Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-<i>O</i>-Desacetyl-Rifabutin in Healthy Subjects

Vourvahis, Manoli; Davis, John D.; Wang, Rong; Layton, Gary; Choo, Heng Wee; Chong, Chew Lan; Tawadrous, Margaret

doi:10.1128/aac.06282-11

Cited by 16 publications

(6 citation statements)

References 29 publications

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“…Conversely, rifabutin significantly reduces lersivirine half-life and steady-state plasma concentrations when administered in combination. These effects are enhanced following steady-state rifampin coadministration (20), similar to effects on bedaquiline pharmacokinetics seen here in the rifampin treatment group.…”

Section: Discussionsupporting

confidence: 74%

“…Steady-state rifampin during period 2 reduced overall exposure (AUC 0 -336 ) of bedaquiline by nearly half and increased apparent clearance 76%, compared to period 1 values within the same treatment group (Table 4). This is similar to reduced antiviral exposure seen when rifampin is coadministered with other CYP3A4 substrates, including amprenavir (19), efavirenz (9), and lersivirine (20). Winter et al (21), reported that the bedaquiline C max and AUC were reduced by approximately 58% in healthy subjects following a single 400-mg dose of bedaquiline combined with steady-state rifapentine or rifampin (22 days of 600-mg daily dosing) compared to a single 400-mg dose of bedaquiline alone.…”

Section: Discussionmentioning

confidence: 56%

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Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Healan

Griffiss

Proskin³

et al. 2018

Antimicrob Agents Chemother

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Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, = 17) or rifampin (600 mg/day, = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.).

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 56%

Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Healan

Griffiss

Proskin³

et al. 2018

Antimicrob Agents Chemother

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“…Another experimental study, which evaluated the antiviral inhibitors against SARS-CoV-2, has confirmed that GC376 in combination with the nucleoside analog, Remdesivir, completely inhibited the replication mechanism in SARS-CoV-2 infected cells [53] . Similarly, Rifabutin, which is a first-line anti-tuberculosis drug, has demonstrated remarkable clinical efficacy by inhibiting RNA polymerase and has been used as an alternative drug among HIV patients co-infected with tuberculosis as reported by a clinical trial experimental study [54] . Likewise, the findings of another experimental study have suggested that Umifenovir and its analog to be promising antiviral agents as it showed direct inhibitory effect on the SARS-infected cells by disrupting the early viral replication [55] .…”

Section: Resultsmentioning

confidence: 99%

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

Gangadharan

Ambrose²,

Rajajagadeesan³

et al. 2022

Journal of Infection and Public Health

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“…Before running DDIs simulations, the drug models for the strong inducer rifampicin [ 18–20 ] and the moderate inducer rifabutin [ 21 , 22 ] were developed and their predictive performance verified against clinically observed data. The drug parameters used to develop the models are detailed in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Management of Drug-Drug Interactions Between Long-Acting Cabotegravir and Rilpivirine and Comedications With Inducing Properties: A Modeling Study

Bettonte

Berton

Stader³

et al. 2022

Clinical Infectious Diseases

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Background Long-acting (LA) intramuscular cabotegravir and rilpivirine are prone to drug-drug interactions (DDI). However, given the long dosing interval, the conduct of clinical DDIs studies with LA antiretrovirals is challenging. We performed virtual clinical DDI studies using physiologically based pharmacokinetic (PBPK) modelling to provide recommendations for the management of DDIs with strong or moderate inducers such as rifampicin or rifabutin. Methods Each DDI scenario included a cohort of virtual individuals (50% female) between 20-50 years of age with a body mass index of 18-30 kg/m2. Cabotegravir and rilpivirine were given alone and in combination with rifampicin or rifabutin. The predictive performance of the PBPK model to simulate cabotegravir and rilpivirine pharmacokinetics after oral and intramuscular administration and to reproduce DDIs with rifampicin and rifabutin was first verified against available observed clinical data. The verified model was subsequently used to simulate unstudied DDI scenarios. Results At steady-state, the strong inducer rifampicin was predicted to decrease the area under the curve (AUC) of LA cabotegravir by 61% and rilpivirine by 38%. An increase in the dosing frequency did not overcome the DDI with rifampicin. The moderate inducer rifabutin was predicted to reduce the AUC of LA cabotegravir by 16% and rilpivirine by 18%. The DDI with rifabutin can be overcome by administering LA cabotegravir/rilpivirine monthly together with a daily oral rilpivirine dose of 25 mg. Conclusion LA cabotegravir/rilpivirine should be avoided with strong inducers but coadministration with moderate inducers is possible by adding oral rilpivirine daily dosing to the monthly injection.

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Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

Cited by 16 publications

References 29 publications

Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

Management of Drug-Drug Interactions Between Long-Acting Cabotegravir and Rilpivirine and Comedications With Inducing Properties: A Modeling Study

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