Pharmacokinetic–pharmacodynamic modelling of acute N‐terminal pro B‐type natriuretic peptide after doxorubicin infusion in breast cancer

Liang, Shuang; Brundage, Richard C.; Jacobson, Pamala A.; Blaes, Anne; Kirstein, Mark N.

doi:10.1111/bcp.12989

Cited by 12 publications

(22 citation statements)

References 50 publications

(81 reference statements)

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“…The clinical dosing scenarios were simulated at 60 and 75 mg/m 2 IV bolus infusion of DOX over 15 minutes. 31 , 32 The average BSA of 1.71 m 2 reported from a previously published clinical study in breast cancer patients 32 was used to calculate the DOX amount (mg). C DOX , Cp 2 , and Cp 3 represent drug amounts in the central and two peripheral compartments; k el_DOX is the first-order elimination rate constant of DOX from the central compartment; k 12 , k 21 , k 13 , k 31 are first-order inter-compartmental transfer rate constants; Vc DOX , Vp 2 , and Vp 3 represent the volumes of distribution in the central and two peripheral compartments.…”

Section: Methodsmentioning

confidence: 99%

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

Fleisher¹,

Lezeau²,

Werkman³

et al. 2021

BCTT

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Background Doxorubicin (DOX) and its pegylated liposomal formulation (L_DOX) are the standard of care for triple-negative breast cancer (TNBC). However, resistance to DOX often occurs, motivating the search for alternative treatment approaches. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC treatment since its expression has been associated with resistance to DOX-based therapy. Methods DOX (0.01–20 μM) combination with abemaciclib (ABE, 1–6 μM) was evaluated over 72 hours on Rb-positive (MDA-MB-231) and Rb-negative (MDA-MB-468) TNBC cells. Combination indices (CI) for DOX+ABE were calculated using Compusyn software. The TNBC cell viability time-course and fold-change from the control of phosphorylated-Rb (pRb) protein expression were measured with CCK8-kit and enzyme-linked immunosorbent assay. A cell-based pharmacodynamic (PD) model was developed, where pRb protein dynamics drove cell viability response. Clinical pharmacokinetic (PK) models for DOX, L_DOX, and ABE were developed using data extracted from the literature. After scaling cancer cell growth to clinical TNBC tumor growth, the time-to-tumor progression (TTP) was predicted for human dosing regimens of DOX, ABE, and DOX+ABE. Results DOX and ABE combinations were synergistic (CI<1) in MDA-MB-231 and antagonistic (CI>1) in MDA-MB-468. The maximum inhibitory effects (Imax) for both drugs were set to one. The drug concentrations producing 50% of Imax for DOX and ABE were 0.565 and 2.31 μM (MDA-MB-231) and 0.121 and 1.61 μM (MDA-MB-468). The first-orders rate constants of abemaciclib absorption (k a ) and doxorubicin release from L_DOX (k Rel ) were estimated at 0.31 and 0.013 h −1 . Their linear clearances were 21.7 (ABE) and 32.1 L/h (DOX). The estimated TTP for intravenous DOX (75 mg/m2 every 21 days), intravenous L_DOX (50 mg/m 2 every 28 days), and oral ABE (200 mg twice a day) were 125, 31.2, and 8.6 days shorter than drug-free control. The TTP for DOX+ABE and L_DOX+ABE were 312 days and 47.5 days shorter than control, both larger than single-agent DOX, suggesting improved activity with the DOX+ABE combination. Conclusion The developed translational systems-based PK/PD model provides an in vitro-to-clinic modeling platform for DOX+ABE in TNBC. Although model-based simulations suggest improved outcomes with combination over monotherapy, tumor relapse was not prevented with the combination. Hence, DOX+ABE may not be an effective treatment combination for TNBC.

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Section: Methodsmentioning

confidence: 99%

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

Fleisher¹,

Lezeau²,

Werkman³

et al. 2021

BCTT

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“…Few exposure-response models for NT-proBNP in other indications are available in the literature. For example, an indirect PD model with transit compartments was developed that best described the relationship of doxorubicin exposure and acute NT-proBNP response in patients with breast cancer [35]. For the oral, selective, prostacyclin receptor agonist selexipag, approved for the treatment of pulmonary arterial [NT-proBNP] baseline considered for simulation: 250 pg/mL (gray), 500 pg/mL (orange), 1000 pg/mL (green), 3000 pg/mL (purple), 5000 pg/mL (light blue), and 10,000 pg/mL (dark blue) hypertension, a log-linear regression model was established linking model-predicted steady-state exposure to PD, and exposure to selexipag and NT-proBNP response at steady state [36].…”

Section: Pk/pd Modeling Of Nt-probnpmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

et al. 2021

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Background Vericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%. Objective The objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure-response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625). Methods Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. Results Vericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP]. Conclusions Vericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP. Clinical Trial Identifier NCT01951625.

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“…All have concentrated on short‐term, rather than cumulative, exposure–effect relationships using biomarkers of cardiotoxicity. In breast cancer patients 58 and in children with solid tumours or leukaemia 59 plasma concentrations of biomarkers for ventricular wall stress (e.g. natriuretic peptides including NT‐proBNP) increased significantly from baseline within 24–48 hours following the first cycle of chemotherapy, whilst plasma concentrations of cardiac troponins (biomarkers of myocyte damage or death) became elevated by 2 weeks following the second cycle of chemotherapy 59 .…”

Section: Systemic Exposure‐ Effect Relationshipsmentioning

confidence: 99%

“…natriuretic peptides including NT-proBNP) increased significantly from baseline within 24-48 hours following the first cycle of chemotherapy, whilst plasma concentrations of cardiac troponins (biomarkers of myocyte damage or death) became elevated by 2 weeks following the second cycle of chemotherapy. 59 A linear effect model indicated a significant association between doxorubicin plasma concentrations and increases in NT-proBNP, 58 whilst correlations were reported between cumulative doxorubicin dose and plasma troponin or natriuretic peptide concentrations, and an association between total doxorubicin plus doxorubicinol AUC and troponin concentrations. 59 Using pharmacokinetic-pharmacodynamic modelling in children, Kunarajah et al 60 3) can result in >2-fold differences in calculated absolute doses in very young children.…”

Section: Cardiotoxicitymentioning

confidence: 99%

Is there scope for better individualisation of anthracycline cancer chemotherapy?

Sallustio

Boddy

2020

Brit J Clinical Pharma

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Anthracyclines are used to treat solid and haematological cancers, particularly breast cancers, lymphomas and childhood cancers. Myelosuppression and cardiotoxicity are the primary toxicities that limit treatment duration and/or intensity. Cardiotoxicity, particularly heart failure, is a leading cause of morbidity and mortality in cancer survivors. Cumulative anthracycline dose is a significant predictor of cardiotoxicity risk, suggesting a role for anthracycline pharmacokinetic variability. Population pharmacokinetic modelling in children has shown that doxorubicin clearance in the very young is significantly lower than in older children, potentially contributing to their higher risk of cardiotoxicity. A model of doxorubicin clearance based on body surface area and age offers a patient‐centred dose‐adjustment strategy that may replace the current disparate initial‐dose selection tools, providing a rational way to compensate for pharmacokinetic variability in children aged <7 years. Population pharmacokinetic models in adults have not adequately addressed older ages, obesity, hepatic and renal dysfunction, and potential drug–drug interactions to enable clinical application. Although candidate gene and genome‐wide association studies have investigated relationships between genetic variability and anthracycline pharmacokinetics or clinical outcomes, there have been few clinically significant reproducible associations. Precision‐dosing of anthracyclines is currently hindered by lack of clinically useful pharmacokinetic targets and models that predict cumulative anthracycline exposures. Combined with known risk factors for cardiotoxicity, the use of advanced echocardiography and biomarkers, future validated pharmacokinetic targets and predictive models could facilitate anthracycline precision dosing that truly maximises efficacy and provides individualised early intervention with cardioprotective therapies in patients at risk of cardiotoxicity.

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Pharmacokinetic–pharmacodynamic modelling of acute N‐terminal pro B‐type natriuretic peptide after doxorubicin infusion in breast cancer

Cited by 12 publications

References 50 publications

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

Is there scope for better individualisation of anthracycline cancer chemotherapy?

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