RESUMEN
Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging properties and to adequately monitor susceptible patients.
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Síndrome de QT Prolongado , Torsades de Pointes , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/complicaciones , Síndrome de QT Prolongado/diagnóstico , Factores de Riesgo , Torsades de Pointes/inducido químicamenteRESUMEN
ABSTRACT: This therapeutic drug monitoring (TDM) grand round describes a patient with serious valproic acid intoxication. A total valproic acid level of 844 mg/L and an unbound valproic acid level of 604 mg/L were observed. Meropenem was administered to enhance the clearance of valproic acid. This off-label usage of meropenem is based on the drug-drug interaction between carbapenems and valproic acid, which reduced the level of valproic acid within 24 hours after administration.
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Anticonvulsivantes , Ácido Valproico , Antibacterianos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Interacciones Farmacológicas , Humanos , Meropenem/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
Tenofovir disoproxil fumarate (TDF) is recommended as part of antiretroviral therapy (ART) for pregnant women with HIV and as monotherapy for pregnant women with hepatitis B virus (HBV) monoinfection at high risk of transmitting infection to their infants. Tenofovir (TFV) plasma exposures are reduced during pregnancy; however, concomitant antiretrovirals and the viral infection itself can also influence TFV pharmacokinetics. Our aim was to compare TFV pharmacokinetics in pregnant women receiving TDF-based ART, with or without a ritonavir-boosted protease inhibitor (r/PI), to pregnant women with HBV receiving TDF monotherapy. Non-r/PI regimens were primarily integrase strand transfer inhibitors or nonnucleoside reverse transcriptase inhibitor-based regimens. Data were combined from a pharmacokinetic study of pregnant women with HIV on ART (PANNA), and a study assessing TFV pharmacokinetics in pregnant women with HBV (iTAP). A total of 196 pregnant women, 59 with HIV (32 receiving r/PIs) and 137 with HBV monoinfection were included. Intraindividual TFV area under the plasma concentration-time curve from time 0 to 24 hours was 25%, 26%, and 21% lower during the third trimester compared to 1 month postpartum in women with HIV using TDF and an r/PI or TDF and non-r/PI and women with HBV receiving TDF monotherapy, respectively. TFV area under the plasma concentration-time curve from time 0 to 24 hours was similar in pregnant women receiving non-r/PI to pregnant women with HBV receiving TDF monotherapy (1.84 vs 1.86 µg ⢠h/mL); however, pregnant women receiving TDF with an r/PI had higher exposures (2.41 µg ⢠h/mL; P < .01). Pregnancy reduces TFV exposure and the relative size was not impacted by concomitant antiretroviral drugs or viral infection, but a drug-drug interaction between TDF and r/PI remains during pregnancy, leading to higher exposures than those on TDF and non-r/PI or TDF monotherapy.
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Infecciones por VIH/tratamiento farmacológico , Hepatitis B/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Tenofovir/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Área Bajo la Curva , Interacciones Farmacológicas , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Periodo Posparto , Embarazo , Complicaciones Infecciosas del Embarazo/virología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/farmacocinética , Tenofovir/administración & dosificación , Adulto JovenRESUMEN
INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.
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Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos/métodos , Enfermedades Renales/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Alanina/administración & dosificación , Alanina/análogos & derivados , COVID-19/diagnóstico , COVID-19/epidemiología , Ensayos Clínicos como Asunto/métodos , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Hidroxicloroquina/administración & dosificación , Enfermedades Renales/diagnóstico , Enfermedades Renales/epidemiología , Hepatopatías/diagnóstico , Hepatopatías/epidemiologíaRESUMEN
Since the beginning of the outbreak of severe acute respiratory syndrome (SARS) coronavirus (CoV) 2, lopinavir/ritonavir was selected for treatment. The recent publication of Cao et al. in the New England Journal of Medicine showed that lopinavir/ritonavir treatment did not accelerate clinical improvement compared with standard of care. This raised the question of whether in retrospect we could have known this. The aim of this paper is to gather all the available evidence and to comprehensively discuss this issue.
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Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Lopinavir/administración & dosificación , Ritonavir/administración & dosificación , SARS-CoV-2 , Quimioterapia Combinada , HumanosRESUMEN
AIMS: Vancomycin is an important antibiotic for critically ill patients with Gram-positive bacterial infections. Critically ill patients typically have severely altered pathophysiology, which leads to inefficacy or toxicity. Model-informed precision dosing may aid in optimizing the dose, but prospectively validated tools are not available for this drug in these patients. We aimed to prospectively validate a population pharmacokinetic model for purpose model-informed precision dosing of vancomycin in critically ill patients. METHODS: We first performed a systematic evaluation of various models on retrospectively collected pharmacokinetic data in critically ill patients and then selected the best performing model. This model was implemented in the Insight Rx clinical decision support tool and prospectively validated in a multicentre study in critically ill patients. The predictive performance was obtained as mean prediction error and relative root mean squared error. RESULTS: We identified 5 suitable population pharmacokinetic models. The most suitable model was carried forward to a prospective validation. We found in a prospective multicentre study that the selected model could accurately and precisely predict the vancomycin pharmacokinetics based on a previous measurement, with a mean prediction error and relative root mean squared error of respectively 8.84% (95% confidence interval 5.72-11.96%) and 19.8% (95% confidence interval 17.47-22.13%). CONCLUSION: Using a systematic approach, with a retrospective evaluation and prospective verification we showed the suitability of a model to predict vancomycin pharmacokinetics for purposes of model-informed precision dosing in clinical practice. The presented methodology may serve a generic approach for evaluation of pharmacometric models for the use of model-informed precision dosing in the clinic.
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Antibacterianos , Cuidados Críticos , Vancomicina , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Enfermedad Crítica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Vancomicina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Treatment of hepatitis B virus (HBV) infection with current therapy suppresses HBV DNA, but loss of hepatitis B surface antigen (HBsAg; functional cure), is rare. Multiple compounds are under investigation. AIMS: To describe the pharmacology, including drug interactions, efficacy, safety and mechanisms of action of investigational compounds for HBV infection. METHODS: Descriptive review using PubMed and Google to identify literature/conference papers on investigational compounds (≥Phase 2) with data on efficacy and safety in HBV-infected patients. RESULTS: Bulevirtide, JNJ-56136379, ABI-H0731, REP-2139, and inarigivir decrease HBV DNA/RNA, with greater potency than current nucleos(t)ide analogues. REP-2139 (25%-75% of patients, 20-48 weeks treatment) and inarigivir (26% of patients, 12-24 weeks treatment) induce HBsAg loss. ARO-HBV reduced (>1.5 log10 UI/mL) HBsAg in 85% of patients (12 weeks treatment). There are some safety concerns with investigational agents (e.g., increased bile acids with bulevirtide, and liver enzyme flares with REP-2139) which will require a risk benefit assessment compared with current therapies. Single and multidose pharmacokinetic data are available for bulevirtide, JNJ-56136379, ABI-H0731; no such data are available for REP-2139, ARO-HBV, inarigivir. Initial drug interaction assessments have been performed with bulevirtide and inarigivir (only in vitro). CONCLUSIONS: There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk-benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging.
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Antivirales/uso terapéutico , Hepatitis B/terapia , Terapias en Investigación/métodos , Terapias en Investigación/tendencias , Hepatitis B/epidemiología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/terapia , Humanos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Ácidos Nucleicos/uso terapéutico , Polímeros/uso terapéutico , Resultado del TratamientoRESUMEN
A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was successfully treating her Crohn's disease. We measured MP and its metabolites in plasma and breast milk and found after 4 hours of intake of MP, no MP or its metabolites in breast milk. We concluded that 4 hours after intake of MP, no exposure of the suckling infant to MP and its metabolites was found while being breastfed.
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Lactancia Materna , Enfermedad de Crohn/tratamiento farmacológico , Lactancia , Mercaptopurina/sangre , Leche Humana/química , Adulto , Femenino , Humanos , Lactante , Mercaptopurina/administración & dosificación , Leche Humana/metabolismo , EmbarazoRESUMEN
BACKGROUND: Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple antiretrovirals (ARVs) for PMCT-HIV in resource-constrained settings. METHODS: This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as monotherapy or in combination with other ARVs: irrespective of the reason for receiving the drug (for example, HIV, HBV or pre-exposure prophylaxis); and reported pharmacokinetics. RESULTS: The area under the concentration-time curve (AUC), maximum plasma concentrations (Cmax) and last measurable plasma concentration (Clast) of TFV were decreased in the second and third trimester compared with first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of Cmax of 300 ng/ml reached, but the 50% effective concentration (EC50) of TFV is lower for treatment of HBV compared with HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose. CONCLUSIONS: Most knowledge of pharmacokinetics of TFV in pregnancy results from studies on HIV involving multiple ARVs. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the pharmacokinetics of TFV monotherapy and hepatitis B pharmacodynamics in pregnancy.
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Antivirales/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lactancia , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Tenofovir/farmacocinética , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Femenino , VIH-1 , Humanos , Embarazo , Tenofovir/administración & dosificación , Tenofovir/uso terapéuticoRESUMEN
It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug-drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.
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Antivirales/farmacocinética , Hepatitis C/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Interacciones Farmacológicas , Hepatitis C/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1ß but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.
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Interacciones Huésped-Patógeno/efectos de los fármacos , Hipoglucemiantes/farmacología , Metformina/farmacología , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/metabolismo , Tuberculosis/microbiología , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Voluntarios Sanos , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/microbiología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Fagocitosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug-drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (ß-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.
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Antivirales/farmacocinética , Fármacos Cardiovasculares/farmacocinética , Enfermedades Cardiovasculares/metabolismo , Hepatitis C/metabolismo , Antivirales/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Interacciones Farmacológicas , Quimioterapia Combinada , Hepatitis C/tratamiento farmacológico , Humanos , RiesgoRESUMEN
Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (Ctrough) was determined. The simeprevir area under the-concentration time curve (AUClast) and Ctrough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and Ctrough was 0.532 mg/L. Sofosbuvir AUClast and Ctrough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUClast and Ctrough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment.
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Antivirales/farmacocinética , Derivación Gástrica , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Obesidad/cirugía , Ribavirina/farmacocinética , Simeprevir/farmacocinética , Sofosbuvir/farmacocinética , Antivirales/administración & dosificación , Índice de Masa Corporal , Quimioterapia Combinada , Ingestión de Alimentos , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/virología , Humanos , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/fisiopatología , Ribavirina/administración & dosificación , Simeprevir/administración & dosificación , Sofosbuvir/administración & dosificación , Resultado del Tratamiento , Pérdida de PesoRESUMEN
BACKGROUND: To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct-acting antivirals (DAAs) against HCV. METHODS: This is a retrospective, cross-sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available. RESULTS: We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir ± dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART. CONCLUSIONS: This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART.
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Antirretrovirales/uso terapéutico , Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Amidas , Benzofuranos/uso terapéutico , Carbamatos , Terapia Combinada , Estudios Transversales , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada , VIH/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/uso terapéutico , Persona de Mediana Edad , Quinoxalinas/uso terapéutico , Estudios Retrospectivos , Ritonavir/uso terapéutico , Sulfonamidas , Adulto JovenRESUMEN
BACKGROUND: Direct-acting antivirals have improved treatment of chronic hepatitis C virus infection significantly. Direct-acting antivirals inhibit/induce and can also be substrates of drug-metabolising enzymes and transporters. This increases the risk for drug-drug interactions. OBJECTIVE: The purpose of this study was to predict drug-drug interactions with co-medication used by hepatitis C virus-infected patients. METHODS: We assembled a nationwide cohort of hepatitis C patients and collected cross-sectional data on co-medication use. We compiled a list of currently available direct-acting antiviral regimens and cross-checked for potential drug-drug interactions with used co-medication. RESULTS: The cohort included 461 patients of which 77% used co-medication. We identified 260 drugs used as co-medication. Antidepressants (7.4%), proton pump inhibitors (7.1%) and benzodiazepines (7.1%) were most frequently used. Of the patients, 60% were at risk for a clinically relevant drug-drug interaction with at least one of the direct-acting antiviral regimens. Interactions were most common with paritaprevir/ritonavir/ombitasvir/dasabuvir and least interactions were predicted with grazoprevir/elbasvir. CONCLUSION: Co-medication use is rich in frequency and diversity in chronic hepatitis C patients. The majority of patients are at risk for drug-drug interactions which may affect efficacy or toxicity of direct-acting antivirals or co-medication. The most recently introduced direct-acting antivirals are associated with a lower risk of drug-drug interactions.
RESUMEN
AIM: The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS: This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS: The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.