Pseudohyponatremia Caused by an Intravenously Administered Liposome Drug Product in a 1-Month Nonclinical Toxicity Study in Cynomolgus Monkeys

Pseudohyponatremia is a laboratory artifact whereby measured serum sodium concentration is falsely low, despite normal plasma osmolality and sodium concentration in plasma water. This occurs when sodium is measured by indirect ion-selective electrode (ISE) methods on samples with hyperlipidemia or hyperproteinemia. In contrast, hyponatremia (low serum sodium concentration with hypotonic serum) is a potentially life-threatening electrolyte disturbance that can cause severe neurologic symptoms, and treatment carries risk of osmotic demyelination syndrome. Therefore, distinguishing between pseudohyponatremia and hyponatremia is critical for patient management since treating pseudohyponatremia as hyponatremia (despite normal serum tonicity) can cause hyperosmolar injury and serious neurologic complications. We observed pseudohyponatremia in a 1-month nonclinical toxicity monkey study evaluating a liposomal drug product administered intravenously. Pseudohyponatremia also occurred in the control group receiving the liposome carrier alone, indicating an effect from the liposome formulation. Normal serum osmolality in samples from both groups confirmed pseudohyponatremia rather than hyponatremia. Since projected human doses would have been at the same level as tested in monkeys, pseudohyponatremia would have been anticipated in early clinical trials and clinical trial protocols would have required serum sodium measurement using a direct ISE and/or serum osmolality assessment to avoid misdiagnosis.