Pharmacodynamic dose adjustment in renal failure: importance of the Hill coefficient

The most commonly applied pharmacodynamic model is the sigmoid E(max) model which can be applied for evaluation of dose adjustment schemes in renal failure. It is not known whether the Hill coefficient (H) is a shape factor that only improves the mathematical fit or whether the Hill coefficient is a pharmacodynamic parameter that independently affects drug effects and drug dosage adjustment.

We performed simulations applying a mechanism-based mathematical pharmacokinetic-pharmacodynamic model for antimicrobial drugs. For the case of renal failure, two dose adjustment rules were evaluated.

Administering the drug as 3 dose fractions per day increased the predicted total effect in the case of H = 1 but decreased the predicted total effect in the case of H = 2 compared to once-daily dosing. In renal failure, administration of the normal dose and prolongation of the interval leads to an increased total effect for the simulated drugs for both cases, namely H = 1 and H = 2. However, reducing the dose in renal failure might produce underdosage for a drug with a high Hill coefficient.

The predicted effects of once- versus thrice-daily dose fractions as well as the predicted effects of dose reduction versus interval prolongation in renal failure critically depend on the Hill coefficient. Methods to estimate the Hill coefficient more precisely should be explored.