- Design
- Population pharmacokinetic analysis with dosing simulation
- Population
- 15 Japanese patients on tacrolimus given nirmatrelvir/ritonavir (83 levels)
- Primary outcome
- Tacrolimus clearance and bioavailability; optimal restart schedule
- Effect
- Clearance near-completely inhibited; bioavailability ×7.99; restart 10→20→50→100% on days 1, 3, 6, 9
A population pharmacokinetic study in CPT: Pharmacometrics & Systems Pharmacology (1 September) pooled 83 tacrolimus levels from 15 patients across Japanese university hospitals who received nirmatrelvir/ritonavir. Ritonavir strongly inhibits CYP3A and P-glycoprotein, and the label advises withholding or reducing tacrolimus, but gives little on when and how to restart.
With ritonavir on board, tacrolimus clearance was almost completely inhibited and relative bioavailability rose about eightfold (7.99-fold). Simulations favoured withholding tacrolimus during the five-day antiviral course, then restarting at 10% of the baseline dose on day 1 after it ends, 20% on day 3, 50% on day 6 and the full dose on day 9.
The mechanism explains the slow step-up: ritonavir inactivates CYP3A irreversibly, so enzyme activity takes several days to recover after the last dose. Restarting at full dose the day after the course ends risks toxic levels. The schedule comes from a small cohort and simulation, so trough levels, not the calendar, should decide each step.
- Withhold tacrolimus during the 5-day nirmatrelvir/ritonavir course, after discussion with the transplant team
- Check a tacrolimus trough before restarting
- Restart at about 10% of the usual dose, stepping up to full dose over about nine days
- Measure troughs at each step and adjust; watch creatinine and potassium
- Apply the same caution to ciclosporin, sirolimus and everolimus
Why it matters
The dangerous moment is not starting the antiviral but restarting tacrolimus too soon at full dose.
Don't overread it
The schedule is model-derived from 15 patients and has not been validated in a prospective study.
The statistics, in plain English
The eightfold rise in bioavailability and near-zero clearance are model estimates from 83 levels in 15 patients. Simulations test dosing plans against those estimates; they have not been tested prospectively, so individual patients may need faster or slower steps.
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