Tacrolimus clearance effectively stops on nirmatrelvir, and restarting is the hard part

The edition in brief

A Japanese population pharmacokinetic analysis of 83 tacrolimus concentrations from 15 patients before and after nirmatrelvir/ritonavir found clearance almost completely inhibited and relative bioavailability increased 7.99-fold. Package inserts advise withholding or reducing tacrolimus at the start of antiviral therapy but say little about restarting. The simulated schedule withholds tacrolimus throughout, then restarts at 10% of baseline dose on day 1 after the antiviral stops, 20% on day 3, 50% on day 6 and 100% on day 9. Fifteen patients is a small basis for a model, and therapeutic drug monitoring remains the safeguard. Among 996 patients on metoprolol tartrate in the Montreal Heart Institute cohort, followed a median 101.4 months, higher CYP2D6 metabolizer status was associated with lower mortality (hazard ratio 0.82, 95% CI 0.67-0.99, p=0.04) after adjustment including for CYP2D6 inhibitors. Metoprolol concentration itself was not associated with mortality once confounders were included - so the signal tracks the genotype rather than the measured exposure, which argues for caution about the mechanism. A population model built from 25 preterm neonates of median 26.3 weeks' gestation gives the first anakinra pharmacokinetics in this group. Clearance at birth was about 45% of its early postnatal maximum, reaching full value by day 10, and the simulated regimen escalates from 0.6 mg/kg twelve-hourly at birth to 1.15 mg/kg from day 4. A commentary uses South African metformin-dolutegravir and colistin data to argue that dosing derived in healthy volunteers needs explicit verification in the populations that will receive it.