Journal of Clinical Toxicology
Open Access

Abstract

Toxicology and Safety Determination for a Novel Therapeutic Dual Carbon Monoxide and Oxygen Delivery Agent

Hemant Misra, Friedericke Kazo and Judith A. Newmark

Conditions in patients with hemoglobinopathies are far more complex and variable than in healthy humans due to the cascade of injury from hypoxia. Resulting complications can lead to tissue death, organ dysfunction and even death. Multi-faceted treatment is needed to address the array of complications. SANGUINATE™ (PEGylated, bovine carboxyhemoglobin) has multiple mechanisms of action that may prove effective. It acts both as a carbon monoxidereleasing molecule and as an oxygen transfer agent and is designed to safely perfuse the microvasculature to oxygenate tissue. Designing toxicology studies must not only deal with ensuring the safety of its mechanisms but deal with the potential safety issues of using bovine hemoglobin for both acute and chronic administration. Similar products have previously been shown to have effects on inflammation, vasoactivity, cardiac toxicity and nephrotoxicity as well as pro-coagulant activity. Therefore, studies were designed to thoroughly address the potential of these effects in conjunction with the traditional toxicology and safety pharmacology studies. These toxicology and safety studies were designed to address the FDA’s particular concerns of this novel drug candidate. There were several unique features to this preclinical program including a renal functional study, immunohistochemical and special staining of tissues, measurement of hemoglobin in the urine, measurement of troponin in the serum, inclusion of high dose/high volume groups, and analysis of interference for clinical pathology parameters. To address toxicity and safety concerns of its use as a single or repeating dose therapeutic, SANGUINATE was tested in pivotal studies using three species in repeating doses. There were no adverse effects identified for any doses and therefore, a no observed adverse effect level (NOAEL) was not determined even at dosage levels of 1200 mg/kg (monkey), 1600 mg/kg (pig) and 2400 mg/kg (rat). The completion of these studies permitted SANGUINATE to move into clinical trials.