Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency

Matthews, Randolph P.; Cao, Youfang; Patel, Malini; Weissler, Vanessa L.; Bhattacharyya, Arinjita; Lepeleire, Inge De; Last, Stefanie; Rondon, Juan Carlos; Vargo, Ryan; Stoch, S. Aubrey; Iwamoto, Marian

doi:10.1128/aac.00931-22

Cited by 7 publications

(1 citation statement)

References 22 publications

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“…Age greater than or equal to 18 years, continuous use of mechanical ventilation and sedative use (midazolam, propofol or remimazolam) greater than or equal to 24 h are the inclusion criteria for this study. Exclusion criteria: (1) using two or more sedatives concurrently; (2) women who are pregnant or lactating; (3) patients allergic to benzodiazepines, opioids or propofol, or have contraindications; (4) patients with a history of drug use such as heroin, marijuana, and methamphetamine; (5) patients with positive serum ethanol test, with a history of alcoholism or alcohol dependence; (6) patients with mental illness; (7) patients with severe liver or kidney dysfunction (Kidney: Rifle criteria ≥ F; Liver: total plasma protein < 30 g/l; bilirubin > 85 mol/l) [ 20 – 22 ]; (8) hemodynamic instability: bradycardia (heart rate < 50 beats/min), hypotension (systolic blood pressure < 90 mmHg even with vasoactive drugs), second degree and above atrioventricular block and no pacemaker; (9) refusing to sign an informed consent form; (10) patients who have been included in other clinical studies.…”

Section: Methodsmentioning

confidence: 99%

Remimazolam tosylate's long-term sedative properties in ICU patients on mechanical ventilation: effectiveness and safety

Yao,

Liao,

et al. 2023

Eur J Med Res

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Objective This study compared remimazolam tosylate with propofol or midazolam to assess its safety and effectiveness for long-term sedation of intensive care unit (ICU) patients requiring mechanical ventilation. Methods Adult patients in the ICU receiving sedation and mechanical ventilation for longer than 24 h were included in this single-center, prospective, observational study. Depending on the sedatives they were given, they were split into two groups (midazolam or propofol group; remimazolam group). ICU mortality was the main result. Laboratory tests, adverse events, and the length of ICU stay were considered secondary outcomes. Results A total of 106 patients were involved (46 received propofol or midazolam versus 60 received remimazolam). Age (P = 0.182), gender (P = 0.325), and the amount of time between being admitted to the ICU and receiving medication infusion (P = 0.770) did not substantially differ between the two groups. Multivariate analysis revealed no statistically significant difference in ICU mortality between the two groups. The remimazolam group showed less variability in heart rate (P = 0.0021), pH (P = 0.048), bicarbonate (P = 0.0133), lactate (P = 0.0002), arterial blood gas analyses, liver, and kidney function. The Richmond Agitation and Sedation Scale scores, length of ICU stay, and occurrence of adverse events did not exhibit significant differences between the two groups. Conclusion Remimazolam tosylate did not increase the total inpatient cost, the incidence of adverse events, and ICU mortality in patients with mechanical ventilation. These findings suggest that remimazolam may represent a promising alternative for sedation in the ICU setting.

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Section: Methodsmentioning

confidence: 99%

Remimazolam tosylate's long-term sedative properties in ICU patients on mechanical ventilation: effectiveness and safety

Yao,

Liao,

et al. 2023

Eur J Med Res

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A Phase 1 Study to Evaluate the Pharmacokinetic Drug‐Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy

Matthews,

Ankrom,

Handy

et al. 2024

Clinical Pharm in Drug Dev

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Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV‐1. People living with HIV‐1 receiving methadone maintenance therapy may benefit from islatravir. This study was designed to evaluate single‐dose islatravir on steady‐state methadone pharmacokinetics. A nonrandomized, open‐label study (NCT04568603) was conducted and included adult participants receiving methadone therapy. Participants received their standard methadone therapy and a single oral dose of islatravir 60 mg concomitantly. Blood samples were collected to determine methadone and islatravir pharmacokinetics. Fourteen participants aged 26‐63 years were enrolled; 13 completed the study. The geometric mean ratios for methadone area under the concentration‐time curve from time 0 to 24 hours (AUC0‐24), maximum plasma concentration (Cmax), and concentration at 24 hours (C24) were 1.03, 1.01, and 1.07, respectively. Similar effects were seen for the R‐ and S‐enantiomer of methadone (R‐methadone: AUC0‐24, 1.03; Cmax, 1.02; and C24, 1.06; S‐methadone: AUC0‐24, 1.03; Cmax, 1.01; and C24, 1.08). For islatravir, based on a comparison with historical data, the geometric mean ratios for AUC0‐inf and Cmax were 1.18 and 0.86, respectively. Coadministration of a single dose of islatravir and methadone was generally well tolerated. Single‐dose islatravir did not affect steady‐state methadone pharmacokinetics in a clinically meaningful way.

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Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults

McCrea,

Patel,

Liu

et al. 2024

The Journal of Clinical Pharma

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Islatravir, a deoxyadenosine analog that inhibits HIV‐1 replication by multiple mechanisms of action, including reverse transcriptase translocation inhibition, is being developed for use in HIV‐1 treatment. People living with HIV often have comorbidities, such as dyslipidemia or type 2 diabetes mellitus, necessitating long‐term concomitant drug therapy. This nonrandomized, two‐period, fixed‐sequence, open‐label, phase 1, drug‐drug interaction study was conducted to evaluate the effects of islatravir coadministration on atorvastatin and metformin pharmacokinetics (PK) in healthy adults. In period 1, participants received a single dose of atorvastatin 20 mg and metformin 1000 mg. After a 5‐day washout, participants received atorvastatin 20 mg and metformin 1000 mg coadministered with a single oral dose of islatravir 60 mg (period 2). In both periods, blood samples were collected up to 72 h post dose to characterize the plasma PK of atorvastatin and metformin. Safety was monitored throughout the study. Fourteen participants were enrolled and completed the study. Atorvastatin and metformin plasma PK were similar after administration of atorvastatin and metformin with or without islatravir. The geometric mean ratio and 90% confidence interval of the area under the concentration‐time curve from time zero to infinity (AUC0‐∞) for atorvastatin and metformin with or without a single oral dose of islatravir were 1.04 (1.00‐1.10) and 0.87 (0.79‐0.96), respectively. Coadministration of islatravir with atorvastatin and metformin was well tolerated. Overall, coadministration of atorvastatin and metformin with a single oral dose of islatravir did not have a clinically meaningful effect on the PK profiles of either drug.

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Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency

Cited by 7 publications

References 22 publications

Remimazolam tosylate's long-term sedative properties in ICU patients on mechanical ventilation: effectiveness and safety

Remimazolam tosylate's long-term sedative properties in ICU patients on mechanical ventilation: effectiveness and safety

A Phase 1 Study to Evaluate the Pharmacokinetic Drug‐Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy

Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults

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