Paliperidone palmitate

BALB/c mice (female, about 20 g, 6-8 weeks old)+Sprague Dawley rats (male, about 250 g, 6-8 weeks old)^[2]

Mice: 62.4 mg/kg of Paliperidone palmitate, 5 U or 15 U of hyaluronidase (dissolved in normal saline)
Rats: 20 mg/kg of Paliperidone palmitate, 5 U or 15 U of Hyaluronidase (dissolved in phosphate buffered saline)

Intramuscular injection, single dose; for mice, 4-week study period; for rats, 21-28-day study period

In mice, co-administration of hyaluronidase increased paliperidone plasma exposures in the first week after injection. The overall long-acting release nature of the formulation was maintained. Macrophages showed infiltration between individual myocytes when paliperidone palmitate was co-administered with hyaluronidase.
In rats, co-administration of hyaluronidase also increased exposure in the first 4 days, but the effect was less than that in mice. The long-acting exposure was still maintained for about 20 days. Co-administration of hyaluronidase did not discernably affect the granulomas or the surrounding myocytes in rats. The lymph node retention of paliperidone palmitate was diminished upon treatment with hyaluronidase in both mice and rats. The biphasic plasma concentration-time profiles of paliperidone in both species could be described by an open first-order disposition model with parallel fast and slow absorption processes.
The macrophage infiltration and angiogenesis at the injection site affected the drug release and absorption, and the effect of hyaluronidase on these processes was different between mice and rats.