Precipitation of the renin inhibitor ditekiren upon i.v. infusion; in vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey.
Ditekiren is a pseudo-octapeptide being developed as an inhibitor of human renin. Preclinical drug safety studies with this drug involved continuous i.v. infusions through indwelling catheters in the right internal jugular vein of the cynomolgus monkey for up to 30 days. The following physiocochemical properties of ditekiren make it susceptible to intravascular precipitation immediately following iv infusion: (1) the water solubility of ditekiren is high at acidic pH where the drug is formulated (pH 4) but low at physiologic pH, and (2) the water solubility of ditekiren decreases by roughly 50% from room temperature (25 degrees C) to physiologic temperature (37 degrees C). Studies of 28- and 30-day infusion durations revealed intravascular precipitation in monkeys using drug solutions and rates of infusion that were expected to be precipitation-free, based on the solubility of ditekiren and assumptions about blood flow in the monkey right internal jugular vein. Therefore, an in vitro apparatus was used to study the relationship among the drug concentration in the infusate, the rate of infusion, and the occurrence of precipitation in a fluid stream of phosphate-buffered bovine serum albumin solution (a facsimile of plasma). Maximum rates of infusion without precipitation were determined for a range of concentrations of drug in two separate formulations. Infusion conditions identified by the in vitro method as precipitation-free were then tried in a definitive 14-day monkey study. Of 24 monkeys infused with solutions of ditekiren, none showed evidence of intravascular precipitation.(ABSTRACT TRUNCATED AT 250 WORDS)
Davio
S R
SR
Upjohn Company, Kalamazoo, Michigan 49001.
McShane
M M
MM
Kakuk
T J
TJ
Zaya
R M
RM
Cole
S L
SL
D000818:Animals; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007601:Jugular Veins; D008252:Macaca fascicularis; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D012542:Scattering, Radiation; D000092502:Renin Inhibitors
D009842:Oligopeptides; D000092502:Renin Inhibitors; C050898:ditekiren