AIDSWEEKLY Plus, Monday, 9 June 1997
Michelle Marble
Results of toxicity and pharmacokinetic studies of the antiviral phosphorothioate oligonucleotide ISIS 5320 conducted in cynomolgus monkeys were presented at the American Association for Cancer Research conference, held April 12-16, 1997, in San Diego, California.
"ISIS 5320 is a phosphorothioate oligonucleotide which binds to the V3 loop of the viral envelope protein gp120, preventing fusion of HIV to the cellular CD4 receptor," explained researcher Karen Schwikart, of the U.S. National Cancer Institute, Bethesda, Maryland at the conference. "It is active against HIV-1 and HIV-2 isolates, including clinical strains."
Schwikart's group conducted studies in the cynomolgus monkeys to determine the toxicity and pharmacokinetics of intravenously (i.v.) administered doses of ISIS 5320. The oligonucleotide was formulated in 5.0 mM potassium phosphate, 4.0 percent dextrose, with a pH of 7.4. It was administered to female monkeys, and the animals were observed for signs of clinical toxicity. Blood samples were drawn for plasma drug levels, clinical pathology, coagulation, and complement determinations.
Eight animals were given doses ranging from 1.26-10 mg/kg in a single i.v. bolus for the pilot study. Three other animals were given 4-6 mg/kg as a single i.v. bolus for a hemodynamic study. Eight additional monkeys were given 10-20 mg/kg as a single two hour infusion for a pharmacokinetic and toxicity study, and six additional monkeys were given 2-10 mg/kg as multiple two hour infusions (qodx7 doses) for a pharmacokinetic and toxicity study.
During the clinical observations and clinical pathology portion of the study, the researchers found that the 10 mg/kg i.v. bolus was lethal to 2/2 animals within 30-45 minutes due to cardiopulmonary collapse. An animal given 3.74 mg/kg had hemolysis and a weak pulse.
Animals given ISIS 5320 as a single two hour infusion (10- 20 mg/kg) appeared normal without noticeable cytotoxic effects. Animals given 10 mg/kg as a multiple two hour infusion exhibited hematuria.
Results from the hemodynamic portion of the study showed that a dose of 4 mg/kg i.v. bolus did not alter blood pressure or heart rate in the animals. A dose of 6 mg/kg i.v. bolus, however, resulted in immediate changes in heart rate and blood pressure, including transient sinus arrest in one of two animals, noted the researchers.
Coagulation time was prolonged 3-4 times above normal within two hours of administration of >=10 mg/kg by two hour infusion. Complement activation (Bb) correlated with adverse events after i.v. bolus dosing. Bb was elevated after a single i.v. bolus dose of >=3.74 mg/kg. These doses were associated with weak pulse, hemolysis, and/or death, noted the researchers. Bb occurred at >=6 mg/kg on the multiple two hour infusion studies, although no abnormal clinical signs were observed.
Examination of the plasma and tissue drug levels showed that plasma concentrations decreased monoexponentially following i.v. bolus administration of 1.26-10 mg/kg. The C[max] ranged from 4.7-163 (micro)m within 2-10 minutes of dosing. ISIS 5320 did not accumulate in the plasma after the multiple two hour infusions. One to three percent of the total dose was eliminated in the urine within four hours of the end of dosing.
On Day 14, ISIS 5320 levels were highest in liver and kidney tissue after the completion of the multiple two hour infusion study. Histopathological analysis found no lesions in animals given a single i.v. bolus dose of 10 mg/kg. Intratubular hemorrhage and/or tubular cell necrosis was found, however, in animals given 10 mg/kg as multiple two hour infusions, which correlated with the hematuria seen in the animals.
"The toxicity (cardiovascular and renal) observed with ISIS 5320 was similar to toxicity seen with other phosphorothioate oligonucleotides," concluded Schwikart at the conference. "Cardiovascular toxicity is associated with activation of complement and increased APTT, as seen with other phosphorothioates. However, complement activation and coagulation abnormalities may occur without cardiovascular toxicity.
"Toxicity associated with i.v. bolus dosing may be ameliorated by lengthening the time of infusion and delivering multiple doses," she added. "Repeated two hour infusions of 2 mg/kg dose, which produces ISIS 5320 plasma levels of 6 (micro)m, are well-tolerated with no evidence of toxicity."
This research was supported by NCI contract N01-CM-37834. Karen Schwikart can be reached at the U.S. National Cancer Institute, Bethesda, Maryland 20892.
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