RESUMEN
BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; Pâ=â0.0271) and C24 (-53%; Pâ=â0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
RESUMEN
BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15â days. Plasma and spot urine were collected on Day 15 (0-336â h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90â=â64â ng/mL) and minimum effective concentration (MECâ=â324â ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500â ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0â h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4â ng/mL (22.1-32.7). Tenofovir in urine reached 1500â ng/mL by 101â h (58.6-205) with an equivalent plasma concentration of 6.20â ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500â ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Pruebas en el Punto de Atención , Piridonas , Tenofovir , Humanos , Piridonas/orina , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/orina , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Masculino , Emtricitabina/orina , Emtricitabina/farmacocinética , Emtricitabina/uso terapéutico , Emtricitabina/sangre , Adulto , Piperazinas/orina , Piperazinas/sangre , Lamivudine/orina , Lamivudine/farmacocinética , Lamivudine/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Tenofovir/orina , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Tenofovir/sangre , Fármacos Anti-VIH/orina , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Persona de Mediana Edad , Profilaxis Pre-Exposición/métodos , Adulto Joven , Plasma/química , Cumplimiento de la MedicaciónRESUMEN
Favipiravir is a broad-spectrum antiviral that is metabolised intracellularly into the active form, favipiravir ribofuranosyl-5'-triphosphate (F-RTP). Measurement of the intracellular concentration of F-RTP in mononuclear cells is a crucial step to characterising the pharmacokinetics of F-RTP and to enable more appropriate dose selection for the treatment of COVID-19 and emerging infectious diseases. The described method was validated over the range 24 - 2280 pmol/sample. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and lysed using methanol-water (70:30, v/v) before cellular components were precipitated with acetonitrile and the supernatant further cleaned by weak anion exchange solid phase extraction. The method was found to be both precise and accurate and was successfully utilised to analyse F-RTP concentrations in patient samples collected as part of the AGILE CST-6 clinical trial.
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Amidas , Antivirales , Leucocitos Mononucleares , Pirazinas , Humanos , Amidas/química , Antivirales/farmacocinética , Antivirales/análisis , COVID-19 , Tratamiento Farmacológico de COVID-19 , Leucocitos Mononucleares/metabolismo , Cromatografía Líquida con Espectrometría de Masas , Pirazinas/farmacocinética , Pirazinas/análisis , Reproducibilidad de los Resultados , SARS-CoV-2/efectos de los fármacos , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
Background: A rapid and sensitive LC-MS method has been developed and validated for the quantification of nucleoside di/triphosphates using a novel plasma separation card (HemaSep). Materials & methods: Cards were spotted with whole blood and stored at -80°C. Metabolites were extracted using 70:30 MeOH:20% formic acid, followed by weak anion exchange SPE and eluted using a Biobasic-AX column. Quantification was performed using a triple quadrupole mass spectrometer with a calibration range of 1.25-250 pmol/sample. Results: The recovery of metabolites was high (>93%). Precision and accuracy were acceptable and metabolites remained stable on the card after 29 days (stored at ambient temperature). Conclusion: HemaSep dried blood spots are a useful microsampling tool and offer an alternative to liquid plasma as they maintain stability over time.
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Nucleósidos , Inhibidores de la Transcriptasa Inversa , Cromatografía Liquida/métodos , Nucleótidos , Espectrometría de Masas en Tándem/métodos , Pruebas con Sangre Seca/métodos , Reproducibilidad de los ResultadosRESUMEN
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.
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Antivirales/administración & dosificación , Nitrocompuestos/administración & dosificación , Nitrocompuestos/efectos adversos , Nitrocompuestos/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Reposicionamiento de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. METHODS: Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. RESULTS: One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. CONCLUSIONS: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.
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Antituberculosos , Tuberculosis , Antituberculosos/uso terapéutico , Teorema de Bayes , Etambutol , Humanos , Isoniazida , Pirazinamida , Tuberculosis/tratamiento farmacológicoRESUMEN
A high-performance liquid chromatography tandem mass spectrometric method was developed and validated for cenicriviroc (CVC) quantification in human plasma and cerebrospinal fluid (CSF). The method involved precipitation with acetonitrile and injecting supernatants onto the column. Separation was achieved on an XBridge C18 column with a gradient elution of 0.1% formic acid in water and acetonitrile. Analyte detection was conducted in positive ion mode using selected reaction monitoring. The m/z transitions were: CVC (697.3 â 574.3) and CVC-d7 (704.4 â 574.3). Calibration curve ranged from 5 to 1000 ng/mL for plasma and from 0.241 to 15.0 ng/mL for CSF. The intra- and inter-day precision and accuracy were <15% for both plasma and CSF across four different concentrations. CVC recovery from plasma and artificial CSF was >90%. The method was utilized for the measurement of patients' plasma and CSF samples taking a dose of 50, 150 and 300 mg q.d.
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Cromatografía Liquida/métodos , Imidazoles/sangre , Imidazoles/líquido cefalorraquídeo , Espectrometría de Masas en Tándem/métodos , Estabilidad de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Humanos , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Límite de Detección , Reproducibilidad de los Resultados , SulfóxidosAsunto(s)
Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5/administración & dosificación , Disfunción Cognitiva/tratamiento farmacológico , Infecciones por VIH/complicaciones , Imidazoles/farmacocinética , Fármacos Anti-VIH/líquido cefalorraquídeo , Fármacos Anti-VIH/uso terapéutico , Cognición/efectos de los fármacos , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Imidazoles/líquido cefalorraquídeo , Imidazoles/uso terapéutico , ARN Viral/líquido cefalorraquídeo , SulfóxidosRESUMEN
BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879.
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Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Benzoxazinas/uso terapéutico , Anticonceptivos Femeninos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Levonorgestrel/farmacocinética , Embarazo no Planeado , Adolescente , Adulto , Alquinos , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Femeninos/efectos adversos , Anticonceptivos Femeninos/sangre , Ciclopropanos , Interacciones Farmacológicas , Femenino , Infecciones por VIH/etnología , VIH-1/efectos de los fármacos , Humanos , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Levonorgestrel/sangre , Nevirapina/uso terapéutico , Embarazo , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Factores de Tiempo , UgandaRESUMEN
HCV infection affects over 170 milions people in the world. Up to now standard-of-care therapy consisted in ribavirin plus interferon-α 2a or 2b. Recently, two new Direct Acting Antivirals (DAA), inhibitors of NS3 HCV protease, have been developed and approved for the routine use on HCV genotype 1 infected patients: boceprevir and telaprevir. Protease inhibitors show complex pharmacokinetics (strong metabolism of both drugs by CYP3A and drug interactions), they require a TID dosage and, furthermore, they are present in plasma patients in two different isomeric forms. In this work, we developed and validated an UPLC-tandem mass spectrometry assay method capable of monitoring the telaprevir and boceprevir concentrations in plasma, discriminating each isomer of both drugs. Blank plasma used for Standards and QCs preparation, was obtained from blood of healthy donors. The calibration curves for each isomer of telaprevir and boceprevir were linear in a range from 46.87 ng/mL to 6000 ng/mL and from 23.43 to 3000 ng/mL, respectively (mean r(2)>0.998 for all analytes). QCs at three different concentration were prepared: High, Medium and Low. Each Standard, QC and patient sample was treated with a protein precipitation protocol with a solution containing acidified acetonitrile and Internal Standard (6,7-Dimethyl-2,3-di(2-pyridyl)quinoxaline). An aliquot of supernatant was diluted and then directly analyzed by reverse-phase UPLC-MS/MS. Accuracy (mean 98.47%), intra-day (mean <5.21%) and inter-day (mean <7.57%) precision for telaprevir and boceprevir quality controls fitted all FDA guidelines. All compounds resulted stable in our method conditions and the extraction procedure showed a recovery near to 100%. Finally, we tested this method by monitoring plasma concentrations in 9 HCV+ patients, for each triple combined therapy, with good results. The observed median ratio between S and R isomers for boceprevir and telaprevir were 1.22 (IQR 1.10-1.33) and 1.52 (IQR 1.21-1.67), respectively. The use of this simple assay method could be an important tool for management of HCV-1 DAAs treated patients.