Drug-drug interaction of Nirmatrelvir/ritonavir and tacrolimus: A potential risk disproportionality analysis of nephrotoxicity from COVID-19 reports in FAERS.

BACKGROUND: Nirmatrelvir/ritonavir is a new oral antiviral agent for COVID-19, and tacrolimus is a widely used immunosuppressant. Drug-drug interaction between Nirmatrelvir/ritonavir and tacrolimus is expected. However, information regarding the drug-drug interaction in a real-world setting is limited. We aim to evaluate drug-drug interaction between tacrolimus and Nirmatrelvir/ritonavir and perform a disproportionality analysis to assess the potential risk of nephrotoxicity due to their combination for COVID-19 treatment based on the FAERS database. RESEARCH DESIGN AND METHODS: Disproportionality analysis was performed using the reporting odds ratio (ROR) method, and subset analysis was conducted based on the background of COVID-19 drugs combined with tacrolimus more than 10 times. RESULTS: In disproportionality analysis, combination of Nirmatrelvir/ritonavir and tacrolimus was significantly associated with acute kidney injury (41.13%), serum creatinine increased (14.18%), renal failure (2.84%), and renal impairment (2.84%). These positive signals of acute kidney injury and serum creatinine increased still strongly retained in subset analysis. No similar positive signals were detected in Nirmatrelvir/ritonavir-single group. Only in Cilgavimab/Tixagevimab-tacrolimus group and Remdesivir-tacrolimus group, acute kidney injury was recognized as weakly positive signals and disappeared in subset analysis. CONCLUSIONS: The study results show significant drug-drug interaction between Nirmatrelvir/ritonavir and tacrolimus and confirm that their combination for COVID-19 treatment greatly increases risk of acute kidney injury.

Preparation and evaluation of a timolol maleate drug-resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo.

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug-resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 µm and drug loading at 43.00 ± 0.09%. The results indicate that drug released from the drug-resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug-resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.