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Pharmacokinetics and Tolerability of Intravenous Trecovirsen (GEM®91), an Antisense Phosphorothioate Oligonucleotide, in HIV‐Positive Subjects
Author(s) -
Séréni Daniel,
Tubiana Roland,
Lascoux Caroline,
Katlama Christine,
Taulera Oliver,
Bourque Andre,
Cohen Aharon,
Dvorchik Barry,
Martin R. Russell,
Tournerie Christophe,
Gouyette Alain,
Schechter Paul J.
Publication year - 1999
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912709922007552
Subject(s) - pharmacokinetics , tolerability , pharmacology , partial thromboplastin time , adverse effect , human immunodeficiency virus (hiv) , chemistry , plasma concentration , medicine , half life , immunology , coagulation
Trecovirsen, a 25‐mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV‐positive volunteers as an IV infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmacokinetic parameters could be assessed at doses ≥0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half‐life increased and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, transitory increase in activated partial thromboplastin time at doses ≥ 2.0 mg/kg that was related to plasma trecovirsen concentrations and is attributed to the polyanionic character of the molecule. Thus, trecovirsen administration was well tolerated in single IV doses up to 2.5 mg/kg.