Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer

Oyaga-Iriarte, Esther; Insausti, Asier; Sayar, Onintza; Aldaz, Azucena

doi:10.1007/s00228-018-02609-6

Cited by 7 publications

(6 citation statements)

References 30 publications

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“…In the previous PopPK analysis of irinotecan, the SN38 (a metabolite of irinotecan) concentration was also included to build a combined model, because irinotecan is a prodrug and SN38 showed a 300–1,000 times higher activity than irinotecan ( Berg et al, 2015 ; Adiwijaya et al, 2017 ; Oyaga-Iriarte et al, 2019 ; Brendel et al, 2021 ; Liu et al, 2022 ). In this study, although TQ-B3203 also could be metabolized to produce SN38, the conversion ratio was very low (<5%), and TQ-B3203 mainly existed in the form of the prototype in vivo .…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic analysis of TQ-B3203 following intravenous administration of TQ-B3203 liposome injection in Chinese patients with advanced solid tumors

Yang

Yin

et al. 2023

Front. Pharmacol.

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Background: TQ-B3203 is a novel topoisomerase I inhibitor currently in development for the treatment of advanced solid tumors. Great differences in pharmacokinetic characteristics were found among individuals according to the phase I clinical trial following intravenous administration of TQ-B3203 liposome injection (TLI) in Chinese patients with advanced solid tumors. Thus, it is significant to establish a population pharmacokinetic model to find the key factors and recognize their effect on pharmacokinetic parameters in order to guide individualized administration.Methods: Non-linear mixed effect models were developed using the plasma concentrations obtained from the phase I clinical trial by implementing the Phoenix NLME program. Covariates that may be related to pharmacokinetics were screened using stepwise methods. The final model was validated by goodness-of-fit plots, visual predictive check, non-parametric bootstrap and a test of normalized prediction distribution errors.Results: A three-compartment model with first-order elimination was selected as the best structural model to describe TQ-B3203 disposition adequately. Direct bilirubin (DBIL) and body mass index (BMI) were the two most influential factors on clearance, while lean body weight (LBW) was considered to affect the apparent distribution volume of the central compartment. The population estimations of clearance and central volume were typical at 3.97 L/h and 4.81 L, respectively. Model-based simulations indicated that LBW had a great impact on Cmax, BMI exerted a considerable influence on AUC0-t, and the significance of DBIL on both AUC0-t and Cmax was similarly excellent.Conclusion: The first robust population pharmacokinetic model of TQ-B3203 was successfully generated following intravenous administration of TLI in Chinese patients with advanced solid tumors. BMI, LBW and DBIL were significant covariates that affected the pharmacokinetics of TQ-B3203. This model could provide references for the dose regimen in the future study of TLI.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic analysis of TQ-B3203 following intravenous administration of TQ-B3203 liposome injection in Chinese patients with advanced solid tumors

Yang

Yin

et al. 2023

Front. Pharmacol.

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“…Conventional PK compartmental models fail to describe this complex behaviour for such compounds, so more sophisticated PK models are required. In this respect, a series of models has been developed to describe the multiple peaking phenomenon such as models with variable absorption and EHC process 9–15 . For instance, in the PopPK modelling of nevirapine, Ibarra et al 10 .…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15] For instance, in the PopPK modelling of nevirapine, Ibarra et al 10 divided the GI tract (GIT) compartment into 2 compartments, GIT1 and GIT2, to preserve the unidirectional property of both excretion and reabsorption processes. And they also added several transit compartments on absorption phase.…”

mentioning

confidence: 99%

Population pharmacokinetics and enterohepatic recirculation of hyzetimibe and its main metabolite in Chinese healthy subjects

Ruan

Chen

Yang

et al. 2022

Brit J Clinical Pharma

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, a new drug approved for hypercholesterolaemia, exhibits obvious enterohepatic recirculation (EHC) after oral administration. Up to now, little is known about the kinetics of HS-25. Therefore, we performed this population pharmacokinetic (PopPK) analysis aiming to describe the PK behaviour of HS-25 and its main metabolite (M1), and to identify significant covariates contributing to the variability. Methods:The plasma concentration data used for modelling were obtained from an open-label, single-dose, randomized, 2-period crossover bioequivalence study. PopPK modelling was performed with NONMEM 7.4.1 using nonlinear mixed effect modelling approach. Goodness of fit plots, bootstrap and visual predictive check were used for model internal validation. Data from another study were used for external validation.Results: Data from 16 male and 8 female subjects were used in the PopPK analysis.HS-25 and M1 concentrations in the modelling cohort were well described by a 1-compartment model incorporating first-pass metabolism and a gallbladder compartment, accounting for the EHC process. The release kinetic of gall was mimicked by a first-order constant plus a switch on/off effect. Body weight was identified as a significant covariate effecting on the clearance and apparent distribution volume of HS-25, as well as k mg , the transfer rate from metabolite compartment to gallbladder compartment. Internal and external validation demonstrated an acceptable predictive ability of the final model. Conclusion:We present the first PopPK model describing HS-25 and M1 concentrations simultaneously, with the EHC process considered. The modelling and simulation results could provide reference for the clinical use of HS-25.

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“…However, a (Makihara et al, 2017), possibly due to uridine diphosphate glucuronosyltransferase isoform 1A1, organic anion transporter 1B1, genetic variation factors such as irinotecan-induced wide interindividual variability in drug response and toxicity (Riera et al, 2018). More detailed studies on individualized dose adjustment for cancer patients in clinical practice may be accomplished by developing a combined population pharmacokinetic model of irinotecan and its metabolites to prevent adverse effects caused by excessive drug/metabolite accumulation (Oyaga-Iriarte et al, 2019).…”

Section: Concomitant Drugs Involving Inhibition or Induction Of Cyp3a...mentioning

confidence: 99%

“…However, the efficacy of anticancer drugs is compromised by the frequent emergence of adverse effects, which may result in therapeutic failure (Bins et al, 2019;Oyaga-Iriarte et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy

et al. 2023

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Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzyme's activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human in vitro models and clinical studies, the pharmacokinetics of most anticancer drugs are influenced by the extent of induction or inhibition of CYP3A4-mediated metabolism, and these details are not fully recognized and highlighted. Therefore, this interindividual variability due to genetic and nongenetic factors, together with the narrow therapeutic index of most anticancer drugs, contributes to their unique set of exposures and responses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in individuals. To elucidate the mechanisms of CYP3A4-mediated activation/inactivation of anticancer drugs associated with personalized therapy, this review focuses on the underlying determinants that contribute to differences in CYP3A4 metabolic activity and provides a comprehensive and valuable overview of the significance of these factors, which differs from current considerations for dosing regimens in cancer therapy. We also discuss knowledge gaps, challenges and opportunities to explore optimal dosing regimens for drug metabolic activation/inactivation in individual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity.

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Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer

Cited by 7 publications

References 30 publications

Population pharmacokinetic analysis of TQ-B3203 following intravenous administration of TQ-B3203 liposome injection in Chinese patients with advanced solid tumors

Population pharmacokinetic analysis of TQ-B3203 following intravenous administration of TQ-B3203 liposome injection in Chinese patients with advanced solid tumors

Population pharmacokinetics and enterohepatic recirculation of hyzetimibe and its main metabolite in Chinese healthy subjects

Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy

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