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Bioequivalence and Pharmacokinetic Study of Prurisol™ and Abacavir Sulfate in Healthy Volunteers

Primary Purpose

Psoriasis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Prurisol

Ziagen

About this trial

This is an interventional other trial for Psoriasis focused on measuring bioequivalence, pharmacokinetics, psoriasis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Individuals who meet ALL of the following criteria are eligible for participation in this study:

Provided written informed consent
Male or female adult aged 18-65 years old (inclusive). At least 20% of enrolled subjects will be aged 55-65 years, inclusive. Effort will be made to enroll equivalent numbers of males and females
BMI of 19-32 kg/m2
Identified as a non-smoker at the Consent/Screening Visit. A urine cotinine test will be performed at screening and during each clinic check-in before for each of the three Treatment Visits
Willing and able to comply with all aspects of the study protocol including avoiding use of certain concomitant medications and attending the required clinic visits

Exclusion Criteria:

Subjects are not eligible for participation in the study if any of the following criteria are met:

Females of childbearing potential not using reliable contraception, (e.g., abstinence, double barrier method, oral/implantable/transdermal contraception. Depo-provera, intrauterine device)
Female who is pregnant, lactating, has a positive serum pregnancy test drawn at the Consent/Screening Visit, or has a positive urine pregnancy test at check-in performed prior to any of the 3 Treatment Days
Presence of any uncontrolled (in the Investigator's medical opinion) systemic disease, including, but not limited to renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease
History of any immune disorder, or disease/condition potentially affecting the immune system
Regular use of oral or parenteral corticosteroids (inhaled corticosteroids for stable asthma or chronic obstructive pulmonary disease are permitted)
ECG obtained at Consent/Screening Visit which shows medically significant abnormalities (e.g. bundle branch block, frequent premature ventricular contractions, corrected QT interval (QTc) prolongation >450 msec for males and >470 msec for females)
Presence of a condition that makes it unlikely that the requirements of the protocol will be completed
Urine screening test(s) positive for evidence of amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamine, opiates, phencyclidine, marijuana
Positive urine cotinine test
Positive breath alcohol test
History of hypersensitivity to any formulation of abacavir
Previous treatment with any abacavir-containing product
Current participation or participation in a drug/device or biologic investigational research study within 30 days prior to the Treatment A Visit
An elective surgical or medical procedure is planned or scheduled to be performed during the period of the study
Past surgical history of any degree of gastric resection or gastric banding
History of a clinically diagnosed upper respiratory tract infection or any acute illness requiring antibiotic therapy within 14 days prior to the Treatment A Visit
Systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg or heart rate <45 bpm in a subject under the age of 40 years and heart rate <50 bpm in a subject aged ≥40 years or >100 bpm (any subject age) on repeat determinations at the Consent/Screening Visit or at check-in on the day prior to each of the 3 Treatment Days and at pre-dose if drug administered on different day than check-in
Clinical laboratory results at the Consent/Screening Visit that show any one or more of the following:
- Hemoglobin <11 Gm/dL, Hematocrit<30%
- Total white blood cell count <3000cells/mm3
- Absolute neutrophil count <1500cells/mm3
- Platelet count <100,000/mm3
- alanine aminotransferase or aspartate aminotransferase >1.5 x Upper Limit of Normal (ULN)
- Serum amylase above ULN
- Serum creatinine >1.5 x ULN
- Positive serum human chorionic gonadotropin
- Positive serologic test for HBsAg, HIV, hepatitis C virus
- Positive test for HLA-B*5701 allele by certified laboratory
- Urinalysis showing medically significant abnormality

Sites / Locations

Phase One Solutions Inc.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Arm Label

Pharmacokinetics of low dose Prurisol

Pharmacokinetics medium dose Prurisol

Pharmacokinetics of high dose Prurisol

Bioequivalence of Prurisol (350 mg)

Bioequivalence of Ziagen (300 mg)

Arm Description

Pharmacokinetics of single dose of Prurisol™ 50 mg (1 tablets) to 6 subjects

Pharmacokinetics of single dose of Prurisol™ 100 mg (2 tablets) to 6 subjects

Pharmacokinetics of single dose of Prurisol™ 200 mg (4 tablets) to 6 subjects

Single dose of Prurisol™ 350 mg (7 x 50 mg tablets)

Single dose of Ziagen 300 mg (1 x 300mg tablet)

Outcomes

Primary Outcome Measures

Area under the plasma concentration versus time curve (AUC) of abacavir derived from Prurisol and Ziagen

Part B of the study will determine the average bioequivalence of abacavir derived from Prurisol (abacavir acetate) 350mg compared with abacavir derived from the commercially available tablet formulation of Ziagen (abacavir sulfate) 300mg. After completion of Part A, subjects will be randomly assigned to cross-over treatment sequence Prurisol then Ziagen, or Ziagen then Prurisol. Five to 21 days later, each subject will receive the alternate study drug. Evaluable subjects in the PK population will be those who received both alternate treatments and for whom an adequate number of post-dose PK sample results are available.

Peak plasma concentration (Cmax) of abacavir derived from Prurisol and Ziagen

Time to Cmax (Tmax) of abacavir derived from Prurisol and Ziagen

Secondary Outcome Measures

Area under the plasma concentration versus time curve (AUC) of abacavir derived from Prurisol

Pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2) of abacavir derived from Prurisol will be determined in Part A of this study. Three cohorts, each comprising 6 subjects, will be administered escalating single doses of Prurisol. Part A consists of single doses of open-label Prurisol at doses of 50mg (1 tablet), 100mg (2 tablets) and 200 mg (4 tablets) administered to approximately equal numbers of male and female subjects. These treatments will be administered in 3 sequential cohorts with at least a 24 hour interval (safety period) between subjects in each of the 3 cohorts. Plasma concentrations of abacavir will be assayed by a validated liquid chromatography-mass spectrometry (LC/MS/MS) method and PK parameters will be calculated.

Peak plasma concentration (Cmax) of abacavir derived from Prurisol

Time to Cmax (Tmax) of abacavir derived from Prurisol

Elimination half-life (t1/2) of abacavir derived from Prurisol

Number of participants with adverse events

To evaluate the safety and tolerability of Prurisol in healthy volunteers, completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Adverse events from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing their first treatment, there will be a 5 to 21 day washout period before being given the next dose of study drug. Subjects completing their first treatment will be randomly assigned to receive either Prurisol or Ziagen in the second dosing period. After a 5-21 day washout period, subjects will receive the alternate treatment (Ziagen or Prurisol) in the third dosing period. The sequential dosing specified will allow for observation of any possible adverse effects of Prurisol at the respective doses.

Number of participants with vital sign changes

To evaluate the safety and tolerability of Prurisol in healthy volunteers, completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Vital signs from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing their first treatment, there will be a 5 to 21 day washout period before being given the next dose of study drug. Subjects completing their first treatment will be randomly assigned to receive either Prurisol or Ziagen in the second dosing period. After a 5-21 day washout period, subjects will receive the alternate treatment (Ziagen or Prurisol) in the third dosing period. The sequential dosing specified will allow for observation of any possible adverse effects of Prurisol at the respective doses.

Number of participants with changes in standard laboratory tests

To evaluate the safety and tolerability of Prurisol in healthy volunteers, completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Laboratory tests (standard hematology and clinical chemistry panels) from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing their first treatment, there will be a 5 to 21 day washout period before being given the next dose of study drug. Subjects completing their first treatment will be randomly assigned to receive either Prurisol or Ziagen in the second dosing period. After a 5-21 day washout period, subjects will receive the alternate treatment (Ziagen or Prurisol) in the third dosing period. The sequential dosing specified will allow for observation of any possible adverse effects of Prurisol at the respective doses.

Full Information

NCT ID

NCT02101216

First Posted

March 24, 2014

Last Updated

October 24, 2018

Sponsor

Cellceutix Corporation

1. Study Identification

Unique Protocol Identification Number

NCT02101216

Brief Title

Bioequivalence and Pharmacokinetic Study of Prurisol™ and Abacavir Sulfate in Healthy Volunteers

Official Title

A Randomized, Open-Label, Single-Dose, 2 Period Crossover Pharmacokinetic and Bioequivalence Study, With a Lead-In Dose Period, Evaluating Oral Abacavir Acetate (Prurisol™) and Oral Abacavir Sulfate (Ziagen®) in Healthy Volunteers

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Completed

Study Start Date

March 2014 (undefined)

Primary Completion Date

July 2014 (Actual)

Study Completion Date

October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Cellceutix Corporation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Cellceutix Corporation has created a new chemical entity for the treatment of psoriasis, termed Prurisol™, which is an ester of abacavir. This first-in-human study of Prurisol (abacavir acetate) is being performed to evaluate the pharmacokinetics, safety and tolerance of a single oral doses of Prurisol administered to healthy volunteers and the bioequivalence to abacavir sulfate (Ziagen). This study will be followed by a 505(b)(2) Phase 2 trial in patients with moderate to severe plaque psoriasis.

Detailed Description

Prurisol™, abacavir acetate, is an ester of abacavir. Prurisol is believed to act as an immune response modifier in certain conditions, including psoriasis. Abacavir is a synthetic nucleoside analogue. Ziagen, abacavir sulfate, was developed and marketed as a treatment for HIV-1 infection for over a decade. Ziagen inhibits viral DNA synthesis. Consequently, Prurisol is under consideration as a possible new therapy for moderate to severe plaque psoriasis. The nonclinical efficacy of Prurisol has been demonstrated in the human psoriatic skin xenograft model in irradiated severe combined immune deficient mice. Histologic as well as visual observations confirmed a treatment benefit of Prurisol in this animal model. Interleukin-20 (IL-20) is a recently discovered cytokine displaying increased levels in psoriatic lesions, and levels of IL-20 have been shown to decrease with anti-psoriasis treatment and correlate with clinical improvement. IL-20 has been suggested as a specific target in psoriasis treatment. In comparison to vehicle-treated animals, the mice transplanted with human psoriatic tissue and treated with Prurisol had significant reductions in plasma IL-20 levels which were greater than those seen with methotrexate treatment. The expression of PRINS (psoriasis susceptibility-related RNA gene induced by stress) was significantly lower with twice daily Prurisol treatment compared to control. This study is designed as an open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose intensive pharmacokinetic (PK) study conducted in healthy volunteers. In addition, a lead-in dosing period will allow the evaluation of the PK of abacavir from 3 escalating single doses of Prurisol (50mg, 100mg, 200mg). Completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Adverse Events, vital signs, physical examination, and safety laboratory tests (clinical chemistry and hematology) from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing the first part, there will be a 5 to 21 day washout period before the next dose of study drug. Subjects will be randomly assigned to receive either a single dose of 350mg Prurisol or 300mg of Ziagen in the second dosing period. After a 5 to 21 day washout period, subjects will receive the alternate treatment in the third dosing period. Blood samples for PK analysis will be obtained over a 24 hour period for each dose. Safety and tolerability will be assessed by ascertainment of adverse events, results of clinical laboratory testing and physical examination.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Psoriasis

Keywords

bioequivalence, pharmacokinetics, psoriasis

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Pharmacokinetics of low dose Prurisol

Arm Type

Experimental

Arm Description

Pharmacokinetics of single dose of Prurisol™ 50 mg (1 tablets) to 6 subjects

Arm Title

Pharmacokinetics medium dose Prurisol

Arm Type

Experimental

Arm Description

Pharmacokinetics of single dose of Prurisol™ 100 mg (2 tablets) to 6 subjects

Arm Title

Pharmacokinetics of high dose Prurisol

Arm Type

Experimental

Arm Description

Pharmacokinetics of single dose of Prurisol™ 200 mg (4 tablets) to 6 subjects

Arm Title

Bioequivalence of Prurisol (350 mg)

Arm Type

Experimental

Arm Description

Single dose of Prurisol™ 350 mg (7 x 50 mg tablets)

Arm Title

Bioequivalence of Ziagen (300 mg)

Arm Type

Active Comparator

Arm Description

Single dose of Ziagen 300 mg (1 x 300mg tablet)

Intervention Type

Drug

Intervention Name(s)

Prurisol

Other Intervention Name(s)

abacavir acetate

Intervention Description

Experimental Drug

Intervention Type

Drug

Intervention Name(s)

Ziagen

Other Intervention Name(s)

abacavir sulfate

Intervention Description

Active comparator

Primary Outcome Measure Information:

Title

Area under the plasma concentration versus time curve (AUC) of abacavir derived from Prurisol and Ziagen

Description

Time Frame

24 hours after second and third dose of study drug or reference drug

Title

Peak plasma concentration (Cmax) of abacavir derived from Prurisol and Ziagen

Description

Time Frame

24 hours after second and third dose of study drug or reference drug

Title

Time to Cmax (Tmax) of abacavir derived from Prurisol and Ziagen

Description

Time Frame

24 hours after second and third dose of study drug or reference drug

Secondary Outcome Measure Information:

Title

Area under the plasma concentration versus time curve (AUC) of abacavir derived from Prurisol

Description

Time Frame

0 to 24 hours after the first dose of study drug

Title

Peak plasma concentration (Cmax) of abacavir derived from Prurisol

Description

Time Frame

0 to 24 hours after the first dose of study drug

Title

Time to Cmax (Tmax) of abacavir derived from Prurisol

Description

Time Frame

0 to 24 hours after the first dose of study drug

Title

Elimination half-life (t1/2) of abacavir derived from Prurisol

Description

Time Frame

0 to 24 hours after the first dose of study drug

Title

Number of participants with adverse events

Description

Time Frame

Day 1, Day 2, Day 3

Title

Number of participants with vital sign changes

Description

To evaluate the safety and tolerability of Prurisol in healthy volunteers, completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Vital signs from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing their first treatment, there will be a 5 to 21 day washout period before being given the next dose of study drug. Subjects completing their first treatment will be randomly assigned to receive either Prurisol or Ziagen in the second dosing period. After a 5-21 day washout period, subjects will receive the alternate treatment (Ziagen or Prurisol) in the third dosing period. The sequential dosing specified will allow for observation of any possible adverse effects of Prurisol at the respective doses.

Time Frame

Day 1, Day 2, Day 3

Title

Number of participants with changes in standard laboratory tests

Description

To evaluate the safety and tolerability of Prurisol in healthy volunteers, completion of each dosing cohort will be followed by a 24-hour safety evaluation period before moving to a higher dose. Laboratory tests (standard hematology and clinical chemistry panels) from each dosed cohort will be reviewed prior to any dose escalation for next cohort. For each subject completing their first treatment, there will be a 5 to 21 day washout period before being given the next dose of study drug. Subjects completing their first treatment will be randomly assigned to receive either Prurisol or Ziagen in the second dosing period. After a 5-21 day washout period, subjects will receive the alternate treatment (Ziagen or Prurisol) in the third dosing period. The sequential dosing specified will allow for observation of any possible adverse effects of Prurisol at the respective doses.

Time Frame

Day 1, Day 2, Day 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Individuals who meet ALL of the following criteria are eligible for participation in this study: Provided written informed consent Male or female adult aged 18-65 years old (inclusive). At least 20% of enrolled subjects will be aged 55-65 years, inclusive. Effort will be made to enroll equivalent numbers of males and females BMI of 19-32 kg/m2 Identified as a non-smoker at the Consent/Screening Visit. A urine cotinine test will be performed at screening and during each clinic check-in before for each of the three Treatment Visits Willing and able to comply with all aspects of the study protocol including avoiding use of certain concomitant medications and attending the required clinic visits Exclusion Criteria: Subjects are not eligible for participation in the study if any of the following criteria are met: Females of childbearing potential not using reliable contraception, (e.g., abstinence, double barrier method, oral/implantable/transdermal contraception. Depo-provera, intrauterine device) Female who is pregnant, lactating, has a positive serum pregnancy test drawn at the Consent/Screening Visit, or has a positive urine pregnancy test at check-in performed prior to any of the 3 Treatment Days Presence of any uncontrolled (in the Investigator's medical opinion) systemic disease, including, but not limited to renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease History of any immune disorder, or disease/condition potentially affecting the immune system Regular use of oral or parenteral corticosteroids (inhaled corticosteroids for stable asthma or chronic obstructive pulmonary disease are permitted) ECG obtained at Consent/Screening Visit which shows medically significant abnormalities (e.g. bundle branch block, frequent premature ventricular contractions, corrected QT interval (QTc) prolongation >450 msec for males and >470 msec for females) Presence of a condition that makes it unlikely that the requirements of the protocol will be completed Urine screening test(s) positive for evidence of amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamine, opiates, phencyclidine, marijuana Positive urine cotinine test Positive breath alcohol test History of hypersensitivity to any formulation of abacavir Previous treatment with any abacavir-containing product Current participation or participation in a drug/device or biologic investigational research study within 30 days prior to the Treatment A Visit An elective surgical or medical procedure is planned or scheduled to be performed during the period of the study Past surgical history of any degree of gastric resection or gastric banding History of a clinically diagnosed upper respiratory tract infection or any acute illness requiring antibiotic therapy within 14 days prior to the Treatment A Visit Systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg or heart rate <45 bpm in a subject under the age of 40 years and heart rate <50 bpm in a subject aged ≥40 years or >100 bpm (any subject age) on repeat determinations at the Consent/Screening Visit or at check-in on the day prior to each of the 3 Treatment Days and at pre-dose if drug administered on different day than check-in Clinical laboratory results at the Consent/Screening Visit that show any one or more of the following: Hemoglobin <11 Gm/dL, Hematocrit<30% Total white blood cell count <3000cells/mm3 Absolute neutrophil count <1500cells/mm3 Platelet count <100,000/mm3 alanine aminotransferase or aspartate aminotransferase >1.5 x Upper Limit of Normal (ULN) Serum amylase above ULN Serum creatinine >1.5 x ULN Positive serum human chorionic gonadotropin Positive serologic test for HBsAg, HIV, hepatitis C virus Positive test for HLA-B*5701 allele by certified laboratory Urinalysis showing medically significant abnormality

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Krishna Menon

Organizational Affiliation

Cellceutix Corporation

Official's Role

Study Director

Facility Information:

Facility Name

Phase One Solutions Inc.

City

Miami Gardens

State/Province

Florida

ZIP/Postal Code

33169

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

9585869

Citation

Foster RH, Faulds D. Abacavir. Drugs. 1998 May;55(5):729-36; discussion 737-8. doi: 10.2165/00003495-199855050-00018.

Results Reference

background

PubMed Identifier

11730031

Citation

Galadari I, Rigel E, Lebwohl M. The cost of psoriasis treatment. J Eur Acad Dermatol Venereol. 2001 Jul;15(4):290-1. No abstract available.

Results Reference

background

PubMed Identifier

11726000

Citation

Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, Lafon S, Pearce G, Steel H. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. 2001 Oct;23(10):1603-14. doi: 10.1016/s0149-2918(01)80132-6.

Results Reference

background

PubMed Identifier

15579086

Citation

Imamichi T. Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors. Curr Pharm Des. 2004;10(32):4039-53. doi: 10.2174/1381612043382440.

Results Reference

background

PubMed Identifier

15855153

Citation

Sonkoly E, Bata-Csorgo Z, Pivarcsi A, Polyanka H, Kenderessy-Szabo A, Molnar G, Szentpali K, Bari L, Megyeri K, Mandi Y, Dobozy A, Kemeny L, Szell M. Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS. J Biol Chem. 2005 Jun 24;280(25):24159-67. doi: 10.1074/jbc.M501704200. Epub 2005 Apr 26.

Results Reference

background

PubMed Identifier

18394087

Citation

Tzu J, Kerdel F. From conventional to cutting edge: the new era of biologics in treatment of psoriasis. Dermatol Ther. 2008 Mar-Apr;21(2):131-41. doi: 10.1111/j.1529-8019.2008.00180.x.

Results Reference

background

Links:

URL

http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020977s019,020978s022lbl.pdf

Description

Ziagen® Highlights of Prescribing Information

URL

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.

Description

Ziagen® NDA # 020977 (December 1998),

URL

http://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf

Description

CDER FDA Guidance for Industry (January 2001). Statistical Approaches to Establishing Bioequivalence

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Bioequivalence and Pharmacokinetic Study of Prurisol™ and Abacavir Sulfate in Healthy Volunteers

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