Drug Rescue for Paxlovid–Induced Tacrolimus Toxicity: A Pooled Analysis of Case Reports

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Rationale & Objective Despite case reports suggesting the use of cytochrome P450 3A4 (CYP3A4) inducers for the treatment of Paxlovid–induced tacrolimus (TAC) toxicity, systematic validation is lacking. This study aimed to investigate whether inducers (rifampin or phenytoin) could reduce TAC concentrations and restore renal function more effectively and safely than drug withdrawal alone. Study Design A case report and a pooled analysis of case reports registered with PROSPERO (CRD420251138667). Setting & Participants : The presented patients and 51 individual patients from 41 publications were categorized into drug rescue (n=23) and natural recovery (n=29) groups. Search Strategy & Sources Case reports and series were identified from the PubMed, Embase, Web of Science, and Chinese databases (from January 1, 2020, to December 1, 2025), with a primary search strategy of "(Tacrolimus OR FK506) AND (Ritonavir OR Paxlovid OR "Nirmatrelvir–Ritonavir"). Analytical Approach Kaplan–Meier curves and directed acyclic graph–informed multivariable linear regression analysis. Results In a posttransplant female, Paxlovid–induced supratherapeutic TAC levels resolved within 2 days of rifampin initiation, and acute kidney injury recovered within 3 days. Pooled analysis showed that, compared with natural recovery, drug rescue therapy demonstrated significantly faster recoveries of TAC (median = 4.0 days vs. 6.0 days; log–rank p < 0.001) and SCr (median = 3.0 days vs. 7.0 days; p=0.024). Drug rescue was independently associated with a 2.6–day (p < 0.001) shorter recovery time for TAC levels and a 4.0–day (p=0.043) shorter recovery time for SCr levels. Rifampin and phenytoin showed no significant difference in the recovery time for TAC or SCr levels. No serious adverse events or secondary toxicity were reported. Conclusions CYP3A4 inducers were significantly associated with accelerated TAC clearance and renal recovery in patients with Paxlovid–induced TAC toxicity and appeared safe for clinical use.