Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Lipid Regulating Agents

All Drugs and Chemicals

Bone Density Conservation Agents

Rosuvastatin Calcium

Calcium

Calcium, Dietary

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Enzyme Inhibitors

All subjects will receive a single dose BAY1841788 (ODM-201) (600 mg) followed by multiple doses BAY1841788 (ODM-201) (600 mg BID) as well as 2 times a single dose rosuvastatin (5 mg), once alone and once in combination with BAY1841788 (ODM-201).

5 mg tablet single dose on Day 01 in Period 1 and on Day 08 in Period 2.

Rosuvastatin

600 mg single dose, administered as 2 x 300 mg tablets on Day 01 in Period 2; 600 mg BID multiple dose, administered as 2 x 300 mg tablets on Day 04 to Day 08 in Period 2.

BAY1841788 (ODM-201)

Bayer Study Director

Evaluation of the potential perpetrator effect of BAY1841788 (ODM-201) on rosuvastatin pharmacokinetics.

PK of BAY1841788 (ODM-201) after single and repeated administration in male and female subjects.

Drug-drug Interaction Study Using Rosuvastatin as a Breast Cancer Resistant Protein (Efflux Transporter), Organic Anion-transporting Polypeptide (OATP)1B1, and OATP1B3 (Uptake Transporters) Probe Substrate

A Phase 1, Open Label, Fixed-sequence Study to Evaluate the Effect of BAY1841788 (ODM-201) on Drug Transporters Using Rosuvastatin as Probe Substrate and to Assess Pharmacokinetics and Safety of BAY1841788 in Female and Male Volunteers

Bayer

Gastrointestinal Agents

Anti-Infective Agents

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Amino Acids

Esomeprazole

Endothelial Growth Factors

Mitogens

Tyrosine Kinase Inhibitors

Ketoconazole

Adenosine

Tyrosine

Administration of oral pazopanib 400mg (2 200-mg tablets) once-daily each morning for at least 7 consecutive doses during Period 1. Then administration of oral ketoconazole 400 mg (2 - 200 mg tablets) followed immediately by pazopanib 400 mg (2 -200 mg tablets) once-daily each morning for a total of 5 consecutive doses during Period 2.

Subjects will receive orally administered pazopanib 800mg (4 - 200mg tablets) once-daily each morning for at least 7 consecutive doses in Period 1. In the evening on the last day of Period 1, subjects will take their initial dose of esomeprazole 40 mg (1 - 40 mg capsule) approximately 3 hours after the evening meal. Subjects will continue to receive pazopanib (each morning) and esomeprazole each evening once-daily for a total of 5 consecutive doses.

Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet derivative growth factor receptor (PDGFR)

pazopanib

GSK Clinical Trials

The purpose of this study is to determine how dosing with ketoconazole (Nizoral) or esomeprazole (Nexium) affects the pharmacokinetics of oral pazopanib. The study will also test for safety of pazopanib when administered with ketoconazole or esomeprazole.

The study is a 2-arm, open-label, repeat-dose, single sequence, crossover, study designed to evaluate the effects of ketoconazole (Arm A) and esomeprazole (Arm B) on the pharmacokinetics (PK) of oral pazopanib in subjects with solid tumor malignancies. This study will compare the PK parameters of oral pazopanib and its metabolite concentrations when given alone and when co-administered with either ketoconazole (Arm A) or esomeprazole (Arm B). Safety assessments (physical examinations, vital signs, 12-lead electrocardiograms, Eastern Cooperative Oncology Group performance status, clinical laboratory assessments, and monitoring of adverse events) will also be evaluated during the study.

VEG113971: An Open-Label Study of the Effects of Ketoconazole or Esomeprazole on Pazopanib PK

An Open-Label Study to Evaluate the Effects of Ketoconazole and the Effects of Esomeprazole on the Pharmacokinetics of Orally Administered Repeat Doses of Pazopanib in Subjects With Solid Tumor Malignancies

Blood samples for pharmacokinetic (PK) analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours.

Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma.

Blood samples for PK analysis of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Nominal data collection time points (TPs) were defined in the protocol; however, the actual data collection TP often differed slightly from the nominal TP for various reasons. This leads to medians and ranges that don't coincide with planned nominal data collection TPs.

Pazopanib plasma concentration-time data were analyzed by non-compartmental methods with WinNonlin. Calculations were based on the actual sampling times. From the plasma concentration-time data, the PK parameter C24 was determined.

Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter AUC(0-24) was determined by standard non-compartmental analysis using WinNonlin. Plasma AUC(0-24) is a measure of the amount of drug a participant has been exposed to in 24 hours.

Blood samples for PK analysis of the metabolites of pazopanib were obtained at pre-dose (within 60 minutes prior to pazopanib administration) and at 1, 2, 3, 4, 6, 8, and 24 hours after pazopanib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. The concentration-time curve is the result of time points of blood sampling and its measured concentration of pazopanib in the plasma.

Blood samples for the determination of plasma ketoconazole concentrations were collected before (pre-dose \[within 60 minutes prior to pazopanib administration\]) and after the final pazopanib and ketoconazole dose (fifth dose) during Period 2 at the indicated time points, relative to pazopanib administration (at 1 and 2 hours after pazopanib administration). Blood samples were obtained via peripheral intravenous cannula or central line. Concentrations of ketoconazole were determined in plasma samples using the currently approved analytical methodology.

AEs were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grades range from 0 (no toxicity) to 4 (life-threatening or disabling). A Grade 3 AE is severe; defined as considerable interference with the participant's daily activities, medical intervention/therapy required, and hospitalization possible. A Grade 4 AE is life-threatening; defined as extreme limitation in activity, significant medical intervention/therapy required, and hospitalization probable.

The following were considered DLTs only while participants were receiving pazopanib co-administered with either ketoconazole or esomeprazole: Grade 4 hematologic toxicities, excluding lymphopenia; and Grade 3/4 non-hematologic toxicities, excluding alopecia and nausea/vomiting/diarrhea for which adequate supportive therapy had not been instituted. Toxicities observed once co-administration of pazopanib with ketoconazole or esomeprazole was complete (after Day 5 of Period 2) could also be considered DLTs if judged to be relevant by the investigator and the GlaxoSmithKline Medical Monitor.

GlaxoSmithKline

Pazopanib 400 milligrams (mg) (2x200 mg tablets) once daily (QD), for at least 7 consecutive days in the morning during Period 1

Pazopanib 400 mg QD

Ketoconazole 400 mg (2x200 mg tablets) QD in combination with pazopanib 400 mg (2x200 mg tablets) QD for 5 consecutive days in the morning during Period 2

Pazopanib 400 mg QD + Ketoconazole 400 mg QD

Pazopanib 800 mg (4x200 mg tablets) QD, for at least 7 consecutive days in the morning during Period 1

Pazopanib 800 mg QD

Pazopanib 800 mg (4x200 mg tablets) QD in the morning in combination with esomeprazole 40 mg (1x40 mg capsule) QD in the evening (administered 1 hour after the evening meal) for 5 consecutive days during Period 2

Pazopanib 800 mg QD + Esomeprazole 40 mg QD

Pazopanib 400 milligrams (mg) (2x200 mg tablets) once daily (QD), for at least 7 consecutive days in the morning during Period 1, followed by ketoconazole 400 mg (2x200 mg tablets) QD in combination with pazopanib 400 mg (2x200 mg tablets) QD for 5 consecutive days in the morning during Period 2

Pazopanib, Followed by Pazopanib + Ketoconazole

Pazopanib 800 mg (4x200 mg tablets) QD, for at least 7 consecutive days in the morning during Period 1, followed by pazopanib 800 mg (4x200 mg tablets) QD in the morning in combination with esomeprazole 40 mg (1x40 mg capsule) QD in the evening (approximately 3 hours after the evening meal) for 5 consecutive days during Period 2

Pazopanib, Followed by Pazopanib + Esomeprazole

Total

Years

Age Continuous

Sex: Female, Male

African American/African Heritage

Asian - Central/South Asian Heritage

Asian - South East Asian Heritage

White - White/Caucasian/European Heritage

Native Hawaiian or Other Pacific Islander

Race/Ethnicity, Customized

GSK Response Center

Pharmacokinetic (PK) Population: all participants who underwent plasma PK sampling and had evaluable PK assay results from at least one analyte

Plasma Pazopanib Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC[0-24]) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole

Plasma Maximum Observed Concentration (Cmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole

Time of Occurrence of Cmax (Tmax) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole

Plasma Concentration at 24 Hours After Administration (C24) of Pazopanib Alone and of Pazopanib in Combination With Ketoconazole and Esomeprazole

GSK1268992, n=21, 16, 12, 12

GSK1268997, n=20, 13, 12, 12

GSK1071306, n=21, 15, 12, 12

PK Population. One participant from the Pazopanib + Ketoconazole treatment arm was not analyzed for GSK1071306 due to mishandling of PK samples during shipping. Only those participants providing samples were analyzed.

Plasma AUC(0-24) for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole

GSK1268992

GSK1268997

GSK1071306

Plasma Cmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole

Tmax for the Indicated Metabolites of Pazopanib When Administered Alone or in Combination With Ketoconazole and Ezomeprazole

Pre-dose

1 hr

2 hr

Plasma Ketoconazole Concentration at the Indicated Time Points

Hypertension

Hypokalemia

Hypophosphatemia

Lymphopenia

All Treated Population: all participants who were enrolled into the study and received at least one dose of study drug

Number of Participants With the Indicated Grade 3 or 4 Adverse Events (AEs)

All Treated Population. Per protocol, a DLT could not occur during single-agent pazopanib administration in Period 1; thus, data were only collected and analyzed for those participants receiving pazopanib co-administered with either ketoconazole or esomeprazole in Period 2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Drug-drug Interaction Study Using Rosuvastatin as a Breast Cancer Resistant Protein (Efflux Transporter), Organic Anion-transporting Polypeptide (OATP)1B1, and OATP1B3 (Uptake Transporters) Probe Substrate	NCT02671097	Healthy Volunte... Pharmacokinetic... Drug Interactio...	Rosuvastatin BAY1841788 (ODM...	45 Years - 65 Years	Bayer
VEG113971: An Open-Label Study of the Effects of Ketoconazole or Esomeprazole on Pazopanib PK	NCT01205230	Cancer	pazopanib	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for drug interaction