1421. IV Brincidofovir (BCV): Pharmacokinetics (PK) and Safety of Multiple Ascending Doses (MAD) in Healthy Subjects
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall

Background: BCV is a lipid conjugated nucleotide analog that has shown rapid viral clearance with oral administration in patients with adenovirus infection, and improved survival in animal models of smallpox.  Phase I single ascending dose evaluation of IV BCV demonstrated that 2 hour infusions of 10, 25, and 50 mg were well tolerated and not associated with significant adverse events (AEs) or laboratory abnormalities.  This study evaluated the safety and PK of multiple ascending doses of IV BCV in healthy subjects.

Methods: Twenty-eight subjects were to be randomized 3:1 to receive blinded IV BCV or placebo in sequential MAD cohorts (Table A).  Study drug was given twice a week (BIW) for 2 weeks or once a week (QW) for 4 weeks.  Plasma PK samples were collected on Day 1 and after the last dose and assayed by HPLC-MS.  Plasma BCV PK parameters were determined by non-compartmental analysis and dose proportionality and accumulation was assessed.  Safety assessments were performed during the dosing period through 14 days post last dose.

Results: Twenty-seven male and female subjects (29-65y, 93% White) were enrolled and 26 completed the study.  Plasma BCV Cmax and AUC increased in proportion to dose with no accumulation (Table A).  AEs were generally mild and included diarrhea and headache.  Alanine aminotransferase (ALT) elevations were asymptomatic and resolved upon cessation of dosing.  No serious AEs occurred.

Table A. BCV PK on Day 1 and Safety

Plasma BCV PK1

BCV 10 mg BIW

2-h infusion
(n=9)

BCV 20 mg QW
2-h infusion

(n=6)

BCV 20 mg QW
1-h infusion

(n=5)

Pooled Placebo (n=7)

Cmax (ng/mL)

553 (33%)

1110 (19%)

1720 (19%)

NA

AUC (ng*h/mL)

1374 (34%)

2982 (23%)

2919 (18%)

NA

Drug-Related AEs in >2 subjects

Diarrhea

0

3 (50%)

1 (20%)

0

Headache

4 (44%)

3 (50%)

3 (60%)

 4 (57%)

Fatigue

0

2 (33%)

0

2 (29%)

1. Cmax and AUC: geometric means (%CVb)

Conclusion:   Multiple doses of IV BCV given as 10 mg BIW or 20 mg QW were generally safe and well tolerated.  Mild diarrhea was reported only after IV BCV 20 mg QW. As seen with oral BCV, ALT increases were reversible upon cessation of drug, and were not associated with hyperbilirubinemia.  BCV exposure was dose-proportional and no accumulation was observed.  The data support evaluation of repeat dose administration in virally infected patients.

Odin Naderer, PharmD1, Virna Schuck, Ph.D.2, Marion Morrison, MD1, Maggie Anderson, BS1, Thangam Arumugham, PhD1 and John Dunn, PhD1, (1)Chimerix, Durham, NC, (2)Clinical Pharmacology, Certara, Parsippany, NJ

Disclosures:

O. Naderer, Chimerix: Employee , Salary .

V. Schuck, Chimerix: Research Contractor , Consulting fee .

M. Morrison, Chimerix: Employee , Salary .

M. Anderson, Chimerix: Employee , Salary .

T. Arumugham, Chimerix: Employee , Salary .

J. Dunn, Chimerix: Employee , Salary .

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