Hyaluronidase: Its effects on HI-6 dichloride and dimethanesulphonate pharmacokinetic profile in pigs

• New promising strategy after oxime HI-6 i.m. application was described.
• Previously published data (Toxicology) about HI-6 DMS salt were confirmed.
• Better pharmacokinetics profile was found in combination with hyaluronidase.
• Hyaluronidase is able to increase tissue permeability and therapy effectiveness.

Pigs were administered intramuscularly molar equivalents of HI-6 salts (HI-6 dichloride 10.71 mg/kg and HI-6 DMS 13.59 mg/kg) either with or without hyaluronidase (60 U/kg). Hyaluronidase is supposed to increase tissue permeability and diminishes discomfort caused by the intramuscular injection. Doses of HI-6 salts corresponded with standard HI-6 dichloride dose in one autoinjector (500 mg) and were recalculated for 1 kg of body weight.According to the results, both HI-6 salts applied in combination with hyaluronidase had increased tissue absorption and improved pharmacokinetic profile. The Cmax was significantly higher in case of HI-6 DMS plus hyaluronidase (29.6 ± 2.98 μg/ml) administration increase compared to HI-6 DMS (23.8 ± 3.04 μg/ml) and HI-6 dichloride (19.0 ± 0.93 μg/ml); both without hyaluronidase. Bioavailability calculated as AUCtotal (HI-6 DMS with hyaluronidase, 4119 ± 647 min μg/ml) was also significantly higher compared to HI-6 DMS (2259 ± 329 min μg/ml) and HI-6 dichloride (1969 ± 254 min μg/ml); both without hyaluronidase.The results suggest that administration of HI-6 salt with higher solubility is the first step in the improvement of application strategy, but use some substances with spreading effect (hyaluronidase) may also leads to better absorption and better bioavailability. Improved bioavailability could to go hand in hand with increased effectiveness of therapy without the need of multiple autoinjector applications.