A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis

Hanke, Nina; Teifel, Michael; Moj, Daniel; Wojtyniak, Jan-Georg; Britz, Hannah; Aicher, Babette; Sindermann, H.; Ammer, Nicola; Lehr, Thorsten

doi:10.1007/s00280-017-3495-2

Cited by 18 publications

(23 citation statements)

References 29 publications

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“…Cytotoxic GnRH agonist Zoptarelin Doxorubicin is an effective therapeutic agent for the treatment of GnRH receptor‐positive breast cancers . Glycolysis inhibitor 2DG, a compound which targets a primary source of cell energy of cancer cells, induces apoptotic cell death in different cancers .…”

Section: Discussionmentioning

confidence: 99%

“…Cytotoxic GnRH agonist Zoptarelin Doxorubicin is an effective therapeutic agent for the treatment of GnRH receptor-positive breast cancers. 5,[18][19][20][21][22][23][24] Glycolysis inhibitor 2DG, a compound which targets a primary source of cell energy of cancer cells, induces apoptotic cell death in different cancers. [9][10][11][12][13] In this study, we have analyzed whether the effectiveness of the GnRH receptor-mediated chemotherapy using Zoptarelin Doxorubicin in triple-negative breast cancer (TNBC) cells can be strengthened by co-treatment with 2DG in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

Gründker

Wokoun

Hellriegel

et al. 2019

J of Obstet and Gynaecol

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Aim A characteristic of cancer cells including triple‐negative breast cancers (TNBC) is an increased aerobic glycolysis for ATP production representing a selective therapeutic target. More than 70% of TNBC express gonadotropin‐releasing hormone receptors (GnRH‐R). These receptors can be used for targeted chemotherapy with cytotoxic GnRH agonists such as Zoptarelin Doxorubicin, in which doxorubicin is covalently linked to [D‐Lys6]GnRH. In this study, we have analyzed whether inhibition of aerobic glycolysis can enhance the antitumor efficacy of GnRH‐R‐targeted chemotherapy using Zoptarelin Doxorubicin. Methods Triple‐negative breast cancers cell lines MDA‐MB‐231 and HCC1806 were treated with Zoptarelin Doxorubicin, glycolysis inhibitor 2‐deoxy‐D‐glucose (2DG) or the combination of both agents. Cell viability was measured using Alamar blue. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted MDA‐MB‐231 tumors. Results Treatment of TNBC cells with Zoptarelin Doxorubicin or with 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with Zoptarelin Doxorubicin in combination with 2DG resulted in significantly reduced viability and enhanced apoptosis compared with single‐agent treatments. Combinational index (CI) analysis revealed the co‐treatment effect as a synergistic. The antitumor effects of Zoptarelin Doxorubicin or 2DG were confirmed in nude mice. The tumor reducing effects of Zoptarelin Doxorubicin were enhanced by combination with 2DG. Conclusion The glycolytic phenotype of TNBC can be used to improve antitumor therapies. Co‐treatment of Zoptarelin Doxorubicin with glycolysis inhibitor 2DG might be a suitable therapeutic option for GnRH receptor‐positive TNBC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

Gründker

Wokoun

Hellriegel

et al. 2019

J of Obstet and Gynaecol

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“…Inhibition of ASBT (Ki = 54.60 µM) [38], NTCP (Ki = 4.04 µM) [40], and OAT3 (Ki =1.02 µM) [41] was implemented by PIO. Inhibition of ASBT (Ki =10.40 To predict the potential DDI of MT921, SIMV and PIO models already developed by Hanke, along with MT921 and AMLO PBPK models, were used [61,62]. K i values of ASBT, NTCP, OAT3, and OATP1B3 obtained from in vitro tests and literature were added to developed PBPK models.…”

Section: Prediction Of Potential Ddi Between Mt921 and The Inhibitors Of Uptake Transportersmentioning

confidence: 99%

Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

Ryu

Moon

Lee³

et al. 2021

Pharmaceuticals

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MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug–drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

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“…The compartmental structure of PBPK models is based on the body anatomy of the species modeled (Nestorov, 2007). Sequential metabolism PBPK models allow the simultaneous prediction of prodrug, active drug, and metabolite concentrations under different settings (Djebli et al, 2015;Eissing, Lippert, & Willmann, 2012;Hanke et al, 2018;Hu, Edginton, Laizure, & Parker, 2014;Vossen et al, 2007;Willmann, Edginton, Coboeken, Ahr, & Lippert, 2009). PBPK models can be used to scale to special populations such as pediatric (Björkman, 2005;Johnson, Rostami-Hodjegan, & Tucker, 2006).…”

Section: Introductionmentioning

confidence: 99%

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue

Alsmadi

Alfarah

Albderat

et al. 2019

Biopharm & Drug Disp

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Background Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney‐transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non‐invasive alternative compared with plasma. Methods A population physiologically based pharmacokinetic (Pop‐PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney‐transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC‐MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. Results The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop‐PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop‐PBPK predicted and observed) and MPA (Pop‐PBPK predicted). Conclusion Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney‐transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop‐PBPK model.

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A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis

Abstract: The first whole-body PBPK model of zoptarelin doxorubicin and its active metabolite doxorubicin has been successfully established. Zoptarelin doxorubicin shows no potential for DDIs via OATP1B3 and OCT2.

Cited by 18 publications

References 29 publications

Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

Evaluation for Potential Drug–Drug Interaction of MT921 Using In Vitro Studies and Physiologically–Based Pharmacokinetic Models

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue

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