Long-term pharmacokinetic efficacy and safety of low-dose ritonavir as a booster and atazanavir pharmaceutical formulation based on solid dispersion system in rats.
Atazanavir (ATV) is clinically coadministered with low-dose ritonavir (RTV), which boosts the oral bioavailability (BA) of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway; however, it is well known that in the chronic phase, the inhibition effect of RTV on Pgp and CYP3A becomes an induction effect. In this study, we investigated the long-term efficacy and safety of RTV-boosted ATV in rats with a clinical relevant dosage of ATV and RTV, 7 mg/kg and 2 mg/kg, respectively, and drew a direct comparison with RTV-boosted ATV and the previously reported ATV pharmaceutical formulation based on a solid dispersion system (ATV-SLS SD+G). Rats received RTV-boosted ATV or ATV-SLS SD+G for 14 d in the pharmacokinetic study. In addition, after 14-d repeated administration of each formulation, cyclosporine A (CyA) was administered to rats and Western blot analysis of Pgp and CYP3A was performed to investigate the impact on pharmacokinetic interaction of each ATV formulation. After repeated administration of both formulations, there was no significant difference between ATV pharmacokinetic parameters on day 1 and 14; therefore, it was considered that the long-term efficacy of both ATV formulations was maintained. However, after treatment with RTV-boosted ATV, the Cmax and AUC0-infinity of the following CyA significantly decreased to 49% and 47% in comparison to the control, respectively, and the Pgp expression in the small intestine by Western blot analysis was approximately 2-fold higher than the control, whereas after treatment with ATV pharmaceutical formulation, neither significant alteration of CyA nor notable change in the expression of intestinal Pgp and hepatic CYP3A was observed. Therefore, it was considered that the BA of CyA after treatment with RTV-boosted ATV would decrease by the induction effect of RTV in chronic phase as described above. The results of this study revealed that the chronic use of low-dose RTV as a booster has great potential to compromise drug-drug interactions; therefore, it is recommended that the BA of protease inhibitors be improved by a pharmaceutical approach without pharmacokinetic interaction by RTV.
Fukushima
Keizo
K
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan. keizo@mb.kyoto-phu.ac.jp
Haraya
Kenta
K
Terasaka
Shuichi
S
Ito
Yukako
Y
Sugioka
Nobuyuki
N
Takada
Kanji
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D001682:Biological Availability; D015153:Blotting, Western; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004304:Dosage Forms; D006207:Half-Life; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D004304:Dosage Forms; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir