Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

Wenning, Larissa; Hanley, William D.; Brainard, Diana M.; Petry, Amelia S.; Ghosh, Kalyan; Jin, Bo; Mangin, Eric; Marbury, Thomas; Berg, Jolene Kay; Chodakewitz, Jeffrey A.; Stone, Julie A.; Gottesdiener, Keith; Wagner, John A.; Iwamoto, Marian

doi:10.1128/aac.01468-08

Cited by 154 publications

(110 citation statements)

References 14 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…This interaction was also confirmed in a separate study (43). Efavirenz and rifampin are inducers of UGT1A1 expression (14,40) and have been shown to decrease raltegravir plasma exposure (22,39). Other interactions were reported previously for omeprazole (21) and fosamprenavir (28).…”

supporting

confidence: 65%

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

Moss

Kwan

Liptrott

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM VBL100 , and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM VBL100 , and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The K m and V max for SLC22A6 transport were 150 M and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentrationdependent manner. Raltegravir inhibited 1 M tenofovir with a 50% inhibitory concentration (IC 50 ) of 14.0 M, and tenofovir inhibited 1 M raltegravir with an IC 50 of 27.3 M. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.HIV infection and AIDS continue to be a major cause of worldwide mortality in the 21st century. A UNAIDS/WHO report in 2009 estimated that 33.4 million people worldwide were infected with HIV in 2008, with AIDS-related deaths numbering 2 million. Recent attempts to develop a vaccine for HIV have been largely unsuccessful (18). This, combined with increasing drug resistance, has emphasized the need to develop new drugs with unique mechanisms of action.Raltegravir represents a new class of antiretroviral treatment (8), targeting the HIV-1 integrase enzyme by binding to the active site and preventing viral DNA insertion into the host genome (11). Recent trials have shown raltegravir to have a sustained antiretroviral effect and good tolerability in treatment-experienced HIV-1 patients (33). The primary route of raltegravir metabolism is glucuronidation via UGT1A1, and raltegravir is not a substrate or an inhibitor of the major cytochrome P450 enzymes (19,24). However, the involvement of human drug transporters in raltegravir absorption, disposition, metabolism, and excretion (ADME) has not been fully investigated. Raltegravir has been described as being an ABCB1 substrate (25), but there are no data yet in the public domain. Raltegravir has shown higher concentrations (1.7-fold) in semen (4) and lower concentrations (0.04-to 0.39-fold) in cerebrospinal fl...

show abstract

supporting

confidence: 65%

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

Moss

Kwan

Liptrott

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…For integrase inhibitors and entry inhibitors, studies now indicate that rifampin significantly accelerates the metabolism of raltegravir and maraviroc and results in subtherapeutic levels of the antiretroviral drugs when administered at standard doses (85,258). The use of rifampin with raltegravir or maraviroc should thus be avoided if possible.…”

Section: Rifampin Accelerates Metabolism Of Protease Inhibitors Raltmentioning

confidence: 99%

“…The use of rifampin with raltegravir or maraviroc should thus be avoided if possible. If coadministered with rifampin, the dose of raltegravir or maraviroc must be increased (85,258). Rifabutin has less of an effect on raltegravir metabolism and may be more appropriate for coadministration (30).…”

Section: Rifampin Accelerates Metabolism Of Protease Inhibitors Raltmentioning

confidence: 99%

HIV and Tuberculosis: a Deadly Human Syndemic

2011

View full text Add to dashboard Cite

SUMMARY A syndemic is defined as the convergence of two or more diseases that act synergistically to magnify the burden of disease. The intersection and syndemic interaction between the human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had deadly consequences around the world. Without adequate control of the TB-HIV syndemic, the long-term TB elimination target set for 2050 will not be reached. There is an urgent need for additional resources and novel approaches for the diagnosis, treatment, and prevention of both HIV and TB. Moreover, multidisciplinary approaches that consider HIV and TB together, rather than as separate problems and diseases, will be necessary to prevent further worsening of the HIV-TB syndemic. This review examines current knowledge of the state and impact of the HIV-TB syndemic and reviews the epidemiological, clinical, cellular, and molecular interactions between HIV and TB.

show abstract

“…Rifampicin is an inducer of this enzyme and reduces drug levels of raltegravir [204]. Because the antiviral activity of raltegravir may depend on its AUC, pharmacokinetic data suggests this is maintained if raltegravir dose is doubled when given with rifampicin.…”

Section: Rifamycins and Integrase Inhibitorsmentioning

confidence: 99%

“…Because the antiviral activity of raltegravir may depend on its AUC, pharmacokinetic data suggests this is maintained if raltegravir dose is doubled when given with rifampicin. Normal doses of raltegravir and rifabutin can be used based on data to date [204]. Elvitegravir is metabolised by CYP3A4 and should not be given with rifampicin.…”

Section: Rifamycins and Integrase Inhibitorsmentioning

confidence: 99%

Clinical management of tuberculosis and HIV-1 co-infection

Schutz¹,

Meintjes²,

Almajid³

et al. 2010

Eur Respir J

View full text Add to dashboard Cite

In many parts of the world the commonest serious opportunistic infection that occurs in HIV-1 infected persons is tuberculosis (TB). HIV-1 co-infection modifies the natural history and clinical presentation, and adversely affects the outcome of TB. Severe disseminated disease is well-recognised but it is increasingly appreciated that early disease characterised by very few or no symptoms is also common. Immunodiagnostic methods to ascertain latent TB in HIV-1 infected persons are compromised in sensitivity.Chemoprevention of HIV-1-associated TB is effective, its benefits are restricted to those which have evidence of immune sensitisation and appear short-lived in areas of high TB burden. Although promising advances in the microbiological diagnosis of TB have recently occurred, the diagnosis of HIV-1-associated TB remains difficult because of more frequent presentation as sputum negative or extrapulmonary disease.Management of co-infected patients can be complex because of overlapping drug toxicities and interactions. Nevertheless consensus is developing that antiretroviral therapy should be provided as soon as practicable after starting TB treatment in HIV-1 co-infected persons. This has the consequence of increasing the frequency of immune reconstitution inflammatory syndrome, the pathogenesis and management of which is poorly defined.

show abstract

Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

Cited by 154 publications

References 14 publications

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

Raltegravir Is a Substrate for SLC22A6: a Putative Mechanism for the Interaction between Raltegravir and Tenofovir

HIV and Tuberculosis: a Deadly Human Syndemic

Clinical management of tuberculosis and HIV-1 co-infection

Contact Info

Product

Resources

About