1390. Pharmacokinetics of Temsavir, the Active Moiety of the Prodrug Fostemsavir, in Subjects with Hepatic Impairment
Session: Poster Abstract Session: HIV: Antiretroviral Therapy
Friday, October 6, 2017
Room: Poster Hall CD
Background: Fostemsavir (FTR) is a prodrug of temsavir (TMR), a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized via hydrolytic and oxidative pathways; impaired hepatic function may alter TMR pharmacokinetics (PK).

Methods: AI438053 (NCT02467335) was an open-label, nonrandomized study in healthy subjects (HS) and subjects with hepatic impairment (HI), defined by Child-Pugh (CP) score: mild (CPA), moderate (CPB), or severe (CPC). HS were matched for age, body weight, and sex. Subjects received a single oral dose of FTR 600 mg fasted and serial PK samples for TMR were collected up to 96 hours post-dose. Unbound TMR at 1 and 3 hours post-dose was determined. Total and unbound PK parameters were derived by noncompartmental methods. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for HI vs. HS were derived using linear mixed-effects models. Subjects were monitored for adverse events (AEs).

Results: 18 subjects with HI (N=6/CP group) and 12 HS received FTR and completed the study. Total and unbound TMR exposures increased with increasing HI severity (see Table). Total and unbound TMR CLT/F decreased with increasing HI severity. Mean % protein binding of TMR was 81.0% in HS and 79.9%, 81.9%, and 76.5% in CPA, CPB, and CPC HI, respectively, and was independent of TMR concentration. There were no deaths, serious AEs, or discontinuations during the treatment period.

Table: TMR PK in HI and HS

TMR PK in HI vs HS [GMR(90% CI)]

Total TMR

Cmax

AUC(0-T)

CPA

1.34 (1.00-1.79)

1.18 (0.81-1.72)

CPB

1.48 (1.11-1.97)

1.58 (1.08-2.29)

CPC

1.72 (1.29-2.30)

1.74 (1.20-2.54)

Unbound TMR

Cmaxu

AUC(0-T)u

CPA

1.46 (1.05-2.04)

1.29 (0.83-2.00)

CPB

1.42 (1.02-1.97)

1.51 (0.98-2.34)

CPC

2.15 (1.55-3.00)

2.18 (1.41-3.39)

TMR CLT/F in HS and HI [geometric mean (%CV)]

HI Severity

HS

CPA

CPB

CPC

CLT/F (L/hr)

61.8 (30)

51.7 (60)

38.1 (43)

35.8 (33)

CLT/Fu (L/hr)

339 (42)

259 (58)

218 (54)

157 (31)

Conclusion: TMR exposures increase with increasing severity of HI. The increase in TMR exposures in patients with mild or moderate HI is not expected to alter the safety profile of FTR. The risk/benefit of higher TMR exposures in severe HI is under evaluation.

Heather Sevinsky, MS1, Mindy Magee, RPh, PharmD2, Peter Ackerman, MD3, Robert Adamczyk, PharmD4, Jennifer Karkas, BS4, Susan Lubin, RN, MA4, Palanikumar Ravindran, PhD5, Cyril Llamoso, MD3, Timothy Eley, PhD5 and Katy Moore, RPh, PharmD6, (1)ViiV Healthcare, Upper Providence, PA, (2)GlaxoSmithKline, Upper Providence, PA, (3)ViiV Healthcare, Branford, CT, (4)Bristol-Myers Squibb, Hopewell, NJ, (5)Bristol-Myers Squibb, Lawrenceville, NJ, (6)ViiV Healthcare, Research Triangle Park, NC

Disclosures:

H. Sevinsky, ViiV Healthcare: Employee , Salary

M. Magee, GlaxoSmithKline: Employee and Shareholder , Salary

P. Ackerman, ViiV Healthcare/GSK: Employee and Shareholder , Salary and Stock

R. Adamczyk, Bristol-Myers Squibb: Employee , Salary

J. Karkas, Bristol Myers Squibb: Employee and Shareholder , Salary

S. Lubin, Bristol-Myers Squibb: Employee , Salary

P. Ravindran, Bristol-Myers Squibb: Employee , Salary

C. Llamoso, ViiV Healthcare: Employee , Salary

T. Eley, Bristol-Myers Squibb: Former Employee during study conduct , Salary

K. Moore, ViiV Healthcare: Employee , Salary

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