A Bioavailability Study of Methotrexate 25 mg Administered by Needle Injection and a Pre Filled Needle-free Device in Healthy Volunteers.

Study Overview
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Brief Summary
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The objective is to determine whether the test product, Methotrexate 40 mg/mL solution for injection administered subcutaneously by the prefilled and needle-free delivery system Zeneo®, and the reference product, Methotrexate Biodim® 25 mg/mL, solution for injection administered subcutaneously by a conventional syringe with needle are bioequivalent.

Detailed Description
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ABSTRACT Objective: Zeneo1 is a needle-free injection device. We performed a pharmacokinetic study to investigate the bioequivalence of methotrexate administered subcutaneously using either the needle-free injection device or a conventional needle and syringe. Research design and methods: This was a single-dose, open-label, laboratory-blind, randomized crossover study performed in adult healthy volunteers. Each participant received two methotrexate injections (each 25mg), one via needle-free injection device and one via conventional injection, with a 21-28 day wash-out interval between dosing. For each participant, the administration site for both injections was either the abdomen or the thigh. Main outcome measures: The primary pharmacokinetic outcome parameters were AUC(0-t) and Cmax. Bioequivalence was assessed by standard criteria: whether 90% confidence intervals of geometric mean ratios for the two administration methods were within 80-125%. Results: Fifty-two individuals completed the study. Bioequivalence criteria were met for AUC(0-t), for the overall analysis (both injection sites: 90% confidence interval: 99.4-103.1%), and for each injection site separately. Bioequivalence was similarly demonstrated with AUC(0-1). Bioequivalence criteria for Cmax were fulfilled for abdominal administration but not for the overall analysis. Injection via the needle- free injection device was well tolerated. Limitations: Limitations include conducting the study in healthy volunteers and the relatively small subject number (albeit satisfactory for bioequivalence). Conclusions: This study shows that methotrexate injection via needle-free injection device is bioequivalent to a conventional needle and syringe in relation to AUC(0-t) and AUC(0-1). Studies of needle-free injection device use in patients requiring methotrexate therapy are planned.

Official Title
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A Single Center Single Dose Open-label Randomized Two Period Crossover Study to Determine the Bioavailability of Two Formulations of Methotrexate 25 mg Administered by Needle Injection and a Pre-filled Needle-free Device in at Least 48 Healthy Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Other: Zeneo® - Methotrexate
* Drug: Methotrexate Biodim®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects BMI between 18.5 and 30 kg/m2 Body mass > 60 kg Non-tobacco user Written consent given for participation in the study Exclusion Criteria: Evidence of clinically relevant oral, cardiovascular, hematologic, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric or skin disorder Heavy alcohol consumption and regular exposure to drug of abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental A<br>Zeneo® - Methotrexate thigh to Methotrexate Biodim® thigh | Other: Zeneo® - Methotrexate<br>* 0.625 mL of methotrexate solution 40 mg/ML for subcutaneous injection with a prefilled and needle-free delivery system<br>Drug: Methotrexate Biodim®<br>* 1 mL of methotrexate solution 25 mg/mL for subcutaneous injection with a conventional needle and syringe injection<br>|
| Experimental: Experimental B<br>Methotrexate Biodim® thigh to Zeneo® - Methotrexate thigh | Other: Zeneo® - Methotrexate<br>* 0.625 mL of methotrexate solution 40 mg/ML for subcutaneous injection with a prefilled and needle-free delivery system<br>Drug: Methotrexate Biodim®<br>* 1 mL of methotrexate solution 25 mg/mL for subcutaneous injection with a conventional needle and syringe injection<br>|
| Experimental: Experimental C<br>Zeneo® - Methotrexate abdomen to Methotrexate Biodim® abdomen | Other: Zeneo® - Methotrexate<br>* 0.625 mL of methotrexate solution 40 mg/ML for subcutaneous injection with a prefilled and needle-free delivery system<br>Drug: Methotrexate Biodim®<br>* 1 mL of methotrexate solution 25 mg/mL for subcutaneous injection with a conventional needle and syringe injection<br>|
| Experimental: Experimental D<br>Methotrexate Biodim® abdomen to Zeneo® - Methotrexate abdomen | Other: Zeneo® - Methotrexate<br>* 0.625 mL of methotrexate solution 40 mg/ML for subcutaneous injection with a prefilled and needle-free delivery system<br>Drug: Methotrexate Biodim®<br>* 1 mL of methotrexate solution 25 mg/mL for subcutaneous injection with a conventional needle and syringe injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax). |  | serial pharmacokinetic plasma concentrations were drawn prior pre-dose and post-dose at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours | 
| Area under the plasma concentration versus time curve (AUC) time zero to time of the last quantifiable concentration (AUC(0-t)). |  | serial pharmacokinetic plasma concentrations were drawn prior pre-dose and post-dose at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 and 24 hours |