Received for publication August 22, 2006.
Revised December 6, 2006.
Accepted for publication December 12, 2006.

Cross-Species Pharmacokinetic Comparison from Mouse to Man of a Second Generation Antisense Oligonucleotide ISIS 301012, Targeting Human ApoB-100

Abstract

The pharmacokinetics of a 2'-O-(2-methoxyethyl) modified oligonucleotide, ISIS 301012(targeting human apoB-100), was characterized in mouse, rat, monkey, and man. Plasma pharmacokinetics following parental administration was similar across species, exhibiting a rapid distribution phase with t_1/2 of several hour(s) and a prolonged elimination phase with t_1/2 in days. The prolonged elimination phase represents equilibrium between tissues and circulating drug due to slow elimination from tissues. Absorption was nearly complete following s.c. injection, with bioavailability ranging from 80% to 100% in monkeys. Plasma clearance scaled well across species as a function of body weight alone, and this correlation was improved when corrected for plasma protein binding. In all animal models studied, the highest tissue concentrations of ISIS 301012 were observed in kidney and liver. Urinary excretion was less than 3% in monkeys and man in the first 24 hours. ISIS 301012 is highly bound to plasma proteins, likely preventing rapid removal by renal filtration. However, following 25 mg/kg s.c. administration in mouse and 5 mg/kg i.v. bolus administration in rat, plasma concentrations of ISIS 301012 exceeded their respective protein binding capacity. Thus, urinary excretion increased to 16% or greater within the first 24 hours. Albeit slow, urinary excretion of ISIS 301012 and its shortened metabolites is the ultimate elimination pathway of this compound, as demonstrated by 32% of dose recovered in total excreta by 14 days in a rat mass balance study. The pharmacokinetics of ISIS 301012 in man is predictable from the pharmacokinetics measured in animals. The pharmacokinetic properties of ISIS 301012 provide guidance for clinical development and support infrequent dose administration.

Key words: antisense oligonucleotides, drug distribution, mass spectrometry, metabolite identification, pharmacokinetics, protein binding

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