Lymphoma, Malignant, Solid Tumor
Conditions
Brief summary
The purpose of this study is to assess the effect of enzastaurin (LY317615), on a protein (enzyme CYP2C9) which is involved in the metabolic pathway of warfarin in participants with solid tumors or lymphomas. Information about any side effects that may occur will also be collected. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study. This is a Phase 1, open label, fixed sequence, 2 period study conducted in participants with solid tumors or lymphomas. The duration of participation in this study will be up to approximately 38 days not including screening, after which participants will be allowed to continue receiving enzastaurin. There is no planned duration for the extension phase of this study; participants will be allowed to continue to receive enzastaurin until fulfilling one of the criteria for discontinuation, such as unacceptable toxicity or disease progression.
Interventions
DRUGwarfarin
Administered orally
DRUGenzastaurin
Administered orally
Sponsors
Eli Lilly and Company
Study design
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Have given written informed consent approved by Eli Lilly and Company (Lilly) and the ethical review board (ERB) governing the site * Have a histologic or cytologic diagnosis of cancer (lymphoma or solid tumor), with clinical or radiologic evidence of locally advanced and/or metastatic disease for which no life-prolonging therapy exists (Note: participants with glioblastoma, known central nervous system (CNS) metastases and other hematologic malignancies \[except lymphoma\] are excluded from this study) * Men or women with reproductive potential must use an approved contraceptive method, if appropriate, during and for 3 months after discontinuation of study treatment. All methods of contraception should meet the criteria of highly effective contraceptives(failure rate of \<1% per year) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence, or vasectomized partner. Women with childbearing potential must have a negative serum pregnancy test ≤3 days prior to the first dosing day in the study (Period 1, Day 1). * Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale and, in the investigator's opinion, are suitable for participation in the study * Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, anticancer hormone therapy, or other investigational therapy for at least 30 days prior to study entry (6 weeks for mitomycin-C or nitrosoureas), and have recovered from the acute effects of therapy * For participants with hormone refractory prostate cancer, the following exception is permitted: * Participants receiving luteinizing hormone-releasing hormone (LHRH) analogue therapy (leuprolide, goserelin, or triptorelin) prior to starting this study should have that therapy continued while on this study. * In addition, participants who have received nonsteroidal antiandrogen therapy in the form of bicalutamide should have discontinued therapy at least 6 weeks prior to study entry (4 weeks if on flutamide or nilutamide). * Have adequate organ function including: * Bone Marrow Reserve: absolute neutrophil count (ANC) ≥1.5 x 10˄9/liter (L) prior to treatment, platelets ≥100 x 10˄9/L, and hemoglobin ≥10 grams/deciliter (g/dL). Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Participants may be allowed erythropoietin of choice as per standard of care. * Hepatic: bilirubin within 1.5 times the upper limit of normal (ULN), and transaminases ≤2.5 times ULN or ≤5 times ULN when liver metastases are known. * Renal: serum creatinine ≤1.5 milligrams/deciliter (mg/dL). * Electrolytes: Participants may be entered into the study, if the investigator's opinion is that any electrolyte disorders, including potassium \<3.4 milliequivalent per liter (mEq/L), calcium \<8.4 mg/dL, or magnesium \<1.2 mEq/L, may be appropriately managed and stabilized by the time of the laboratory evaluation on the baseline day in Period 1. If electrolytes have not been stabilized during this time, the participant will be discontinued from the study. * Coagulation: normal prothrombin time/INR (PT/INR) and activated partial thromboplastin time (aPTT) * Have an estimated life expectancy, in the judgment of the investigator, which will permit the participant to complete the drug interaction phase and at least 1 cycle of the safety extension phase (if the participant were to take part in the safety extension)
Exclusion criteria
* Have received treatment within 28 days of the initial dose of study drug with an experimental agent for non-cancer indications that has not received regulatory approval for any indication * Participants with glioblastoma, Central Nervous System (CNS) metastases, or hematologic malignancies other than lymphoma are excluded from this study. * Serious concomitant systemic disorder, including active infection, incompatible with the study (at the discretion of the investigator) * History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infections * Cardiac: Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV. Participants with a QTcB prolongation \>450/470 millisecond (msec) (males/females) and participants who have a congenital long-QT-syndrome in their own or family medical history should be excluded at the investigator's discretion. Participants with intraventricular conduction delays (for instance, right or left bundle branch blocks) should also be excluded. * It is recommended that participants with baseline arrhythmias (persistent or paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation \[occasional premature atrial contractions \[APCs\] or premature ventricular contractions \[PVCs\] are acceptable\] or bradycardia (heart rate \<50) be excluded, at the investigator's discretion. * Known family history of unexplained sudden death * Personal history of unexplained syncope within the last year * The use of concomitant medications that prolong the QT/QTc interval * Participants with complete gastrectomy or other significant GI diseases that, in the investigator's opinion, may significantly impact drug absorption * Participants on total parenteral nutrition (TPN) * Inability to swallow tablets * Women who are lactating * Participants with known allergies to enzastaurin or warfarin * Participants with warfarin-related skin necrosis * Participants who are known cytochrome P450 (CYP) 2C9 poor or intermediate metabolizers * Drugs that are known inhibitors or inducers of CYP3A are specifically excluded. Foods that are known inhibitors of CYP3A (for example, grapefruit or grapefruit juice or Seville oranges or Seville orange juice) are also specifically excluded during Period 1 and Period 2 of the study. * Drugs with narrow therapeutic windows and that are also known substrates of CYP2C9, CYP2C8, CYP2C19, and CYP3A are excluded. * Use of any known inducers or inhibitors of CYP2C9 within 30 days (or at least 5 half-lives, whichever is shorter) prior to enrollment. Drugs that are inhibitors or inducers of CYP2C9 are also excluded throughout Periods 1 and 2. Drugs that are known to increase the hypoprothrombinemic effect of warfarin are excluded prior to enrollment and throughout Periods 1 and 2. * Use of other anticoagulants or antithrombolytics within 14 days prior to screening or during Periods 1 and 2 * Use of low-dose aspirin (or higher doses) within 14 days prior to screening and during Period 1 and 2 of the study (allowed during continued safety extension phase) * Use of high-dose acetaminophen (paracetamol) within 14 days of Period 1 and during Period 1 and 2 of the study * Participants who have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) or participants unwilling to stop alcohol consumption for the duration of the drug interaction phase (Periods 1 and 2) of the study (1 unit = 12 ounces (oz) or 360 milliliters (mL) of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits). * Use of drugs of abuse, as evidenced by history, and/or positive findings on urinary drug screening, unless prescribed by a physician (for example, narcotic pain medication) * Failure for any reason to satisfy the investigator for adequate fitness to participate in the study * Major surgery or lumbar puncture in the past 6 weeks * Protein C (functional) activity or Protein S antigen concentration below the normal range * Heme-positive stool * Warfarin is contraindicated in the case of congenital galactosemia, malabsorption syndromes of glucose and galactose, or lactase deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin | Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose | Cmax of S-Warfarin and R-Warfarin determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term. |
| Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin | Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose | — |
| Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin | Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose | AUC(0-∞) determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours post dose | Cav,ss of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin. |
| Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Warfarin Alone | Period 1 (8 days): Predose on Day 1, up to 96 hours postdose or Period 2 (19 up to 30 days): Predose on Day 15, up to 96 hours post warfarin dose | INRmax is the maximum INR over the time points after administration of warfarin alone. INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect, and participant as a random effect and a random term error. |
| Pharmacodynamics: Area Under International Normalised Ratio-time Curve AUC(INR) Following Warfarin Alone | Period 1 (8 days): Predose on Day 1, up to 96 hours postdose or Period 2 (19 up to 30 days): Predose on Day 15, up to 96 hours post warfarin dose | AUC(INR) is the area under INR time curve over the time after administration of warfarin alone. INR is the ratio of actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect, and participant as a random effect and a random term error. |
| Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose | Cmax at steady state (Cmax,ss) of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin. |
| Pharmacodynamics: Area Under International Normalised Ratio-Time Curve AUC(INR) Following Concomitant Administration of Warfarin and Enzastaurin | Period 2 Day 15 (19 up to 30 days): Predose, up to 96 hours post warfarin dose | AUC(INR) is the area under INR time curve over the time after administration of warfarin and enzastaurin. INR is the ratio of actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included predose measurement of INR in warfarin alone (Period 1) as a covariate, treatment as a fixed effect, participant as a random effect and a random error term. (See Outcome Measure 9 for statistical analysis comparing reporting groups Warfarin and Warfarin co-administered with Enzastaurin.) |
| Pharmacodynamics: International Normalised Ratio (INR) Following Enzastaurin Alone | Period 2 Day 14 (19 up to 30 days): Predose and 4 hours postdose | INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from timepoint (Period 1 Lead-in Day, 0 and 4 hours at Period 2, Day 14) as fixed effect, participant as a random effect and a random error term. |
| Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Concomitant Administration of Warfarin and Enzastaurin | Period 2 Day 15 (19 up to 30 days): Predose, up to 96 hours post warfarin dose | INRmax is the maximum INR over the time points after administration of warfarin and enzastaurin. INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included predose measurement of INR in warfarin alone (Period 1) as a covariate, treatment as a fixed effect, participant as a random effect and a random error term. (See Outcome Measure 8 for statistical analysis comparing reporting groups Warfarin and Warfarin co-administered with Enzastaurin) |
| Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose | Tmax at steady state (tmax,ss) of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin. |
| Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose | AUCss of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Warfarin + Enzastaurin Period 1 Day 1 (of an 8-day period): 5 milligram (mg) warfarin administered as a single oral dose. Period included at least a 7-day washout.
Period 2 (19 up to 30 days): 500 mg enzastaurin administered orally once daily for at least 19 consecutive days and 5 mg warfarin administered as a single oral dose on Day 15.
Safety Extension Period: Participants were allowed to continue receiving 500 mg enzastaurin orally once daily alone until disease progression or other discontinuation criteria were met.
Participants were on study for up to a total of 8 months (Period 1, Period 2 and Safety Extension Period). | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1 | Progressive Disease | 1 |
| Period 2 | Progressive Disease | 2 |
| Period 2 | Sponsor Decision | 1 |
| Safety Extension | Progressive Disease | 7 |
Baseline characteristics
| Characteristic | Warfarin + Enzastaurin |
|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 10.3 |
| Race/Ethnicity, Customized White | 13 Participants |
| Region of Enrollment France | 13 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 13 | 8 / 12 | 7 / 10 | 5 / 7 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 10 | 0 / 7 |
Outcome results
Primary
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin
AUC(0-∞) determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term.
Time frame: Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment and had S-warfarin and R-warfarin AUC(0-∞) values.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Warfarin | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin | S-Warfarin | 8422 nanograms*hours/milliliter (ng*h/mL) |
| Warfarin | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin | R-Warfarin | 19122 nanograms*hours/milliliter (ng*h/mL) |
| Warfarin + Enzastaurin | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin | S-Warfarin | 10754 nanograms*hours/milliliter (ng*h/mL) |
| Warfarin + Enzastaurin | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin | R-Warfarin | 24058 nanograms*hours/milliliter (ng*h/mL) |
90% CI: [1.14, 1.44]
90% CI: [1.08, 1.47]
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin
Cmax of S-Warfarin and R-Warfarin determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term.
Time frame: Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Warfarin | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin | S-Warfarin | 245 nanograms/milliliter (ng/mL) |
| Warfarin | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin | R-Warfarin | 253 nanograms/milliliter (ng/mL) |
| Warfarin + Enzastaurin | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin | R-Warfarin | 230 nanograms/milliliter (ng/mL) |
| Warfarin + Enzastaurin | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin | S-Warfarin | 198 nanograms/milliliter (ng/mL) |
90% CI: [0.691, 0.95]
90% CI: [0.815, 1.02]
Primary
Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin
Time frame: Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment and had S-warfarin and R-warfarin tmax values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Warfarin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin | S-Warfarin | 2.04 hours |
| Warfarin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin | R-Warfarin | 3.00 hours |
| Warfarin + Enzastaurin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin | S-Warfarin | 4.50 hours |
| Warfarin + Enzastaurin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin | R-Warfarin | 7.00 hours |
90% CI: [0.76, 3.5]
90% CI: [-1, 6.84]
Secondary
Pharmacodynamics: Area Under International Normalised Ratio-Time Curve AUC(INR) Following Concomitant Administration of Warfarin and Enzastaurin
AUC(INR) is the area under INR time curve over the time after administration of warfarin and enzastaurin. INR is the ratio of actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included predose measurement of INR in warfarin alone (Period 1) as a covariate, treatment as a fixed effect, participant as a random effect and a random error term. (See Outcome Measure 9 for statistical analysis comparing reporting groups Warfarin and Warfarin co-administered with Enzastaurin.)
Time frame: Period 2 Day 15 (19 up to 30 days): Predose, up to 96 hours post warfarin dose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment and at least 1 evaluable AUC(INR) concomitant warfarin and enzastaurin value.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Warfarin | Pharmacodynamics: Area Under International Normalised Ratio-Time Curve AUC(INR) Following Concomitant Administration of Warfarin and Enzastaurin | 95.45 ratio |
Secondary
Pharmacodynamics: Area Under International Normalised Ratio-time Curve AUC(INR) Following Warfarin Alone
AUC(INR) is the area under INR time curve over the time after administration of warfarin alone. INR is the ratio of actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect, and participant as a random effect and a random term error.
Time frame: Period 1 (8 days): Predose on Day 1, up to 96 hours postdose or Period 2 (19 up to 30 days): Predose on Day 15, up to 96 hours post warfarin dose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment and at least 1 evaluable warfarin or warfarin plus enzastaurin AUC(INR) value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Warfarin | Pharmacodynamics: Area Under International Normalised Ratio-time Curve AUC(INR) Following Warfarin Alone | 97.24 ratio |
| Warfarin + Enzastaurin | Pharmacodynamics: Area Under International Normalised Ratio-time Curve AUC(INR) Following Warfarin Alone | 95.45 ratio |
90% CI: [0.95, 1.02]
Secondary
Pharmacodynamics: International Normalised Ratio (INR) Following Enzastaurin Alone
INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from timepoint (Period 1 Lead-in Day, 0 and 4 hours at Period 2, Day 14) as fixed effect, participant as a random effect and a random error term.
Time frame: Period 2 Day 14 (19 up to 30 days): Predose and 4 hours postdose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment and at least 1 evaluable INR enzastaurin result.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Warfarin | Pharmacodynamics: International Normalised Ratio (INR) Following Enzastaurin Alone | Period 2, Day 14, 0 Hours | 0.97 ratio |
| Warfarin | Pharmacodynamics: International Normalised Ratio (INR) Following Enzastaurin Alone | Period 2, Day 14, 4 Hours | 0.96 ratio |
90% CI: [0.99, 1.08]
90% CI: [0.98, 1.06]
Secondary
Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Concomitant Administration of Warfarin and Enzastaurin
INRmax is the maximum INR over the time points after administration of warfarin and enzastaurin. INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included predose measurement of INR in warfarin alone (Period 1) as a covariate, treatment as a fixed effect, participant as a random effect and a random error term. (See Outcome Measure 8 for statistical analysis comparing reporting groups Warfarin and Warfarin co-administered with Enzastaurin)
Time frame: Period 2 Day 15 (19 up to 30 days): Predose, up to 96 hours post warfarin dose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment and had at least 1 evaluable INRmax warfarin and enzastaurin value.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Warfarin | Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Concomitant Administration of Warfarin and Enzastaurin | 1.09 ratio |
Secondary
Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Warfarin Alone
INRmax is the maximum INR over the time points after administration of warfarin alone. INR is the ratio of the actual prothrombin time over normal prothrombin time. Geometric Least Squares (LS) mean model was used that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect, and participant as a random effect and a random term error.
Time frame: Period 1 (8 days): Predose on Day 1, up to 96 hours postdose or Period 2 (19 up to 30 days): Predose on Day 15, up to 96 hours post warfarin dose
Population: All enrolled participants who were assigned to a treatment, received at least 1 dose of study treatment and had at least 1 evaluable INRmax warfarin or warfarin/enzastaurin value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Warfarin | Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Warfarin Alone | 1.18 ratio |
| Warfarin + Enzastaurin | Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Warfarin Alone | 1.09 ratio |
90% CI: [0.86, 1]
Secondary
Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte
AUCss of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin.
Time frame: Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment who had enzastaurin, LSN326020 and total analyte AUC,ss values .
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 35200 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 124 |
| Warfarin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 16300 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 64 |
| Warfarin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 64800 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 103 |
| Warfarin + Enzastaurin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 44100 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 115 |
| Warfarin + Enzastaurin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 19000 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 53.2 |
| Warfarin + Enzastaurin | Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 80500 nanomoles*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 94.1 |
Secondary
Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte
Cav,ss of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin.
Time frame: Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours post dose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment who had enzastaurin, LSN326020 and total analyte Cav,ss values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 1470 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 124 |
| Warfarin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 680 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 64 |
| Warfarin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 2700 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 103 |
| Warfarin + Enzastaurin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 1840 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 115 |
| Warfarin + Enzastaurin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 790 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 53.2 |
| Warfarin + Enzastaurin | Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 3350 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 94.1 |
Secondary
Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte
Cmax at steady state (Cmax,ss) of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin.
Time frame: Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment and had Cmax,ss values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Warfarin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 2170 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 93.3 |
| Warfarin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Metabolite LSN326020 | 769 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 56.5 |
| Warfarin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 3600 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 82.1 |
| Warfarin + Enzastaurin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 2730 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 85.3 |
| Warfarin + Enzastaurin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Metabolite LSN326020 | 872 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 51.8 |
| Warfarin + Enzastaurin | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 4410 nanomoles/liter (nmol/L) | Geometric Coefficient of Variation 74.3 |
Secondary
Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte
Tmax at steady state (tmax,ss) of enzastaurin, the principle metabolite (LSN326020), and the total analytes (enzastaurin, LSN326020, LSN485912 and LSN2406799) when enzastaurin is administered alone and with warfarin.
Time frame: Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose
Population: All enrolled participants who were assigned to a treatment and received at least 1 dose of study treatment who had enzastaurin, LSN326020 and total analyte tmax,ss values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Warfarin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 4.00 hours |
| Warfarin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 6.10 hours |
| Warfarin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 4.04 hours |
| Warfarin + Enzastaurin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | Enzastaurin | 4.00 hours |
| Warfarin + Enzastaurin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | LSN326020 | 8.01 hours |
| Warfarin + Enzastaurin | Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte | Total Analytes | 4.02 hours |