novum® 1/35 daily on Days 1-21 of 3 consecutive 28-day cycles. On the first day of Cycle 2, patients received tocilizumab 8 mg/kg administered intravenously. | 23 |
| Ortho-Novum® 1/35 (Group 2) Healthy volunteers received Ortho-Novum® 1/35 tablets daily on Days 1-21 of one 28-day cycle. | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Withdrew consent | 1 | 1 |
Baseline characteristics
| Characteristic | Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Ortho-Novum® 1/35 (Group 2) | Total |
|---|---|---|---|
| Age Continuous | 35.8 years STANDARD_DEVIATION 7.66 | 25.7 years STANDARD_DEVIATION 5.04 | 30.7 years STANDARD_DEVIATION 8.22 |
| Sex: Female, Male Female | 23 Participants | 23 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 23 | 4 / 23 |
| serious Total, serious adverse events | 1 / 23 | 0 / 23 |
Outcome results
Primary
Serum Progesterone Level
Blood samples were collected prior to the administration of Ortho-Novum® 1/35 on Day 21 of each cycle. Serum levels of progesterone were quantitatively determined using the ADVIA Centaur and ADVIA Centaur XP systems (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA). The assay was a competitive immunoassay using direct chemiluminescent technology.
Time frame: Day 21 of Cycles 1-3 for Group 1 and Day 21 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading. Blood samples were not available for all patients at all time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Progesterone Level | Cycle 3 (n=18, NA) | 0.19 ng/mL | Standard Deviation 0 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Progesterone Level | Cycle 1 (n=22, 16) | 0.21 ng/mL | Standard Deviation 0.07 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Progesterone Level | Cycle 2 (n=19, NA) | 0.22 ng/mL | Standard Deviation 0.1 |
| Ortho-Novum® 1/35 (Group 2) | Serum Progesterone Level | Cycle 1 (n=22, 16) | 0.57 ng/mL | Standard Deviation 0.39 |
| Ortho-Novum® 1/35 (Group 2) | Serum Progesterone Level | Cycle 2 (n=19, NA) | NA ng/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Serum Progesterone Level | Cycle 3 (n=18, NA) | NA ng/mL | — |
Secondary
Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The apparent oral clearance (CL/F) was derived from the plasma concentrations using a non-compartmental method and computed as dose/AUC0-24 with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 10.40 mL/hr | Standard Deviation 3.59 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | 29.23 mL/hr | Standard Deviation 12.88 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | 9.45 mL/hr | Standard Deviation 3.59 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | 26.86 mL/hr | Standard Deviation 9.38 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | 9.53 mL/hr | Standard Deviation 3.72 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 28.49 mL/hr | Standard Deviation 11.4 |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | NA mL/hr | — |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 28.64 mL/hr | Standard Deviation 11.06 |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | NA mL/hr | — |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 9.05 mL/hr | Standard Deviation 3.71 |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | NA mL/hr | — |
| Ortho-Novum® 1/35 (Group 2) | Apparent Oral Clearance (CL/F) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | NA mL/hr | — |
Secondary
Apparent Volume of Distribution (Vz) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The apparent volume of distribution (Vz), computed as CL/Kel where CL is clearance and Kel is the apparent elimination rate, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Apparent Volume of Distribution (Vz) of Tocilizumab | 3.60 L | Standard Deviation 1.37 |
Secondary
Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | 1409 pg•hr/mL | Standard Deviation 552 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 1387 pg•hr/mL | Standard Deviation 453 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | 120505 pg•hr/mL | Standard Deviation 43285 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | 1455 pg•hr/mL | Standard Deviation 487 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | 121667 pg•hr/mL | Standard Deviation 47828 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 108513 pg•hr/mL | Standard Deviation 39795 |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | NA pg•hr/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 1389 pg•hr/mL | Standard Deviation 502 |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | NA pg•hr/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | NA pg•hr/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 128975 pg•hr/mL | Standard Deviation 53276 |
| Ortho-Novum® 1/35 (Group 2) | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | NA pg•hr/mL | — |
Secondary
Area Under the Serum Concentration-time Curve From 0 to Infinity (AUCinf) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The area under the serum concentration-time curve from 0 to infinity (AUCinf) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above). AUCinf was computed using the linear trapezoidal rule to tlast plus Clast/Kel, where tlast is the time of the last measurable concentration, Clast is the last measurable concentration, and Kel is the apparent elimination rate, computed as the magnitude of the slope from the log-linear regression of the apparent terminal elimination phase of the serum concentration-versus-time curve.
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Area Under the Serum Concentration-time Curve From 0 to Infinity (AUCinf) of Tocilizumab | 35038 µg•hr/mL | Standard Deviation 8324 |
Secondary
Clearance (CL) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. Clearance (CL), computed as dose/AUCinf, was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Clearance (CL) of Tocilizumab | 17.51 mL/hr | Standard Deviation 4.59 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The maximum observed plasma concentration (Cmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading. Blood samples were not available for all patients at all time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol, N=22,21 | 183 pg/mL | Standard Deviation 86.2 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol, N=18,NA | 163 pg/mL | Standard Deviation 71.4 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol, N=18,NA | 177 pg/mL | Standard Deviation 104.2 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone, N=22,21 | 13396 pg/mL | Standard Deviation 4687.9 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone, N=18,NA | 14747 pg/mL | Standard Deviation 4215.8 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone, N=18,NA | 15772 pg/mL | Standard Deviation 4863.4 |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone, N=18,NA | NA pg/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol, N=22,21 | 157 pg/mL | Standard Deviation 53.3 |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone, N=22,21 | 18943 pg/mL | Standard Deviation 5570.6 |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol, N=18,NA | NA pg/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone, N=18,NA | NA pg/mL | — |
| Ortho-Novum® 1/35 (Group 2) | Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol, N=18,NA | NA pg/mL | — |
Secondary
Maximum Observed Serum Concentration (Cmax) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated enzyme-linked immunosorbent assay (ELISA). The maximum observed plasma concentration (Cmax) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Maximum Observed Serum Concentration (Cmax) of Tocilizumab | 204 µg/mL | Standard Deviation 63.4 |
Secondary
Serum C-reactive Protein (CRP) Level
Blood samples were collected pre-dose of tocilizumab infusion on Day 1 of Cycle 2 and on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and on Days 1, 7, and 21 of Cycle 3. Serum levels of C-reactive protein were measured by the Tina-quant CRP (latex) high-sensitivity Roche Immunoturbidimetric method.
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 1 | 16.86 mg/L | Standard Deviation 21.55 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 2 | 12.76 mg/L | Standard Deviation 16.07 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 3 | 7.53 mg/L | Standard Deviation 12.61 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 5 | 4.62 mg/L | Standard Deviation 12.47 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 7 | 3.90 mg/L | Standard Deviation 12.42 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 12 | 3.95 mg/L | Standard Deviation 13.22 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 14 | 3.92 mg/L | Standard Deviation 13.03 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 2, Day 21 | 3.97 mg/L | Standard Deviation 12.95 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 3, Day 1 | 3.74 mg/L | Standard Deviation 11.96 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 3, Day 7 | 8.11 mg/L | Standard Deviation 13.62 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum C-reactive Protein (CRP) Level | Cycle 3, Day 21 | 12.37 mg/L | Standard Deviation 9.42 |
Secondary
Serum Soluble Interleukin-6 Receptor (sIL-6R) Level
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, and 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. Serum levels of soluble interleukin-6 receptor were analyzed using a validated ELISA.
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 2 | 100.6 ng/mL | Standard Deviation 23.7 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 1 | 38.5 ng/mL | Standard Deviation 10.3 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 3 | 162.5 ng/mL | Standard Deviation 52.8 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 5 | 249.1 ng/mL | Standard Deviation 68.2 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 7 | 312.9 ng/mL | Standard Deviation 63.6 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 12 | 425.1 ng/mL | Standard Deviation 78 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 14 | 476.2 ng/mL | Standard Deviation 89.1 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 2, Day 21 | 503.2 ng/mL | Standard Deviation 131.8 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 3, Day 1 | 534.9 ng/mL | Standard Deviation 169.4 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 3, Day 7 | 387.3 ng/mL | Standard Deviation 188 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Serum Soluble Interleukin-6 Receptor (sIL-6R) Level | Cycle 3, Day 21 | 45.7 ng/mL | Standard Deviation 12.4 |
Secondary
Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The terminal half-life (t½) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 14.71 hr | Standard Deviation 9.1 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | 14.70 hr | Standard Deviation 7.47 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | 15.24 hr | Standard Deviation 6.78 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 12.18 hr | Standard Deviation 4.49 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | 13.48 hr | Standard Deviation 3.69 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | 16.14 hr | Standard Deviation 10.97 |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 17.05 hr | Standard Deviation 9.71 |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 11.54 hr | Standard Deviation 4.2 |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Terminal Half-life (t½) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | NA hr | — |
Secondary
Terminal Half-life (t½) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The terminal half-life (t½) was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Terminal Half-life (t½) of Tocilizumab | 145.92 hr | Standard Deviation 57.69 |
Secondary
Time to Reach Maximum Serum Concentration (Tmax) of Tocilizumab
Blood samples were collected pre-dose and at the end of infusion of tocilizumab on Day 1 of Cycle 2. Additional blood samples were collected on Days 2, 3, 5, 7, 12, 14, 21 of Cycle 2, and Days 1, 7, and 21 of Cycle 3. The concentration of tocilizumab was determined in serum samples using a validated ELISA. The time to reach maximum serum concentration was derived from the serum concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: From Day 1 of Cycle 2 to Day 21 of Cycle 3 for Group 1
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach Maximum Serum Concentration (Tmax) of Tocilizumab | 4.41 hr | Standard Deviation 8.39 |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone
Blood samples were collected prior to and at 0.5, 1, 1.5, 2, 3, 5, 8, 12 and 24 hours after administration of Ortho-Novum® 1/35 on Day 7 of each cycle. The concentrations of ethinyl estradiol and norethindrone were determined in human heparinized plasma according to a validated gas chromatography coupled to mass spectrometry (GC-MS) method. The time to reach the maximum plasma concentration (Tmax) was derived from the plasma concentrations using a non-compartmental method with the software WinNonlin Enterprise version 5.2 (or above).
Time frame: Day 7 of Cycles 1-3 for Group 1 and Day 7 of Cycle 1 for Group 2
Population: Pharmacokinetic (PK) and pharmacodynamic (PD) population: All patients enrolled in the study who had at least 1 evaluable PK or PD sample reading.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 1.42 hr | Standard Deviation 0.68 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | 1.58 hr | Standard Deviation 0.73 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | 1.30 hr | Standard Deviation 0.46 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 1.33 hr | Standard Deviation 0.73 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | 1.90 hr | Standard Deviation 2.69 |
| Tocilizumab 8 mg/kg + Ortho-Novum® 1/35 (Group 1) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | 1.82 hr | Standard Deviation 1.59 |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, norethindrone | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, norethindrone | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, ethinyl estradiol | 1.28 hr | Standard Deviation 0.54 |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 2, ethinyl estradiol | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 3, ethinyl estradiol | NA hr | — |
| Ortho-Novum® 1/35 (Group 2) | Time to Reach the Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethindrone | Cycle 1, norethindrone | 1.02 hr | Standard Deviation 0.47 |