Dataset Information

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies.

ABSTRACT: Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C_{SS,min ENDX}) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C_{SS,min ENDX} applying conventional tamoxifen dosing. Moreover, 4-75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget C_{SS,min ENDX}. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on C_{SS,min ENDX} target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported C_{SS,min ENDX} in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget C_{SS,min ENDX} even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability.

SUBMITTER: Mueller-Schoell A

PROVIDER: S-EPMC7913149 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies.

Mueller-Schoell Anna A Klopp-Schulze Lena L Michelet Robin R van Dyk Madelé M Mürdter Thomas E TE Schwab Matthias M Joerger Markus M Huisinga Wilhelm W Mikus Gerd G Kloft Charlotte C

Pharmaceuticals (Basel, Switzerland) 20210203 2

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C<sub>SS,min ENDX</sub>) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C<sub>SS,min ENDX</sub> applying conventional tamoxifen dosing. Moreover, 4-75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing ...[more]

PMID: 33546125

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Project description:The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ? 96 ?g h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr - 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr - 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 ?g/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

Dataset Information

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies.

Publications

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies.

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