PHARMACOKINETICS AND ORAL BIOAVAILABILITY OF PIDOTIMOD IN HUMANS

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]- thiazolidine-4- carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response m odifier was investigated in 3 different pharmacokinetic experiments in healthy volunteers. A first trial was carried out with a cross-over d esign in 12 subjects, given the drug in single administration by intra venous route (200 mg in bolus) and by oral route at 3 dose levels: 200 , 400 and 800 mg (tablets). The second experiment was performed in 36 subjects by intramuscular route at 50, 100 and 200 mg (12 volunteers/g roup) twice a day for is days. Blood samples were drawn and urine coll ected at different times after the first and the last administration ( 29th) of the compound. The third experiment,uas done in 12 subjects gi ven the product at the same single oral dose (800 mg) in different gal enic formulations: sachets, vials and tablets, to assess the relative bioavailability, with a crossover design. Pidotimod plasma and urinary levels were measured by HPLC. The plasma levels after parenteral admi nistration followed a second-order pharmacokinetic, while after oral a dministration they were processed by a first order input-output model. The results showed: 1. There was a linear relationship between plasma concentrations and doses, both by oral and intramuscular route; 2. th e compound was quickly absorbed and the plasma half-life was about 4 h , independently of the dose and route of administration; 3. the oral b ioavailability was 42-44%; 4. the drug was not metabolized and was eli minated mainly as unmodified drug in urine; 5. plasma clearance was 5 l x h(-1) and apparent distribution volume was 30 l; 6. after repeated administration there were neither accumulation nor autoinduction phen omena; 7. the different oral galenic formulations were bioequivalent.