A Study to Evaluate the Pharmacokinetics of ASP1707 and Methotrexate in Patients With Rheumatoid Arthritis

A Phase 1 Open-label, Single-sequence, Drug Interaction Study to Evaluate the Pharmacokinetics of ASP1707 and Methotrexate in Patients With Rheumatoid Arthritis

The primary purpose of the study is to evaluate the effect of ASP1707 twice daily on the pharmacokinetics of once weekly oral methotrexate (MTX).

This study will also evaluate the effect of MTX on multiple-dose pharmacokinetics of ASP1707, as well as safety and tolerability of coadministration of ASP1707 and MTX in patients with rheumatoid arthritis (RA).

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: ASP1707; Drug: methotrexate (MTX)

Detailed Description

Patients will check into the clinic on Day -1 and remain in the clinic until all exit procedures have been performed on the morning of Day 10.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2025
    • Site MD37301

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female patient must either:

  • Be of nonchildbearing potential: postmenopausal (defined as at least 2 years after last regular menstrual cycle) prior to screening and follicle-stimulating hormone (FSH) ≥ 30 IU/mL, or
  • documented surgically sterile

• Or, if of childbearing potential,

  • Agree not to try to become pregnant during the study and for 28 days or 5 half-lives, whichever is longer, after the final study drug administration;
  • and have a negative urine pregnancy test at screening;
  • and, if heterosexually active, agree to consistently use 2 forms of highly effective birth control (at least one of which must be a barrier method) starting at screening and throughout the study period and for 28 days or 5 half-lives, whichever is longer, after the final study drug administration.
• Male patient and his female spouse/partner who is of childbearing potential must be using highly effective forms of contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the study period and for 60 days after the final study drug administration.
• Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 28 days or 5 half-lives, whichever is longer, after the final study drug administration.
• Female patient must not donate ova starting at screening and throughout the study period, and for 28 days or 5 half-lives, whichever is longer, after the final study drug administration.
• Male patient must not donate sperm starting at screening and throughout the study period, and for 60 days after the final study drug administration.
• Patient agrees not to participate in another interventional study while on treatment.
• Patient has a body mass index (BMI) of ≤ 35 kg/m2, inclusive, and must weigh at least 50 kg at screening.
• Patient must have a clinical diagnosis of RA according to the 2010 criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) at least 6 months prior to screening.
• Patient meets the ACR 1991 revised criteria for RA Global Functional Status I or II.
• Patient must be on concomitant MTX at a stable 10 to 25 mg/week dose for ≥ 28 days prior to day 1 and throughout the study.

• Patient on other medications (excluding MTX) for the treatment or RA at the time of screening must be able to discontinue these medications 28 days or 5 half-lives (whichever is longer) before first study drug dose:

  o Hydroxychloroquine, cyclosporine, leflunomide and sulfasalazine

• Patient use of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, folic acid, low dose opioids, hormone replacement therapy (HRT), corticosteroids (prednisone equivalent of ≤ 5 mg/day) for treatment of RA may be allowed in the study. These medications must be stable for ≥ 28 days prior to screening and patients should remain on their regimen throughout the study. Occasional acetaminophen use (less than 2 g/day) may be allowed.
• Patient use of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) used to treat RA may be allowed in this study. These medications must be stable for 4 weeks prior to the study and remain stable during the study. Prior approval for its use must be obtained from the sponsor.

Exclusion Criteria:

• Patient has a previous history of clinically significant systemic disease which might confound the results of the study or pose an additional risk in administering study drug(s) to the patient. This may include, but not be limited to, a history of drug or food allergies, uncompensated heart failure, uncontrolled diabetes mellitus, severe hepatic failure, severe pulmonary disease, or history of mental disease.
• Patient has a history of any malignancy in the past 5 years, except for adequately-treated nonmelanoma skin cancer and adequately-treated-in-situ cervical cancer.
• Patient has a positive serology test for hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) 1+2 antibodies.
• Patient received any breast cancer resistance protein (BCRP) transporter inhibitors or substrates, with the exception of MTX, within 28 days or 5 half-lives, whichever is longer, prior to day 1.
• Patient with liver enzyme test abnormalities, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin > 2 times the upper limit of normal (ULN).
• Patient has a recent history (within the last 6 months) of drug or alcohol abuse (as defined by the Investigator) or a positive urine screen for alcohol or drugs of abuse/illegal drugs at screening or check-in.
• Patient has participated in a previous clinical study with treatment with ASP1707.
• Patient has received any investigational agent within 28 days or 5 half-lives, whichever is longer, prior to day 1.
• Patient has had any significant blood loss, donated 1 unit (450 mL) of blood, or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to day 1.
• Patient is an employee of the Astellas group or vendors involved with the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASP1707 and methotrexate (MTX); On day 1 patients will receive prescribed dose of MTX. On Days 3 through 8, patients will receive ASP1707 (twice daily). On Day 9, patients will receive a single dose in the morning. A single dose of MTX will be coadministered on Day 8.	Drug: ASP1707; Oral; Drug: methotrexate (MTX); Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of methotrexate (MTX) in plasma: AUCinf	Area under the concentration-time curve from the time of dosing extrapolated to time infinity (AUCinf)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in plasma: Cmax	Maximum concentration (Cmax)	Up to Day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of methotrexate (MTX) in plasma: AUClast	Area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in plasma: tmax	Time after dosing when Cmax occurs (tmax)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in plasma: t 1/2	Apparent terminal elimination half-life (t 1/2)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in plasma: CL/F	Apparent total systemic clearance after single or multiple extra-vascular dosing (CL/F)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in plasma: Vz/F	Apparent volume of distribution during the terminal elimination phase (Vz/F)	Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in plasma: AUClast		Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in plasma: tmax		Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in plasma: t 1/2		Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in plasma: MPR	Metabolite to parent ratio of AUC using AUC(corr) for the metabolite (corrected by molecular weight ratio of parent to metabolite) (MPR)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in urine: Aelast	Cumulative amount of analyte excreted into the urine up to the collection time of the last measurable concentration (Aelast)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in urine: Aelast%	Percent of drug dose excreted into urine, feces or bile (Aelast) from time of dosing up to the collection time of the last measurable concentration (Aelast%)	Up to Day 8
Pharmacokinetics of methotrexate (MTX) in urine: CLR	Renal clearance (CLR)	Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in urine: Aelast		Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in urine: Aelast%		Up to Day 8
Pharmacokinetics of 7-hydroxymethotrexate (7-OH-MTX) in urine: CLR		Up to Day 8
Pharmacokinetics of ASP1707 in plasma: AUCtau	Area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau)	Up to Day 8
Pharmacokinetics of ASP1707 in plasma: Cmax		Up to Day 8
Pharmacokinetics of ASP1707 in plasma: tmax		Up to Day 8
Pharmacokinetics of ASP1707 in plasma: CL/F		Up to Day 8
Pharmacokinetics of ASP1707 in plasma: Ctrough	Concentration immediately prior to dosing at multiple dosing (Ctrough)	Up to Day 9
Pharmacokinetics of ASP1707 in plasma: MPR		Up to Day 8
Pharmacokinetics of AS1948006 in plasma: AUCtau		Up to Day 8
Pharmacokinetics of AS1948006 in plasma: Cmax		Up to Day 8
Pharmacokinetics of AS1948006 in plasma: tmax		Up to Day 8
Pharmacokinetics of AS1948006 in plasma: Ctrough		Up to Day 8
Pharmacokinetics of AS1948006 in plasma: MPR		Up to Day 8
Safety as assessed by Adverse Events (AEs)		Up to Day 13
Safety assessed by Laboratory Test: hematology		Up to Day 13
Safety assessed by Laboratory Test: biochemistry		Up to Day 13
Safety assessed by Laboratory Test: serology		Up to Day 13
Safety assessed by Laboratory Test: urinalysis		Up to Day 13
Safety assessed by 12- lead electrocardiogram (ECG)	All ECGs should be recorded using the clinic's calibrated equipment. This overall conclusion will be recorded as normal, abnormal not clinically significant, or abnormal clinically significant.	Up to Day 10
Number of participants with Physical Examination abnormalities and/or adverse events		Up to Day 10

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Senior Medical Director, Astellas Pharma Global Development, Inc. (APGD)

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2016
• Primary Completion (Actual): August 30, 2016
• Study Completion (Actual): August 30, 2016

Study Registration Dates

• First Submitted: August 11, 2016
• First Submitted That Met QC Criteria: August 11, 2016
• First Posted (Estimated): August 15, 2016

Study Record Updates

• Last Update Posted (Actual): October 23, 2024
• Last Update Submitted That Met QC Criteria: October 21, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Rheumatoid Arthritis (RA); methotrexate (MTX); ASP1707
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arthritis; Arthritis, Rheumatoid; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Methotrexate
• Other Study ID Numbers: 1707-CL-3002; 2016-001192-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.