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AIM: To design and implement personalized dosing regimens of trastuzumab and pertuzumab for an Asian patient with early breast cancer. METHODS: Trastuzumab and pertuzumab are important therapeutics for patients with HER2-positive breast cancer. Despite the similar pharmacokinetics (PK), their recommended dosing regimens differ: pertuzumab dosing is fixed whereas trastuzumab dosing depends on body weight; the dosing frequency is once every three weeks for pertuzumab but includes both once every week (QW) and once every three weeks (Q3W) for trastuzumab. A practicing physician has limited choices for dosing regimens when using the drugs in combination with chemotherapies. Besides convenience in drug administration, efficacy and safety as responses to the drug must be examined as part of studying dose-exposure-response relationship, which is the basis for deciding a dosing regimen. To understand the dose-exposure-response relationship of an individual patient, we reviewed literature on population PK analyses. The associated PK-covariate relationships including influential covariates such as disease status and demographics (e.g., body weight) that informed the patient's underlying dose-exposure-response relationships. Safety and efficacy factors essential for choosing appropriate dosing regimens were also considered - minimal target concentrations, higher adverse event rates in Asian patients, as well as administration convenience. RESULTS:Based on a thorough review of population PK and PK-covariate relationships of pertuzumab and trastuzumab, an individualized dosing regimen of once every two weeks (Q2W) was selected as the treatment option and implemented for this patient. CONCLUSION: The design of an individualized dosing regimen requires the knowledge of individualized dose-exposure-response relationships, and population analysis is an ideal tool for understanding the individualized dose-exposure-response relationships.
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The aim of this study is to apply 3D printing technology to hospital drug dosing operations, and explore its feasibility and scalability. Drugs often dosed in hospitals are selected as models. The commercially available drug was ground into powder, diluted with medicinal excipients and then mixed with 75% ethanol and binder to prepare a paste for 3D printing. The dose and physicochemical properties of divided tablets were controlled by setting print parameters and printing models in computer software. Different 3D printers were employed to evaluate the impact of the device on the dosing tablet. Two drugs were dosed in this study to explore the scalability of 3D printing technology between different drugs. The drug content of the three divided dose tablets (warfarin sodium 1 mg, 2 mg, hydrochlorothiazide 5 mg) was 1.02±0.03, 1.96±0.01, 5.19±0.06 mg. The content uniformity was 1.0, 5.3, 2.6, respectively. The drug dissolution rate was (99.3±1.2)%, (101.5±0.3)%, (98.1±0.8)% in 45, 45 and 30 min. The mechanical properties of the three sub-doses and the stability within 30 days were in line with the Chinese Pharmacopoeia (2015) requirements. At the same time, it was found that the printing parameters and prescriptions can affect the properties of the divided dose tablets. By controlling the dilution ratio of commercial drug and printing parameters, the drug release rate can be customized to achieve individualized treatment. Both different modes of 3D printers can produce qualified sub-doses, and 3D print dispensing technology was also versatile between the two drugs. 3D printing can prepare small-volume, high-precision, high-repetition dosing tablets, with all properties in compliance with pharmacopoeia regulations. Thus, this method can be used as a new and scalable sub-dosing method.
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Pharmacogenomics is defined as research into the relationship between inherited genetic variations in drug metabolizing enzymes, transporters and targets and individual variations in person's response to drugs (fate of drug in human body, safety and efficacy). Personalized dosing is pharmacogenomics-based therapeutic regimen tailored to other individual characteristics. This article summarizes the progress in clinical application of personalized dosing from the perspective of pharmacogenomics of drug metabolizing enzymes and transporters, and proposes to draw attention to key scientific issues (e.g., the effect of multi-genes and non-genetic factors on drug effects, the integration of therapeutic drug monitoring and pharmacogenomics); meanwhile, bottle necks in the clinical application and corresponding strategies are proposed.