ABSTRACT
BACKGROUND: Bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination (BIC/FTC/TAF 50/200/25 mg) is recommended as an initial regimen in patients who are antiretroviral (ARV)-naïve or virologically suppressed on a stable ARV regimen. However, no real-world pharmacokinetic (PK) data are available in treatment-experienced patients with antiretroviral resistance receiving BIC/FTC/TAF plus a boosted protease inhibitor. SETTING/METHODS: This prospective, single-center, nonrandomized pharmacokinetic study enrolled adult treatment-experienced persons with HIV and creatinine clearance >30 mL/min receiving BIC/FTC/TAF + DRV/c as part of routine clinical care. Steady-state PK profiles of BIC, TAF, tenofovir (TFV), and DRV after daily dosing of BIC/FTC/TAF + darunavir/cobicistat (DRV/c) were obtained with samples at predose and 0.5, 1, 2, and 4 hours postdose. The AUC0-24 at steady state was extrapolated by imputing C0 for C24 for each participant (AUC0-tau,exp). RESULTS: Nine participants were enrolled with a median age of 59 years (range 54-67) and median number of years on ART of 19 (range 5.8-30). The median (interquartile range [IQR]) BIC AUC0-tau,exp and Cmax values were 128.9 µg*h/mL (78.1-159.5) and 6.9 µg/mL (5.1-9.8), respectively. The median (IQR) TAF AUC0-tau,exp and Cmax values were 0.376 µg*h/mL (0.199-0.430) and 0.276 µg/mL (0.149-0.543), respectively. Predose concentrations of TFV and DRV were comparable with historical data. CONCLUSION: Treatment-experienced persons with HIV receiving BIC/FTC/TAF + darunavir/cobicistat (DRV/c) had BIC exposures (AUC0-tau) that were increased by approximately 26% compared with historical PK data. Although TAF exposures were substantially increased, plasma TFV was only modestly higher. These results suggest that BIC/TAF/FTC + DRV/c is a viable antiviral regimen option for treatment-experienced persons.
Subject(s)
Amides/pharmacokinetics , Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Piperazines/pharmacokinetics , Pyridones/pharmacokinetics , Tenofovir/pharmacokinetics , Aged , Amides/blood , Anti-HIV Agents/blood , Antiretroviral Therapy, Highly Active/methods , Chromatography, Liquid , Cobicistat/blood , Darunavir/blood , Female , Heterocyclic Compounds, 3-Ring/blood , Humans , Male , Middle Aged , Piperazines/blood , Prospective Studies , Pyridones/blood , Tandem Mass Spectrometry , Tenofovir/bloodABSTRACT
A sensitive and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for 14 antiretroviral drugs and 2 boosters in human plasma. Plasma (100⯵L) was precipitated with a solution of acetonitrile containing labelled internal standards. The compounds were separated with a total chromatic run time of 6â¯min using an Acclaim TM RSLC 120 C18 column (2.1â¯×â¯100â¯mm, 2.2⯵m). The method was fully validated according to the European Medecines Agency guidelines. Linearity of all analytes concentrations was validated up to 5000â¯ng/mL. Lower limits of quantification were ranged from 2.5â¯ng/mL to 10â¯ng/mL according to compounds. Intra-day and inter-day precision ranged from 0.2% to 8.9% and accuracies were below 13%. This UPLC-MS/MS method can be applied to clinical pharmacology research and therapeutic drug monitoring in patients living with HIV.
Subject(s)
Anti-Retroviral Agents/isolation & purification , Drug Monitoring/methods , HIV Infections/drug therapy , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Amides , Anti-Retroviral Agents/blood , Anti-Retroviral Agents/therapeutic use , Chromatography, High Pressure Liquid/methods , Cobicistat/blood , Cobicistat/isolation & purification , Cobicistat/therapeutic use , HIV Infections/blood , Heterocyclic Compounds, 3-Ring , Heterocyclic Compounds, 4 or More Rings/blood , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Limit of Detection , Piperazines , Pyridones , Reproducibility of Results , Ritonavir/blood , Ritonavir/isolation & purification , Ritonavir/therapeutic use , Tandem Mass Spectrometry/methodsABSTRACT
Objectives: To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods: Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results: Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions: Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Pyridazines/pharmacokinetics , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/blood , Cobicistat/administration & dosage , Cobicistat/blood , Cohort Studies , Darunavir/administration & dosage , Darunavir/blood , Drug Therapy, Combination , Female , HIV/drug effects , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/blood , Humans , Male , Middle Aged , Nitriles , Pyridazines/administration & dosage , Pyridazines/blood , Pyrimidines , RNA, Viral/blood , Young AdultABSTRACT
Objectives: Cobicistat and ritonavir have different inhibitory profiles for drug transporters that could impact the distribution of co-administered drugs. We compared darunavir concentrations in CSF when boosted by cobicistat versus ritonavir relative to plasma concentrations and with WT HIV-1 IC50 and IC90. Methods: An open, single-arm, sequential clinical trial (NCT02503462) where paired CSF and blood samples were taken from seven HIV-infected patients presenting with HIV-associated neurocognitive disorders (HAND) and treated with a darunavir/ritonavir (800/100 mg) once-daily regimen. Ritonavir was subsequently replaced by cobicistat and paired CSF and blood samples were obtained from the same patients after treatment with the darunavir/cobicistat (800/150 mg) once-daily regimen. Darunavir concentrations at the end of the dosing interval were quantified by LC-MS/MS. Results: The median (IQR) darunavir concentrations in CSF with ritonavir and cobicistat boosting were 16.4 ng/mL (8.6-20.3) and 15.9 ng/mL (6.7-31.6), respectively (P = 0.58). The median (IQR) darunavir CSF:plasma ratios with ritonavir and cobicistat boosting were 0.007 (0.006-0.012) and 0.011 (0.007-0.015), respectively (P = 0.16). Darunavir concentrations in CSF exceeded the darunavir IC50 and IC90 by a median of 9.2- and 6.7-fold with ritonavir boosting, and by 8.9- and 6.5-fold with cobicistat boosting, respectively. All patients had darunavir CSF concentrations above the target inhibitory concentrations and remained virologically suppressed in the CSF and plasma. Conclusions: This small study shows that cobicistat and ritonavir give comparable effective darunavir concentrations in CSF, thus suggesting that these boosters can be used interchangeably in once-daily darunavir regimens.
Subject(s)
Anti-HIV Agents/therapeutic use , Cobicistat/therapeutic use , Darunavir/cerebrospinal fluid , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Ritonavir/therapeutic use , Adult , Aged , Anti-HIV Agents/blood , Anti-HIV Agents/cerebrospinal fluid , Cobicistat/administration & dosage , Cobicistat/blood , Darunavir/blood , Darunavir/therapeutic use , Drug Therapy, Combination , Female , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/cerebrospinal fluid , HIV-1/drug effects , Humans , Male , Middle Aged , Ritonavir/administration & dosage , Tandem Mass SpectrometrySubject(s)
Anti-HIV Agents/pharmacokinetics , Cobicistat/blood , Cobicistat/pharmacokinetics , HIV Infections/blood , Postpartum Period/blood , Quinolones/blood , Quinolones/pharmacokinetics , Adult , Anti-HIV Agents/blood , Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/blood , Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/pharmacokinetics , Female , Humans , PregnancyABSTRACT
Background: We investigated the pharmacokinetics (PK) of atazanavir/cobicistat and darunavir/cobicistat once daily over 72 h following drug intake cessation in plasma, saliva and urine. Methods: Healthy volunteers received a fixed-dose combination of 300/150 mg of atazanavir/cobicistat once daily for 10 days, followed by a 10 day washout period and then a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily for 10 days. Full PK profiles were assessed for each phase for 72 h following day 10 and parameters determined to the last measurable concentration in plasma, saliva and urine by non-compartmental methods. Results: Sixteen subjects completed the study. Geometric mean (GM) terminal elimination half-life values to 72 h of atazanavir and darunavir were 6.77 and 6.35 h, respectively. All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/mL 24 h post-dose and 14/16 subjects had concentrations higher than this target at 30 h post-dose (GM of 759 and 407 ng/mL, respectively). Thirteen out of 16 subjects had darunavir concentrations higher than the target of 550 ng/mL at 24 h post-dose and 5/16 subjects had concentrations higher than the target at 30 h post-dose (GM of 1033 and 382 ng/mL, respectively). Cobicistat half-life to 72 h was 4.21 h with atazanavir and 3.62 h with darunavir. GM values 24 h after the observed dose ( C 24 ) for atazanavir and darunavir were 141 and 43 ng/mL, respectively, in saliva and 24857 and 11878 ng/mL, respectively, in urine. Concentration decay in saliva/urine mirrored plasma concentrations for both drugs. Conclusions: Different concentration decay patterns were seen for atazanavir and darunavir, which may be partially explained by cobicistat half-life (longer with atazanavir than darunavir). For the first time, we also measured drug PK forgiveness in saliva and urine, which represent easier markers of adherence.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Atazanavir Sulfate/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Saliva/chemistry , Adolescent , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/blood , Atazanavir Sulfate/administration & dosage , Atazanavir Sulfate/blood , Atazanavir Sulfate/urine , Cobicistat/administration & dosage , Cobicistat/blood , Cobicistat/urine , Darunavir/administration & dosage , Darunavir/blood , Darunavir/urine , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , Half-Life , Healthy Volunteers , Humans , Male , Middle Aged , Young AdultABSTRACT
Objectives: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as a single-tablet regimen (STR) using the PCR signal of the plasma viral load (pVL) assay and determination of plasma drug concentration ( C 24 ). Patients and methods: This was an observational single-centre study enrolling antiretroviral-treated patients with pVL <50â copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal. Results: One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5â years (IQR 3-9) and 24â months (IQR 9-44), respectively. By week (W) 48, 26 (17%) of the patients had discontinued STR due to adverse events. The proportion of patients maintaining pVL <50â copies/mL on treatment was 98%, 96%, 93% and 97% at W12, W24, W36 and W48, respectively. Five patients (3.3%) experienced a virological failure and emergence of resistance was observed in two of them with the selection of M184V and N155H mutations. At baseline, W12, W24, W36 and W48, 70%, 57%, 72%, 61% and 74% of the patients with pVL <20â copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648â ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values >45â ng/mL, the protein-adjusted IC 95 . Conclusions: In this clinical cohort of virologically suppressed patients switching to STR, most subjects had adequate elvitegravir C 24 values with a high proportion maintaining virological suppression with no residual viraemia until W48.
Subject(s)
Cobicistat/therapeutic use , Emtricitabine/therapeutic use , HIV Infections/drug therapy , Quinolones/therapeutic use , Tenofovir/therapeutic use , Viral Load , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cobicistat/administration & dosage , Cobicistat/blood , Cohort Studies , Emtricitabine/administration & dosage , Emtricitabine/blood , Female , HIV Infections/blood , HIV-1/drug effects , Humans , Maintenance Chemotherapy , Male , Middle Aged , Polymerase Chain Reaction , Quinolones/administration & dosage , Quinolones/blood , RNA, Viral/blood , Tablets , Tenofovir/administration & dosage , Tenofovir/blood , Viremia/drug therapyABSTRACT
Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest antiretroviral drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drug monitoring for these drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other antiretroviral drugs. In this work, we describe the development and validation of a new UPLC-MS/MS method to quantify these drugs, together with other fourteen antiretroviral agents, in human plasma. One hundred microliters of plasma samples were added with internal standard (6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline), underwent a simple protein precipitation with methanol:acetonitrile (50:50v/v) followed by sample dilution with water. Chromatographic separation was performed on a Acquity® UPLC HSS T3 column (150mm x 2.1mm I.D) with a particle size of 1.8µm and compounds were detected with a tandem mass detector, monitoring two ion transitions for each drugs. The mean recovery of RPV, DTG and EVG were 101%, 87% and 112.3% respectively. Accuracy and precision inter/intra-day were below 15% for all drugs, in accordance to Food and Drug Administration guidelines requirements. The UPLC-MS/MS method reported here could be used routinely to monitor plasma concentrations of antiviral drugs, including RPV, DTG and EVG.
Subject(s)
Anti-Retroviral Agents/blood , Anti-Retroviral Agents/chemistry , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Anti-HIV Agents/blood , Anti-HIV Agents/chemistry , Cobicistat/blood , Cobicistat/chemistry , Heterocyclic Compounds, 3-Ring/blood , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Limit of Detection , Oxazines , Piperazines , Pyridones , Quinolones/blood , Quinolones/chemistry , Reproducibility of Results , Rilpivirine/blood , Rilpivirine/chemistry , Ritonavir/blood , Ritonavir/chemistryABSTRACT
Dolutegravir and Elvitegravir belongs to a class of integrase inhibitors which has recently been approved by the FDA for the treatment of HIV-infection. Elvitegravir and its co-administered booster drug, Cobicistat, has shown the potential to be a candidate for a one pill once a day regimen and is currently a component of many clinical trials. A sensitive LC-MS/MS method has been developed and validated for the simultaneous determination of these three drugs in human plasma. A liquid- liquid extraction was used as a sample preparation technique using 100µL of plasma. The method was validated from 10 to 4000ng/mL for Dolutegravir, Elvitegravir and Cobicistat. Chromatography was performed on XBridge C18 2.1mm×50mm column, using an 80:20 methanol/water mobile phase containing 0.1% formic acid on a gradient program. This method was successfully applied for ongoing clinical trials.