Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Abstract

The use of highly active antiretroviral therapy (HAART) has resulted in significant reductions in human immunodeficiency virus (HIV)-related mortality and morbidity, and transformed HIV disease to a chronic syndrome.1,2) Despite improved clinical outcomes with protease inhibitor (PI)-based HAART regimens, there are still many problems, such as high pill burden, resistance to antiretrovirals and metabolic abnormalities (e.g., hyperlipidemia, hyperglycemia). [3][4][5] Moreover, the transformation of HIV disease to a chronic syndrome also practically means that once patients start HAART, they should receive the drugs included in the HAART regimen for the rest of their life; therefore, not only long-term efficacy but also the safety of these drugs are of clinical significance.Atazanavir (ATV) is an azapeptide compound and the seventh addition to the family of HIV PIs. ATV may have an advantage over other PIs because of once-daily dosing, a distinct resistance profile, and a lack of insulin resistance and lipid increase.6,7) With these advantages, ATV has been successfully used in treatment-native and -experienced HIV patients.8) Similar to other PIs, however, ATV is poorly watersoluble and is known as a substrate of both a hepatic metabolizing enzyme, cytochrome P450 (CYP) 3A, and an intestinal drug efflux pump, P-glycoprotein (Pgp), thus resulting in low oral bioavailability (BA). 9) Clinically, to resolve this disadvantage, ATV is generally used with low-dose ritonavir (RTV) in the HAART regimen. RTV is also classified as a PI and is well known as a potent inhibitor of both CYP3A and Pgp. With this potent inhibition property, low-dose RTV has been demonstrated clinically to boost the BA of another concomitant PI. [10][11][12] HIV patients are typically treated with multiple drugs in addition to their HAART regimen. Hence, based on pharmacokinetic interaction, RTV-boosted HAART has great potential for drug-drug interactions with CYP3A and Pgp. 13,14) Moreover, it was also reported that RTV is not only a potent inhibitor but also a potent inducer of CYP3A and Pgp with chronic use. 15,16) This contradictory characteristic of RTV would further complicate drug-drug interactions and facilitate the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART. In addition, there are few studies on the effect of chronic use of lowdose RTV on its boosting effect and on pharmacokinetic interactions with concomitant drugs in addition to the HARRT regimen.We previously reported that the ATV pharmaceutical formulation, the physical mixture of Gelucire 50/13 and ATV solid dispersion in sodium lauryl sulfate (ATV-SLS SDϩG), could improve the BA of ATV without pharmacokinetic interaction with RTV.17) The aim of this study was to investigate the long-term efficacy and safety of RTV-boosted ATV and ATV-SLS SDϩG and to directly compare both formulations; therefore, we administered RTV-boosted ATV or ATV-SLS SDϩG for 14 d to rats and compared the pharmacoki- Atazanavir (ATV) is clinically coadminis...

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds

“…The intravenous pharmacokinetics of 3 in rats are characterized by a low CL p (~ 4.5 mL/min/kg) and a moderate V dss (1.1 L/kg), leading to a terminal elimination (t 1/2 ) of 2.8 h. The absolute oral bioavailability ( F ) of 3 was determined to be ~ 28%, a value remarkably similar to that reported for CSA 27–29 . CSA and 3 also showed very similar AUC and C max values following the same oral dose of 10 mg/kg.…”

Time-Dependent Interaction of Ritonavir in Chronic Use: The Power Balance Between Inhibition and Induction of P-Glycoprotein and Cytochrome P450 3A

“…10 In addition, the hepatic and intestinal Pgp and CYP3A were only focused on in this study. Most available drugs are metabolized and mediated by several enzymes and transporters and the induction effect of RTV on them could not be uniform.…”

“…Considering these findings, the inhibition effect of RTV could overcome the induction effect by RTV itself whenever RTV is administered once daily. 10 These observations suggested that the power balance between inhibition and induction effects of RTV in chronic use depends on the elapsed time after the latest RTV administration. This contradictory characteristic of RTV in chronic use could further complicate drugdrug interactions and increase the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART.…”

Two-Layered Dissolving Microneedles for Percutaneous Delivery of Peptide/Protein Drugs in Rats

“…Solid dispersion technology is used to increase the solubility of hydrophobic compounds. Consequently, BAs of the drugs were increased considerably after oral administration (48)(49)(50)(51)(52). In the case of dissolving microneedles, solid dispersion technology was not intended to increase the solubility of the formulated drug, because both rhGH and DDAVP were water-soluble protein and peptide drugs.…”