A novel oral vehicle for poorly soluble HSV-helicase inhibitors: PK/PD validations.
OBJECTIVE
The current study describes the design and validation of a novel oral vehicle for delivering poorly water-soluble herpes simplex virus (HSV)-helicase inhibitors in preclinical pharmacokinetic (PK) and pharmacodynamic (PD) evaluations.


METHODS
Poorly water-soluble compounds were used in solubility and drinking compliance tests in mice. A preferred vehicle containing 0.1% bovine serum albumin (BSA), 3% dextrose, 5% polyethylene glycol (PEG) 400, and 2% peanut oil, pH 2.8 with HCL (BDPP) was selected. This vehicle was further validated with oral PK and in vivo antiviral PD studies using BILS 45 BS.


RESULTS
Solubility screen and drinking compliance tests revealed that the BDPP vehicle could solubilize BILS compounds at 0.5-3 mg/ml concentration range and could be administered to mice without reducing water consumption. Comparative oral PK of BILS 45 BS in HCL or BDPP by gavage at 40 mg/kg showed overlapping PK profiles. In vivo antiviral efficacy and potency of BILS 45 BS in BDPP by oral gavages or in drinking water were confirmed to be comparable as that achieved by gavage in HCL solution.


CONCLUSIONS
These results provide a protein-enriched novel oral vehicle for delivering poorly water-soluble antiviral compounds in a continuous administration mode. Similar approaches may be applicable to other poorly soluble compounds by gavage or in drinking solution.
Duan
Jianmin
J
Department of Biological Sciences, Boehringer Ingelheim (Canada) Ltd, R & D, Laval, Quebec, H75 2G5 Canada. jduan@lav.boehringer-ingelheim.com
Liard
Francine
F
Paris
William
W
Lambert
Michelle
M
D000212:Acyclovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005079:Excipients; D005260:Female; D006561:Herpes Simplex / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D051379:Mice; D008812:Mice, Hairless; D008819:Mice, Nude; D014677:Pharmaceutical Vehicles; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D018139:Simplexvirus / Q000201:enzymology*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D014764:Viral Proteins
D000998:Antiviral Agents; C477783:BILS 45 BS; D004791:Enzyme Inhibitors; D005079:Excipients; D014677:Pharmaceutical Vehicles; D011725:Pyridines; D013844:Thiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases; D000212:Acyclovir