Dog model with implanted pump to test boosters for antiretroviral medication.
A dog model was developed to test the capacity of boosters for antiretroviral medication. Two dogs were implanted with a modified constant-flow Codman 3000 infusion pump, adapted to release viscous solutions of darunavir (TMC114) at a constant rate of 25mg/dog/day in the venous blood stream. Booster candidates were given by oral gavage for at least 4 days up to maximum 7 days in cross-over fashion, separated by a wash-out period of minimum 1 week. The booster candidates were tested at doses of 20 and/or 40mg/kg/day: blood sampling for determination of the boosting effect was performed on the last day of booster administration. The model allowed to (1) compare the boosting ratio of these booster candidates based on the exposure (determination of the area under the curve (AUC) of darunavir in presence versus absence of the booster candidate), (2) detect delay in boosting activity by evaluation of the shift of Cmax of darunavir following booster administration versus the Cmax of the booster candidate) and (3) calculate the intrinsic booster capacity, by correcting for the systemic exposure of booster candidate by normalizing the booster ratio for the booster's AUC. The latter parameter (intrinsic booster capacity) allows to determine the booster's metabolic contribution in inhibiting the metabolism of antiretroviral medication (most likely via inhibition of CYP3A4), minimizing the impact of potential effects of the booster at the level of the gastro-intestinal tract.
Schueller
Laurent
L
Chem-Pharm Development, Tibotec BVBA, Gen. De Wittelaan L11B 3, 2800 Mechelen, Belgium. lschuell@tibbe.jnj.com
Baert
Lieven
L
Lachau-Durand
Sophie
S
Borghys
Herman
H
Clessens
Ellen
E
Van Den Mooter
Guy
G
Van Gyseghem
Elke
E
Jonckers
Tim H M
TH
Van Remoortere
Pieter
P
Wigerinck
Piet
P
Rosier
Jan
J
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000295:instrumentation* / Q000379:methods; D000069454:Darunavir; D003627:Data Interpretation, Statistical; D004285:Dogs; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D015918:Infusion Pumps, Implantable; D008297:Male; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir