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Article: Editorial: Innovative pharmacometric approaches to inform drug development and clinical use.

Garcia-Cremades, Maria / Parra-Guillen, Zinnia P / Mangas-Sanjuan, Victor / Geerts, Hugo

2023 Volume 14, Page(s) 1274139

Language	English
Publishing date	2023-10-04
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1274139
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Article: Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment.

García-Martínez, Teresa / Bellés-Medall, María Dolores / García-Cremades, Maria / Ferrando-Piqueres, Raúl / Mangas-Sanjuán, Victor / Merino-Sanjuan, Matilde

Pharmaceutics

2022 Volume 14, Issue 10

Abstract: The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. ... ...

Abstract	The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and non-linear binding kinetics were evaluated. Monte Carlo simulations were conducted with a fixed combination of creatinine clearance (30-90 mL/min/1.73 m
Language	English
Publishing date	2022-10-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14102226
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Article ; Online: Clinical Pharmacokinetics of Oral Sodium Selenite and Dosing Implications in the Treatment of Patients with Metastatic Cancer.

Jayachandran, Priya / Knox, Susan J / Garcia-Cremades, Maria / Savić, Radojka M

Drugs in R&D

2021 Volume 21, Issue 2, Page(s) 169–178

Abstract: Background: Selenite is a radiosensitizer and inhibitor of androgen receptor expression and function. In a phase I study (NCT02184533) in 15 subjects with metastatic cancer receiving daily oral sodium selenite with palliative radiation therapy, disease ... ...

Abstract	Background: Selenite is a radiosensitizer and inhibitor of androgen receptor expression and function. In a phase I study (NCT02184533) in 15 subjects with metastatic cancer receiving daily oral sodium selenite with palliative radiation therapy, disease stabilization was observed, as evidenced by tumor regression, marked reduction in pain symptoms, and decreased prostate-specific antigen levels (only patients with castrate-resistant prostate cancer). Objective: The aim of this work was to characterize the pharmacokinetics of selenite to suggest dosing strategies and to propose a study design for further investigation. Methods: With selenium plasma concentrations obtained from five dosing cohorts (5.5, 11, 16.5, 33, and 49.5 mg), a population pharmacokinetic model was constructed using NONMEM. The model described externally administered selenite (inorganic) with a baseline component for endogenous selenium levels. Using the pharmacokinetic model, simulations were performed to suggest dosing regimens that achieved in vitro target selenite levels, and optimal pharmacokinetic sampling times for a subsequent study were proposed using PopED. Results: A one-compartment model characterized selenite pharmacokinetics. Parameter estimates were absorption rate constant (0.64 h Discussion: The population model described the pharmacokinetic data well. Three regimens (33 mg daily, 11 mg BID, 5.5 mg TID) achieved in vitro target selenite levels after one dose. The model and optimal sampling times may inform future studies evaluating the efficacy of selenite for metastatic cancer treatment.
MeSH term(s)	Administration, Oral ; Biological Availability ; Humans ; Male ; Neoplasms/drug therapy ; Selenious Acid ; Sodium Selenite
Chemical Substances	Selenious Acid (F6A27P4Q4R) ; Sodium Selenite (HIW548RQ3W)
Language	English
Publishing date	2021-04-17
Publishing country	New Zealand
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	2020476-0
ISSN	1179-6901 ; 1174-5886
ISSN (online)	1179-6901
ISSN	1174-5886
DOI	10.1007/s40268-021-00340-9
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Article ; Online: Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2',2'-difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer.

Garcia-Cremades, Maria / Melillo, Nicola / Troconiz, Iñaki F / Magni, Paolo

Clinical and translational science

2020 Volume 13, Issue 3, Page(s) 608–617

Abstract: The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2',2'-difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence ... ...

Abstract	The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2',2'-difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of this kind of modeling strategy. A mechanistic model characterizing dFdC metabolic pathway (metabolic network) was developed using in vitro literature data from two pancreatic cancer cell lines. The network was able to describe the time course of extracellular and intracellular dFdC metabolites concentrations. Moreover, a physiologically-based pharmacokinetic model was developed to describe clinical dFdC profiles by using enzymatic and physiological information available in the literature. This model was then coupled with the metabolic network to describe the dFdC active metabolite profile in the pancreatic tumor tissue. Finally, global sensitivity analysis was performed to identify the parameters that mainly drive the interindividual variability for the area under the curve (AUC) of dFdC in plasma and of its active metabolite (dFdCTP) in tumor tissue. From this analysis, cytidine deaminase (CDA) concentration was identified as the main driver of plasma dFdC AUC interindividual variability, whereas CDA and deoxycytidine kinase concentration mainly explained the tumor dFdCTP AUC variability. However, the lack of in vitro and in vivo information needed to characterize key model parameters hampers the development of this kind of mechanistic approach. Further studies to better characterize pancreatic cell lines and patient enzymes polymorphisms are encouraged to refine and validate the current model.
MeSH term(s)	Antimetabolites, Antineoplastic/pharmacokinetics ; Antimetabolites, Antineoplastic/therapeutic use ; Area Under Curve ; Cell Line, Tumor ; Cytidine Deaminase/blood ; Cytidine Deaminase/metabolism ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacokinetics ; Deoxycytidine/therapeutic use ; Humans ; Metabolic Networks and Pathways/genetics ; Models, Biological ; Pancreatic Neoplasms/blood ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology
Chemical Substances	Antimetabolites, Antineoplastic ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2020-03-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12747
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Article ; Online: Translational Framework Predicting Tumour Response in Gemcitabine-Treated Patients with Advanced Pancreatic and Ovarian Cancer from Xenograft Studies.

Garcia-Cremades, Maria / Pitou, Celine / Iversen, Philip W / Troconiz, Iñaki F

The AAPS journal

2019 Volume 21, Issue 2, Page(s) 23

Abstract: The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model ... ...

Abstract	The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model combining pre-clinical pharmacokinetic-pharmacodynamic (PKPD) models and parameters, with dosing paradigms used in the clinics along with clinical PK models to derive tumour profiles in humans driving overall survival. Tumour growth inhibition simulations were performed using drug effect parameters obtained from mice, system parameters obtained from mice after appropriate scaling, patient PK models for gemcitabine and carboplatin, and the standard dosing schedules given in the clinical scenario for both types of cancers. Tumour profiles in mice were scaled by body weight to their equivalent values in humans. As models for survival in humans showed that tumour size was the main driver of the hazard rate, it was possible to describe overall survival in pancreatic and ovarian cancer patients. Simulated tumour dynamics in pancreatic and ovarian cancer patients were evaluated using available data from clinical trials. Furthermore, calculated metrics showed values (maximal tumour regression [0-17%] and tumour size ratio at week 12 with respect to baseline [- 9, - 4.5]) in the range of those predicted with the clinical PKPD models. The model-informed Drug Discovery and Development paradigm has been successfully applied retrospectively to gemcitabine data, through a semi-mechanistic translational approach, describing the time course of the tumour response in patients from pre-clinical studies.
MeSH term(s)	Animals ; Antimetabolites, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/therapeutic use ; Data Interpretation, Statistical ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Mice ; Models, Biological ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/mortality ; Ovarian Neoplasms/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/mortality ; Pancreatic Neoplasms/pathology ; Prognosis ; Retrospective Studies ; Survival Analysis ; Treatment Outcome ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antimetabolites, Antineoplastic ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R)
Language	English
Publishing date	2019-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-018-0291-9
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Article ; Online: Emerging Therapeutics, Technologies, and Drug Development Strategies to Address Patient Nonadherence and Improve Tuberculosis Treatment.

Garcia-Cremades, Maria / Solans, Belen P / Strydom, Natasha / Vrijens, Bernard / Pillai, Goonaseelan Colin / Shaffer, Craig / Thomas, Bruce / Savic, Rada M

Annual review of pharmacology and toxicology

2021 Volume 62, Page(s) 197–210

Abstract: Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient ... ...

Abstract	Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variabilityin drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis.
MeSH term(s)	Drug Development ; Humans ; Medication Adherence
Language	English
Publishing date	2021-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	196587-6
ISSN	1545-4304 ; 0362-1642
ISSN (online)	1545-4304
ISSN	0362-1642
DOI	10.1146/annurev-pharmtox-041921-074800
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Article ; Online: Predicting tumour growth and its impact on survival in gemcitabine-treated patients with advanced pancreatic cancer.

Garcia-Cremades, Maria / Pitou, Celine / Iversen, Philip W / Troconiz, Iñaki F

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2018 Volume 115, Page(s) 296–303

Abstract: The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi- ... ...

Abstract	The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi-mechanistic joint TS-OS model. TS and OS data were obtained from one phase II and one phase III study where gemcitabine was administered (1000-1250 mg/kg over 30-60 min i.v infusion) as single agent to patients (n = 285) with advanced pancreatic cancer. Drug exposure, TS and OS were linked using the population approach with NONMEM 7.3. Pancreatic tumour progression was characterized by exponential growth (doubling time = 67 weeks), and tumour response to treatment was described as a function of the weekly area under the gemcitabine triphosphate concentration vs time curve (AUC), including treatment-related resistance development. The typical predicted percentage of tumour growth inhibition with respect to no treatment was 22.3% at the end of 6 chemotherapy cycles. Emerging resistance elicited a 57% decrease in drug effects during the 6th chemotherapy cycle. Predicted TS profile was identified as main prognostic factor of OS, with tumours responders' profiles improving median OS by 30 weeks compared to stable-disease TS profiles. Results of NCT00574275 trial were predicted using this modelling framework, thereby validating the approach as a prediction tool in clinical development. Our analyses show that despite the advanced stage of the disease in this patient population, the modelling framework herein can be used to predict the likelihood of treatment success using early clinical data.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Cell Proliferation/drug effects ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/therapeutic use ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Pancreas/drug effects ; Pancreas/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Prognosis ; Treatment Outcome
Chemical Substances	Antineoplastic Agents ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R)
Language	English
Publishing date	2018-01-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2018.01.033
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Article ; Online: Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Maria Garcia‐Cremades / Nicola Melillo / Iñaki F. Troconiz / Paolo Magni

Clinical and Translational Science, Vol 13, Iss 3, Pp 608-

2020 Volume 617

Abstract: The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2’,2’‐difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence ... ...

Abstract	The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2’,2’‐difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of this kind of modeling strategy. A mechanistic model characterizing dFdC metabolic pathway (metabolic network) was developed using in vitro literature data from two pancreatic cancer cell lines. The network was able to describe the time course of extracellular and intracellular dFdC metabolites concentrations. Moreover, a physiologically‐based pharmacokinetic model was developed to describe clinical dFdC profiles by using enzymatic and physiological information available in the literature. This model was then coupled with the metabolic network to describe the dFdC active metabolite profile in the pancreatic tumor tissue. Finally, global sensitivity analysis was performed to identify the parameters that mainly drive the interindividual variability for the area under the curve (AUC) of dFdC in plasma and of its active metabolite (dFdCTP) in tumor tissue. From this analysis, cytidine deaminase (CDA) concentration was identified as the main driver of plasma dFdC AUC interindividual variability, whereas CDA and deoxycytidine kinase concentration mainly explained the tumor dFdCTP AUC variability. However, the lack of in vitro and in vivo information needed to characterize key model parameters hampers the development of this kind of mechanistic approach. Further studies to better characterize pancreatic cell lines and patient enzymes polymorphisms are encouraged to refine and validate the current model.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	500
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention.

Jayachandran, Priya / Garcia-Cremades, Maria / Vučićević, Katarina / Bumpus, Namandjé N / Anton, Peter / Hendrix, Craig / Savić, Radojka

CPT: pharmacometrics & systems pharmacology

2021 Volume 10, Issue 3, Page(s) 179–187

Abstract: Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir ... ...

Abstract	Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV-1 seronegative adults was used to construct a multicompartment plasma-rectal tissue population PK model for TFV and tenofovir-diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV-1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.
MeSH term(s)	Administration, Oral ; Administration, Rectal ; Adult ; Aged ; Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/pharmacokinetics ; Anti-HIV Agents/pharmacology ; Biological Availability ; Drug Development/methods ; Female ; Gels/pharmacology ; Gels/therapeutic use ; HIV Core Protein p24/drug effects ; HIV Core Protein p24/metabolism ; HIV Infections/prevention & control ; HIV Seronegativity/drug effects ; Humans ; Leukocytes, Mononuclear/drug effects ; Male ; Middle Aged ; Models, Theoretical ; Pre-Exposure Prophylaxis/methods ; Rectum/cytology ; Rectum/drug effects ; Tenofovir/administration & dosage ; Tenofovir/pharmacokinetics ; Tenofovir/pharmacology ; Virus Replication/drug effects
Chemical Substances	Anti-HIV Agents ; Gels ; HIV Core Protein p24 ; Tenofovir (99YXE507IL)
Language	English
Publishing date	2021-02-06
Publishing country	United States
Document type	Clinical Trial ; Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12583
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Article ; Online: Oxypurinol pharmacokinetics and pharmacodynamics in healthy volunteers: Influence of BCRP Q141K polymorphism and patient characteristics.

Vora, Bianca / Brackman, Deanna J / Zou, Ling / Garcia-Cremades, Maria / Sirota, Marina / Savic, Radojka M / Giacomini, Kathleen M

Clinical and translational science

2021 Volume 14, Issue 4, Page(s) 1431–1443

Abstract: The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p ... ...

Abstract	The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Adolescent ; Adult ; Creatinine/blood ; Creatinine/metabolism ; Female ; Glomerular Filtration Rate ; Half-Life ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Models, Biological ; Mutation, Missense ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Oxypurinol/administration & dosage ; Oxypurinol/pharmacokinetics ; Pharmacogenomic Variants ; Polymorphism, Single Nucleotide ; Prospective Studies ; Renal Elimination ; Sex Factors ; Uric Acid/blood ; Uric Acid/metabolism ; Young Adult
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Uric Acid (268B43MJ25) ; Creatinine (AYI8EX34EU) ; Oxypurinol (G97OZE5068)
Language	English
Publishing date	2021-05-01
Publishing country	United States
Document type	Clinical Trial, Phase IV ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12992
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