Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters

Reznicek, Josef; Čečková, Martina; Červený, Lukáš; Müller, Fabian; Štaud, František

doi:10.3109/00498254.2016.1158886

Cited by 28 publications

(16 citation statements)

References 45 publications

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“…In the kidney, TDF is mainly transported by OAT1 and MRP4 [49–52]. Lamivudine is a substrate of OCT2, MATE1 and MATE-K [53–55] and FTC is a substrate of MATE1 [56, 57]. Any change in the expression or activity of these transporters could influence the renal clearance of the drugs.…”

Section: Discussionmentioning

confidence: 99%

Are Standard Doses of Renally-Excreted Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment

Mendes

Chetty

2019

Drugs R D

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Background and ObjectivesThe elderly population receives the majority of prescription drugs but are usually excluded from Phase 1 clinical trials. Alternative approaches to estimate increases in toxicity risk or decreases in efficacy are therefore needed. This study predicted the pharmacokinetics (PK) of three renally excreted antiretroviral drugs in the elderly population and compared them with known exposures in renal impairment, to evaluate the need for dosing adjustments.MethodsThe performance of the physiologically based pharmacokinetic (PBPK) models for tenofovir, lamivudine and emtricitabine were verified using clinical data in young and older subjects. Models were then used to predict PK profiles in a virtual population aged 20 to 49 years (young) and a geriatric population aged 65 to 74 years (elderly). Predicted exposure in the elderly was then compared with exposure reported for different degrees of renal impairment, where doses have been defined.ResultsAn increase in exposure (AUC) with advancing age was predicted for all drugs. The mean ratio of the increase in exposure were 1.40 for emtricitabine, 1.42 for lamivudine and 1.48 for tenofovir. The majority of virtual patients had exposures that did not require dosage adjustments. About 22% of patients on tenofovir showed exposures similar to that in moderate renal impairment, where dosage reduction may be required.ConclusionComparison of the exposure in the elderly with exposure observed in patients with different levels of renal impairment, indicated that a dosage adjustment may not be required in elderly patients on lamivudine, emtricitabine and the majority of the patients on tenofovir. Clinical trials to verify these predictions are essential.

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Section: Discussionmentioning

confidence: 99%

Are Standard Doses of Renally-Excreted Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment

Mendes

Chetty

2019

Drugs R D

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“…Emtricitabine is a substrate of the MATE1 transporter in the kidney 43 and potentially SCL47A1 rs2289669 G>A could reduce function or expression of MATE1. 44 The polymorphism has been linked to response to metformin in patients with type-2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial

Dickinson

Gurjar

Stöhr

et al. 2019

Journal of Antimicrobial Chemotherapy

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Objectives NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. Methods Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0–24 and C24 with time to virological failure was evaluated by Cox regression. Results Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0–24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53–9.80), P=0.269; and 1.82 (0.61–5.41), P=0.279, respectively]. Conclusions Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

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“…Many antiretroviral drugs commonly used in cART are substrates or inhibitors of ABC (ATP-dependent) and/or SLC (solute carrier) drug transporters (6)(7)(8)(9). Their coadministration with other compounds interacting with these transporters can lead to pharmacokinetic drug-drug interactions (DDIs) and to altered plasma and tissue concentrations of the target drug.…”

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confidence: 99%

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption

Reznicek

Čečková

Ptackova

et al. 2017

Antimicrob Agents Chemother

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Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo. Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1-and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.KEYWORDS drug transporter, rilpivirine, abacavir, oral bioavailability, pharmacokinetics, drug-drug interactions, ABC transporters R ilpivirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA (in 2011) and the European Medicines Agency (EMA; in 2012) (1, 2) for treatment of antiretroviral therapy-naive patients (3, 4). In addition, rilpivirine shows fewer adverse effects than efavirenz and represents an important component of combination antiretroviral therapy (cART), particularly in the treatment of HIV-1-infected patients with viral loads of less than 100,000 copies/ml (5).Many antiretroviral drugs commonly used in cART are substrates or inhibitors of ABC (ATP-dependent) and/or SLC (solute carrier) drug transporters (6-9). Their coadministration with other compounds interacting with these transporters can lead to pharmacokinetic drug-drug interactions (DDIs) and to altered plasma and tissue concentrations of the target drug.P-glycoprotein (ABCB1/MDR1) (10, 11), breast cancer resistance protein (ABCG2/ BCRP) (12), and multidrug resistance-associated protein 2 (ABCC2/MRP2) (13) are well-described members of ATP-binding cassette (ABC) drug transporters that are functionally expressed in the small intestine, blood-tissue barriers, and excretory organs (14-17). Together with organic cation transporters (OCTs; SLC22A) of the SLC super-

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Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters

Cited by 28 publications

References 45 publications

Are Standard Doses of Renally-Excreted Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment

Are Standard Doses of Renally-Excreted Antiretrovirals in Older Patients Appropriate: A PBPK Study Comparing Exposures in the Elderly Population With Those in Renal Impairment

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption

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