Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

Abstract

Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatmentnaïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P ‫؍‬ 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC 0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC 50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.The treatment of HIV infection has been revolutionized by the advent of combination antiretroviral therapy (ARV), which suppresses viral replication and preserves immunological function. Currently recommended first-line combination therapy consists of two nucleoside reverse transcriptase inhibitors with either efavirenz or a ritonavir-boosted protease inhibitor (PI) (9).Much interest in the study of nucleoside-sparing regimens has been generated, in view of the toxicities of nucleosides and the development of resistance. The pharmacokinetic interactions between efavirenz and PIs have been studied (11,12). Efavirenz induces cytochrome P450 and reduces PI concentrations, necessitating dosage changes (2). The combination of lopinavir-ritonavir and efavirenz was compared with nucleoside-based therapies. This nucleoside-sparing regimen was found to cause more hyperlipidemia and was not as effective in patients with viral loads of Ͼ100,000 (17). It is also a twicedaily regimen and is not as convenient as current first-line therapies, which are mostly taken once daily.Darunavir (TMC114) is a new-generation PI with activity against viruses resistant to other PIs (7). The FDA-approved dose of darunavir-ritonavir is 600/100 mg twice daily for treatment-experienced HIV-infected patients and 800/100 once daily for treatment-naïve patients (14). Darunavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is used in combination with ritonavir, which is a potent inhibitor of CYP3A4. When darunavir is boosted with ritonavir, the darunavir halflife is 15 h, thus allowing once-daily administration to treatment-naïve patients.Compared to lopinavir-ritonavir, darun...

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

“…Nevertheless, the protein-adjusted EC 50 for both wild-type (55 ng/mL) and protease inhibitor-resistant (550 ng/mL) HIV-1 strains can serve as useful targets to evaluate the likely efficacy of a given regimen for a given virus isolate. 16,18,27 In this study, the simulation of darunavir/ritonavir 600 mg twice daily and 800 mg once daily provided an average darunavir C min substantially above the putative targets of 550 and 55 ng/mL for naive and experienced patients, respectively. However, taking into account the variability of darunavir pharmacokinetics, about one-third of the patients under the 800 mg once-daily regimen would present levels under the 550 ng/mL threshold, thus justifying the idea that this regimen can be considered sub-optimal in patients with resistant HIV-1 strains.…”

Pharmacokinetics of Once-Daily Darunavir/Ritonavir With and Without Etravirine in Human Immunodeficiency Virus-Infected Children, Adolescents, and Young Adults

“…The clinical efficacy of DRV/r 800/100 mg QD in adolescents has been reported by others in treatment-naive adolescents, in which 92% and 83% of patients achieved favorable virologic response ( < 50 copies/mL) at 24 and 48 weeks, respectively [10]. In the case of ETR, the C 24 (C 12 for twice-daily dosing) values were higher than the ETR protein-binding adjusted EC 50 (0.004 mg/L in cell-based assays for wild-type HIV-1) [19,22]. Five patients in group 2A (83.3%) had an ETR C 12 higher than the ETR PBIC 95 (0.116 mg/L) [21], and 8 patients in group 2B (88.9%) had an ETR C 24 higher than the PBIC 95 .…”

Multidomain drug delivery systems of β-casein micelles for the local oral co-administration of antiretroviral combinations

“…Our strategy is substantially distinct from others that in most of cases encapsulate one single drug, as we demonstrate in this work the co-encapsulation, with almost 100% efficiency, of double and triple ARV combinations. As stressed above, TRP:EFV was utilized to optimize the process conditions and the bCN:drugs ratio to maximize encapsulation, DRV:EFV:RTV is an ARV combination administered once daily in healthy volunteers in the amount of 900, 600 and 100 mg respectively [41] .…”