Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients

Abstract

max ]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C min ratio of the combination compared to IDV alone regimen would be >2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C min , AUC 0-24 , and C max for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM ⅐ h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C min (90% CI, 4.0, 9.3), an increase in AUC 0-24 (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C max . Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C min for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C max was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.Single-protease inhibitor regimens significantly reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) following their introduction (19,20). More recently, boosted protease inhibitor regimens combined ritonavir (RTV) with a second protease inhibitor to achieve higher sustained levels of the second protease inhibitor than seen when it was given as part of a single-protease inhibitor regimen. The boosted protease inhibitor regimens may be more effective in suppressing HIV strains with resistance to antiretroviral therapy, including resistance to the second protease inhibitor (2,9,10,18,22,32). In addition, boosted protease inhibitor regimens may be administered less frequently and without regard to meals, potentially improving patient adherence (2, 9, 10, 18, 22, 32). RTV's inhibition of the cytochrome P-450 CYP3A4 enzyme, the primary enzyme in the metabolism of most protease inhibitors, changes the pharmacokinetics of the second protease inhibitor, with elevations of minimum drug concentration (C min ) and area under the concentrationtime curve (AUC) contributing to improved clinical efficacy (2, 10). In addition, RTV's inhibition of P-glycoprotein transport proteins may also contribute to increased concentration of a concomitantly administered protease inhibitor in plasma (33).Indinavir (IDV) is approved for administration every 8 h (q8h) at 800 mg without food (28). Combinations of IDV at 400 to 800 mg and RTV at 100 to 400 mg twice a day (b.i.d.) demonstrated at least equivalent to (and in many cases much higher than) the C min and AUC at 24 h (AUC 24 ) of IDV at 800 mg q8h in normal volunteers and can be administered with food (25). The trough levels maintained with the b.i.d. combinations were above the concentration necessary to inhibit 95% of viral growth of wild-type HIV-1 seen in the absence of drug (8). The most-studied boosted IDV regimen is IDV at 800 mg plus RTV at 100 mg q12h (4,7,21,31). A combination regimen of IDV...

Prevalence of possible drugdrug interactions between antiretroviral agents in different age groups in a section of the private health care sector setting in South Africa

“…Single‐PI regimens significantly reduced the morbidity and mortality associated with HIV following their introduction (17). More recently, boosted PI regimens combined RTV with a second PI to achieve higher sustained levels of the second one than seen when it was given as part of a single‐PI‐regimen (18).…”

Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery

“…In contrast, administration of NP-IDV-BMMs at drug concentrations identical to that of IDV elicited sustained IDV in tissue and sera for up to 10 days. More importantly, NP-IDV-BMM delivery showed drug levels in sera more than 4-and 50-fold of clinical effective plasma concentrations (5-10 M) [19][20][21][22] at 24 hours and 10 days ( Figure 4E). Urine levels demonstrated drug excretion over time.…”

In Vitro Inhibition of Udp Glucuronosyltransferases by Atazanavir and Other Hiv Protease Inhibitors and the Relationship of This Property to in Vivo Bilirubin Glucuronidation

“…An elegant study by Rhame et al (2004) demonstrated that C min may also contribute to hyperbilirubinemia induced by indinavir. A dose of indinavir at 667 mg in combination with ritonavir at 100 mg every 12 h produced a 6-fold increase in indinavir C min (from 0.25 to 1.5 M) as well as 1.6-fold increase in indinavir AUC 0 -24 compared with indinavir alone at 800 mg every 8 h. The indinavir C max level of these two dosing regimens were comparable.…”