Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study.

OBJECTIVE: To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant. DESIGN: An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods. METHODS: Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced. RESULTS: When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required. CONCLUSION: The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir.

The efficacy of HIV-1 protease inhibitors (PIs) as part of highly active antiretroviral therapy is now well established and has provided benefits to many patients with HIV infection. Atazanavir is a new azapeptide PI compound that was recently approved in the US and Europe. Atazanavir is recommended in combination with other antiretroviral agents for the treatment of HIV-1 infection. Atazanavir is rapidly absorbed and administration of a single dose of atazanavir with a light meal resulted in a 70% increase in area under the plasma concentration-time curve (AUC); therefore atazanavir should be taken with food. Atazanavir is 86% bound to human serum protein independently of concentration. Concentration in body fluids appeared to be lower than plasma concentration. Like other PIs, atazanavir is extensively metabolised by hepatic cytochrome P450 (CYP) 3A isoenzymes. The mean terminal elimination half-life in healthy volunteers was approximately 7 hours at steady state following administration of atazanavir 400 mg daily with a light meal. When atazanavir 300 mg was coadministered with ritonavir 100 mg on a once-daily dosage regimen, atazanavir AUC from 0 to 24 hours and minimum plasma concentration were increased by 3- to 4-fold and approximately 10-fold, respectively, compared with atazanavir 300 mg alone. Therefore, ritonavir boosted atazanavir regimen (ritonavir 100 mg and atazanavir 300 mg once daily) is increasingly favoured in some patients. Efavirenz, a potent CYP3A inducer, decreased atazanavir concentrations by 75% and, unexpectedly, tenofovir, a nucleotide reverse transcriptase inhibitor, decreased atazanavir concentrations by 25%. Average predose concentrations in HIV-infected patients who received atazanavir 400mg once daily were 273 ng/mL, which was believed to be several-fold higher than protein-binding corrected 50% inhibitory concentration of wild-type viruses. In HIV-infected patients who received once-daily ritonavir (100mg) boosted atazanavir (300 mg), mean (+/-SD) trough concentration was 862 (+/-838) ng/mL. Several clinical trials showed the efficacy of atazanavir 400 mg once daily with a nucleoside analogue backbone in antiretroviral-naive patients. The atazanavir 300/ritonavir 100 mg once-daily combination coadministered with other antiretrovirals showed the efficacy of this strategy in patients receiving efavirenz or in moderately antiretroviral-experienced HIV-infected patients. Recommended once-daily doses of atazanavir taken with food are either 400 mg or 300 mg in combination with low dose ritonavir (100 mg) in moderately antiretroviral-experienced patients. Major advantages of atazanavir to date are its simplicity of administration (once-daily administration) and its less undesirable effect on the lipid profiles in patients.

Interactions between amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus.

OBJECTIVE: This pharmacokinetic study was designed to characterize interactions between amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed. METHODS: Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy. RESULTS: Median amprenavir concentrations decreased by 54% (P =.004) when lopinavir was added to the amprenavir-ritonavir regimen. Lopinavir weakly displaced amprenavir from plasma proteins: The average unbound fraction of amprenavir was 0.089 in week 2 and 0.114 in week 6 (P =.03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (E(max)) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of E(max)) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P =.005). CONCLUSION: Lopinavir markedly decreases the amprenavir concentration during amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure.

Determination of amprenavir total and unbound concentrations in plasma by high-performance liquid chromatography and ultrafiltration.

Amprenavir is an HIV-1 protease inhibitor with high protein binding (90%) in human plasma. This study was designed to develop an assay to measure the concentration of unbound amprenavir, to study variation with time in patients, and to investigate whether ritonavir and lopinavir, other protease inhibitors that could be combined, interact with amprenavir protein binding in vitro. A reverse-phase high-performance liquid chromatography assay to UV detection was developed and validated to measure total amprenavir in plasma, and this method was adapted to quantitate low concentrations of unbound amprenavir in ultrafiltrate aqueous fluid. Equilibrium dialysis and ultrafiltration were used and compared with separate unbound fraction. The latter method was easier to use and was, therefore, subsequently adopted. In 10 patients who received amprenavir 600 mg bid combined with ritonavir, mean amprenavir free-fraction in plasma was 8.6% (range, 4.4-20%). When added to pooled human plasmas at concentrations close to those found in treated patients, the unbound amprenavir fraction was increased in the presence of lopinavir, but remained unaffected by ritonavir. It remains to be seen whether measurement of unbound concentrations, rather than total concentrations, could improve therapeutic drug monitoring.