Individualized Dosing With High Inter-Occasion Variability Is Correctly Handled With Model-Informed Precision Dosing-Using Rifampicin as an Example

Frontiers in Pharmacology
Lina Keutzer, Ulrika S H Simonsson

Abstract

Rifampicin exhibits complexities in its pharmacokinetics (PK), including high inter-occasion variability (IOV), which is challenging for dose individualization. Model-informed precision dosing (MIPD) can be used to optimize individual doses. In this simulation-based study we investigated the magnitude of IOV in rifampicin PK on an exposure level, the impact of not acknowledging IOV when performing MIPD, and the number of sampling occasions needed to forecast the dose. Subjects with drug-susceptible tuberculosis (TB) were simulated from a previously developed population PK model. To explore the magnitude of IOV, the area under the plasma concentration-time curve from time zero up to 24 h (AUC0-24h) after 35 mg/kg in the typical individual was simulated for 1,000 sampling occasions at steady-state. The impact of ignoring IOV for dose predictions was investigated by comparing the prediction error of a MIPD approach including IOV to an approach ignoring IOV. Furthermore, the number of sampling occasions needed to predict individual doses using a MIPD approach was assessed. The AUC0-24h in the typical individual varied substantially between simulated sampling occasions [95% prediction interval (PI): 122.2 to 331.2 h mg/L], equivalen...Continue Reading

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Citations

Nov 10, 2020·European Journal of Clinical Pharmacology·Anna Mueller-SchoellCharlotte Kloft
Mar 13, 2021·Frontiers in Pediatrics·Alan AbdullaMatthijs de Hoog
Jul 11, 2021·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·Eveline WallenburgRob Ter Heine
Jan 18, 2022·Expert Review of Clinical Pharmacology·Wannee KantasiripitakErwin Dreesen

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Clinical Trials Mentioned

NCT01392911

Software Mentioned

R
MIPD
NONMEM
ggplot2
R Core Team
MCETA
PsN

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