Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Following a 1 mg/kg Intravenous Dose in Healthy Adults

Phase 1

Completed

Conditions: Methemoglobinemia
Congenital Methemoglobinemia

Interventions: Drug: Methylene Blue

Registration Number: NCT02478281

Lead Sponsor: American Regent, Inc.

Brief Summary: A Phase 1 trial to assess the single-dose safety, tolerability, and pharmacokinetic (PK) of Methylene Blue Injection, USP 1 mg/kg in healthy adult volunteers.

Detailed Description: This is an open-label, single-center, one-arm, safety, tolerability, and PK study in healthy male and female volunteers of Methylene Blue Injection, USP. Following an overnight fast, twelve healthy adult male and female volunteers will receive a single dose of study drug at a dose of 1 mg/kg solution per kg given intravenously over a period of 5 minutes followed by serial venous blood sampling at 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours postdose.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Healthy adult male or female volunteers, 18-60 years of age, inclusive.
Weigh at least 52 kg for males and 45 kg for females and within the normal range according to accepted normal values of the Body Mass Index (BMI) chart 18.5-29.9 kg/m² inclusive.
Medically healthy with no clinically significant laboratory profiles, vital signs, or ECG's; as deemed by the PI.
For females of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to the first dose and throughout the study or be using acceptable birth control methods. Female subjects who claim to be sexually inactive, but become sexually active during the course of the study must agree to use a barrier method (e.g. condom, diaphragm)with spermicide from the time of the start of sexual activity through at least 30 days following dosing. In addition, female subjects of childbearing potential will be advised to remain sexually inactive or to keep the same birth control method for at least 30 days following dosing.
Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to Day 1:
- Hysteroscopic tubal ligation (with a copy of the confirmation test) and be using a barrier method (condom or diaphragm) and spermicide throughout the study;
- Bilateral tubal ligation and be using a barrier method (condom or diaphragm) and spermicide throughout the study;
- Hysterectomy;
  - Bilateral oophorectomy or be postmenopausal with amenorrhea for at least 1 year prior to Day 1 and follicle stimulating hormone (FSH) serum levels ≥ 40 milli-International Units per mL (mIU/mL). Females on hormone replacement therapy may be deemed eligible for participation in the study even if their FSH levels < 40 mIU/mL, if they are able to provide documentation of FSH levels 40 mIU/mL before initiation of hormone replacement therapy.
Males must use condom with spermicide when engaged in sexual activity and must agree to refrain from sperm donation from check-in through 90 days postdose.
Willing to answer inclusion and exclusion criteria questionnaire at check-in.
Give voluntary written informed consent to participate in the study.
Be able to comply with the protocol and the assessments therein.

Exclusion Criteria

History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease in the opinion of the PI.
History or presence of alcoholism within the past 2 years.
History or presence of drug abuse within the past 2 years.
History or presence of hypersensitivity or idiosyncratic reaction to Methylene Blue.
History or presence of Glucose-6-Phosphate Dehydrogenase (G6PD) dehydrogenase deficiency, retinopathy, blood disorder, myasthenia gravis, psoriasis, epilepsy, clinically significant allergies (except for mild forms of hay fever), or any other clinically significant medical condition, which in the opinion of the PI, might interfere with study participation.
History or laboratory evidence of renal insufficiency.
Any screening laboratory test with clinically significant abnormalities in the opinion of the PI (including cell blood count, creatinine, or liver function tests).
Have used any drug that acts as a serotonin reuptake inhibitor (SRIs) e.g. selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, or ergot alkaloids within 30 days (or 5 half-lives of the compound, whichever is longer) prior to study drug dosing.
Female subjects who are pregnant or lactating, or female subjects who are likely to become pregnant during the study.
Had positive results for the urine drug/alcohol screen at screening or check-in.
Had positive results at screening for HIV, HBsAg, or hepatitis C virus (HCV).
Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
Heart rate is lower than 40 bpm or higher than 99 bpm at screening.
QTc interval is >430 msec (males) or >450 msec (females) or deemed clinically abnormal by the PI or use of any drug or agent suspected of causing QT prolongation or torsade de pointes within 14 days (or 5 half- lives of the compound, whichever is longer) prior to study drug dosing.
Have been on a special diet (for whatever reason) within the 28 days prior to study drug dosing, and throughout the study.
Have made a donation of blood or had significant blood loss within 56 days prior to study drug dosing.
Have made a plasma donation within 7 days prior to study drug dosing.
Have received Methylene Blue within 72 hours prior to study drug dosing.
Have participated in another clinical trial within 30 days (or 5 half-lives of the compound, whichever is longer) prior to study drug dosing.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Methylene Blue Injection, United States Pharmacopeia (USP)	Methylene Blue	Single dose of Methylene Blue Injection, USP at a dose of 1 mg/kg solution per kg given intravenously over a period of approximately 5 minutes.

Primary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) From Time Zero to the Time of Last Quantifiable Concentration (AUC 0-t)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUC 0-t is defined as AUC from time 0 to the last data point
Area Under the Curve From Time Zero Extrapolated to Infinity (AUC 0-∞)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC 0-∞ is defined as area under the concentration vs. time curve from zero to infinity.
The Percent of Extrapolated Area Under the Curve (AUC%Extrap)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	The AUC%extrap refers to the fraction of the total AUC that is due to the extrapolated AUC
Area Under the Curve Ratio (AUCR)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	AUCR refers to the ratio of AUC 0-t to AUC 0-∞.
Total Body Clearance (CL)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	CL refers to the Dose/AUC 0-∞
Maximum Measured Plasma Concentration (Cmax)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time to Maximum Plasma Concentration (Tmax)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	Tmax refers to the time it takes for a drug to reach maximum concentration
Terminal Elimination Half-life (T1/2)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	T1/2 refers to the time taken for concentration of a drug to decrease from its maximum concentration to half of Cmax
Terminal Elimination Rate Constant (Lambda Z)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	Lambda Z refers to the terminal elimination phase for drug plasma concentration vs. time data
Volume of Distribution (Vz) Based on Terminal Phase	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	Vz refers to the ratio of amount of drug in a body (dose) to concentration of the drug that is measured in blood, plasma, and un-bound in interstitial fluid.
Mean Residence Time (MRT)	pre-dose, 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours post-dose	MRT refers to the average amount of time that a drug molecule spends in the body before being removed