PMID- 33742764
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20220214
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 14
IP  - 4
DP  - 2021 Jul
TI  - Safety, tolerability, pharmacokinetics, and pharmacodynamics of a TLR7 agonist 
      prodrug RO6870868 in healthy volunteers.
PG  - 1524-1534
LID - 10.1111/cts.13016 [doi]
AB  - RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, 
      RO6871765. TLR7 agonists augment host immune activity and are in development to 
      treat hepatitis B infection. We evaluated the safety, tolerability, 
      pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a 
      first-in-human, phase I, randomized, single ascending oral dose study in 
      60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were 
      generally well-tolerated with a predictable safety profile associated with 
      dose-dependent increases in systemic interferon. No serious adverse events (AEs) 
      were reported and no subject withdrew from the study due to an AE. No clinically 
      significant changes were observed in vital signs, electrocardiograms, or 
      laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 
      concentrations increased rapidly, exhibiting mean terminal half-life ranging 
      2-6 h across all cohorts, with area under the plasma concentration versus time 
      curve extrapolated to infinity (AUC(0-infinity) ) increasing proportionally with dose. A 
      pattern of dose and time-dependent PD activity was demonstrated consistent with 
      engagement of the TLR7 system. Single RO6870868 doses activated components of the 
      TLR innate immune system in a dose-dependent manner with adequate safety and 
      tolerability. Single-dose data in healthy volunteers are useful to evaluate 
      safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen 
      selection for further trials in patients with chronic hepatitis B.
CI  - (c) 2021 Deep Dives in Pharma Research, LLC. Clinical and Translational Science 
      published by Wiley Periodicals LLC on behalf of the American Society for Clinical 
      Pharmacology and Therapeutics.
FAU - Grippo, Joseph F
AU  - Grippo JF
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Folitar, Ilia
AU  - Folitar I
AD  - Roche Innovation Center, Basel, Switzerland.
FAU - Passe, Sharon
AU  - Passe S
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Jiang, Qiudi
AU  - Jiang Q
AD  - Roche Innovation Center Shanghai, Shanghai, China.
FAU - Rodriguez, Ignacio
AU  - Rodriguez I
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Fettner, Scott H
AU  - Fettner SH
AD  - Roche Innovation Center, New York, New York, USA.
FAU - Calleja, Elizabeth
AU  - Calleja E
AD  - Roche Innovation Center, New York, New York, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210409
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Immunologic Factors)
RN  - 0 (Prodrugs)
RN  - 0 (TLR7 protein, human)
RN  - 0 (Toll-Like Receptor 7)
RN  - 9008-11-1 (Interferons)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Half-Life
MH  - Healthy Volunteers
MH  - Hepatitis B, Chronic/drug therapy/immunology
MH  - Humans
MH  - Immunity, Innate/drug effects
MH  - Immunologic Factors/administration & dosage/*adverse effects/pharmacokinetics
MH  - Interferons/blood/metabolism
MH  - Male
MH  - Middle Aged
MH  - Prodrugs/administration & dosage/adverse effects/pharmacokinetics
MH  - Signal Transduction/drug effects/immunology
MH  - Toll-Like Receptor 7/*antagonists & inhibitors
MH  - Young Adult
PMC - PMC8301559
COIS- All authors participated in this study while employed by Hoffmann La Roche and 
      declare no additional competing interests for this work.
EDAT- 2021/03/21 06:00
MHDA- 2022/02/15 06:00
PMCR- 2021/07/01
CRDT- 2021/03/20 12:13
PHST- 2021/02/19 00:00 [revised]
PHST- 2020/12/10 00:00 [received]
PHST- 2021/02/24 00:00 [accepted]
PHST- 2021/03/21 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
PHST- 2021/03/20 12:13 [entrez]
PHST- 2021/07/01 00:00 [pmc-release]
AID - CTS13016 [pii]
AID - 10.1111/cts.13016 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2021 Jul;14(4):1524-1534. doi: 10.1111/cts.13016. Epub 2021 Apr 
      9.