- Design
- Population pharmacokinetic analysis with Monte Carlo simulation
- Population
- 114 liver transplant recipients, 1,989 tacrolimus levels
- Primary outcome
- Covariates of tacrolimus clearance; model-informed dosing
- Effect
- Fluconazole −33% clearance; dose 1.5-3.0 vs 2.5-7.0 mg every 12 h
A population pharmacokinetic study in CPT: Pharmacometrics & Systems Pharmacology (September 2026) analysed 1,989 tacrolimus levels from 114 liver transplant recipients in Thailand, with CYP3A5 genotyping of both recipient and donor.
Combined recipient-donor CYP3A5 genotype reduced apparent clearance stepwise from homozygous expressors to non-expressors. Fluconazole reduced clearance by 33%; prednisolone modestly increased it; higher haemoglobin was associated with lower clearance. Simulations suggested patients on fluconazole need about 1.5-3.0 mg every 12 hours against 2.5-7.0 mg without it.
The liver graft contributes its own CYP3A5 activity, which is why the donor genotype matters. The dosing ranges are model simulations from one centre, not a validated protocol, and level monitoring remains the safeguard.
- Reduce tacrolimus dose and recheck levels within days when starting fluconazole
- Expect levels to fall when fluconazole is stopped, and plan the dose increase
- In liver transplantation, remember the graft's CYP3A5 genotype affects clearance, not just the recipient's
- Recheck tacrolimus levels after large changes in haemoglobin or steroid dose
Why it matters
It puts a figure — about a third less clearance — on one of the commonest interactions on a transplant ward.
Don't overread it
The dose ranges are simulations from 114 patients at one centre, not a validated dosing protocol.
The statistics, in plain English
A 33% reduction in clearance means the same dose produces about 50% higher exposure at steady state, because exposure is inversely proportional to clearance.
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