High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets

Nijland, Hanneke M. J.; L'homme, Rafaëlla F. A.; Rongen, Gerard A.; Uden, P. van; Crevel, Reinout van; Boeree, Martin J.; Aarnoutse, Rob E.; Koopmans, P.P.; Burger, David M.

doi:10.1097/qad.0b013e3282faa71e

Cited by 93 publications

(73 citation statements)

References 19 publications

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“…These safety findings were attributed to efavirenz, a CYP3A inducer, as coadministration of the 3D regimen with emtricitabine and tenofovir DF was well tolerated in healthy volunteers. Similar safety findings were observed when the CYP3A inducer rifampin or efavirenz was coadministered with ritonavir-boosted protease inhibitors such as lopinavir and saquinavir in healthy volunteers (28)(29)(30). Patients treated with these therapy combinations reported AEs consistent with our observations, including abdominal symptoms and transaminase elevations.…”

Section: Discussionsupporting

confidence: 88%

Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Khatri

Dutta

Dunbar

et al. 2016

Antimicrob Agents Chemother

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The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n ‫؍‬ 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (<32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen.

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Section: Discussionsupporting

confidence: 88%

Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Khatri

Dutta

Dunbar

et al. 2016

Antimicrob Agents Chemother

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“…These high rates of hepatotoxicity in healthy volunteers might not apply to patients with tuberculosis and HIV. First, in the healthy-volunteer studies, initiating rifampin prior to the protease inhibitor was associated with high rates of hepatotoxicity (6,7,16). In high-burden countries, protease inhibitors are used as part of the second-line antiretroviral treatment (ART) regimen; hence, most patients are established on the protease inhibitor before rifampin is initiated.…”

mentioning

confidence: 99%

“…Subsequent healthy-volunteer studies of the interaction between rifampin and adjusted doses of ritonavir-boosted saquinavir, atazanavir, and lopinavir (tablet formulation) were prematurely terminated because of high incidences of hepatotoxicity (6,7,16). These high rates of hepatotoxicity in healthy volunteers might not apply to patients with tuberculosis and HIV.…”

mentioning

confidence: 99%

Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets

Decloedt

McIlleron

Smith

et al. 2011

Antimicrob Agents Chemother

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Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C 0 ) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC 0-12 ), C 0 , C 12 , maximum concentration of drug in serum (C max ), or half-life (t 1/2 ) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies.Rifampin is a key component of tuberculosis treatment but also a potent inducer of many cytochrome P450 enzymes and the efflux pump p-glycoprotein (15). Protease inhibitors are substrates of both CYP 3A4 and p-glycoprotein, and the trough concentrations of all ritonavir-boosted protease inhibitors are reduced by more than 90% when standard doses are coadministered with rifampin (2). A healthy-volunteer study demonstrated that similar lopinavir (LPV) trough concentrations can be achieved either by adding ritonavir (RTV) to give a lopinavir/ritonavir ratio of 1:1 or by doubling the dose of the capsule formulation of lopinavir-ritonavir (LPV/r) (12).Subsequent healthy-volunteer studies of the interaction between rifampin and adjusted doses of ritonavir-boosted saquinavir, atazanavir, and lopinavir (tablet formulation) were prematurely terminated because of high incidences of hepatotoxicity (6, 7, 16). These high rates of hepatotoxicity in healthy volunteers might not apply to patients with tuberculosis and HIV. First, in the healthy-volunteer studies, initiating rifampin prior to the protease inhibitor was associated with high rates of hepatotoxicity (6,7,16). In high-burden countries, protease inhibitors are used as part of the second-line antiretroviral treatment (ART) regimen; hence, most patients are established on the protea...

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“…However, high rates of elevated transaminases, lipid changes and gastrointestinal toxicity were observed [187]. A pharmacokinetic study in healthy volunteers of such a strategy was terminated early because of high rates of severe increase of liver enzymes/transaminases [188]. Another strategy is to double the dose of lopinavir/ritonavir which also overcomes the effect of rifampicin induction [187].…”

Section: Lopinavir/ritonavirmentioning

confidence: 99%

“…This is done by either adding high-dose ritonavir (additional 300 mg every 12 h) to lopinavir/ritonavir combination or by doubling the lopinavir/ritonavir dose to overcome the induction by rifampicin. In healthy volunteer and patient studies, high rates of hepatic events and gastro-intestinal intolerance have been reported with such strategies and patients should be carefully monitored for the development of jaundice or hepatitis [188,198]. Quadruple nucleosides are also a possibility as ART.…”

Section: Pi and Rifamycins: What To Do?mentioning

confidence: 99%

Clinical management of tuberculosis and HIV-1 co-infection

Schutz¹,

Meintjes²,

Almajid³

et al. 2010

Eur Respir J

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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.

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High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets

Cited by 93 publications

References 19 publications

Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets

Clinical management of tuberculosis and HIV-1 co-infection

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