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19 pages, 3952 KiB

Open AccessArticle

Model-Informed Repurposing of Medicines for SARS-CoV-2: Extrapolation of Antiviral Activity and Dose Rationale for Paediatric Patients

by Federico Romano, Salvatore D’Agate and Oscar Della Pasqua

Pharmaceutics 2021, 13(8), 1299; https://doi.org/10.3390/pharmaceutics13081299 - 19 Aug 2021

Cited by 6 | Viewed by 2801

Abstract

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in [...] Read more.

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in the target patient population, which includes not only adults but also children. Here we show how paediatric regimens can be identified using pharmacokinetic-pharmacodynamic (PKPD) principles to establish the target exposure and evaluate the implications of dose selection for early and late intervention. Using in vitro data describing the antiviral activity and published pharmacokinetic data for the agents of interest, we apply a model-based approach to assess the exposure range required for adequate viral clearance and eradication. Pharmacokinetic parameter estimates were subsequently used with clinical trial simulations to characterise the probability target attainment (PTA) associated with enhanced antiviral activity in the lungs. Our analysis shows that neither remdesivir, nor anti-malarial drugs can achieve the desirable target exposure range based on a mg/kg dosing regimen, due to a limited safety margin and high concentrations needed to ensure the required PTA. To date, there has been limited focus on suitable interventions for children affected by COVID-19. Most clinical trials have defined doses selection criteria empirically, without thorough evaluation of the PTA. The current results illustrate how model-based approaches can be used for the integration of clinical and nonclinical data, providing a robust framework for assessing the probability of pharmacological success and consequently the dose rationale for antiviral drugs for the treatment of SARS-CoV-2 infection in children. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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12 pages, 1134 KiB

Open AccessArticle

A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

by Orwa Albitar, Sabariah Noor Harun, Siti Nor Aizah Ahmad and Siti Maisharah Sheikh Ghadzi

Pharmaceutics 2021, 13(8), 1121; https://doi.org/10.3390/pharmaceutics13081121 - 22 Jul 2021

Cited by 4 | Viewed by 3007

Abstract

Clozapine remains the drug of choice for resistant schizophrenia. However, its dose-response relationship is still controversial. The current investigation aimed to develop a repeated time-to-positive symptoms improvement following the onset of clozapine treatment in Malaysian schizophrenia spectrum disorder patients. Data from patients’ medical [...] Read more.

Clozapine remains the drug of choice for resistant schizophrenia. However, its dose-response relationship is still controversial. The current investigation aimed to develop a repeated time-to-positive symptoms improvement following the onset of clozapine treatment in Malaysian schizophrenia spectrum disorder patients. Data from patients’ medical records in the Psychiatric Clinic, Penang General Hospital, were retrospectively analyzed. Several parametric survival models were evaluated using nonlinear mixed-effect modeling software (NONMEM 7.3.0). Kaplan–Meier-visual predictive check (KM-VPC) and sampling-importance resampling (SIR) methods were used to validate the final model. A total of 116 patients were included in the study, with a mean follow-up of 306 weeks. Weibull hazard function best fitted the data. The hazard of positive symptoms improvement decreased 4% for every one-year increase in age over the median of 41 years (adjusted hazard ratio (aHR), 0.96; 95% confidence intervals (95% CI), (0.93–0.98)). However, patients receiving a second atypical antipsychotic agent had four-folds higher hazard (aHR, 4.01; 95% CI, (1.97–7.17)). The hazard increased 2% (aHR, 1.02; 95% CI, (1.01–1.03)) for every 1 g increase in the clozapine six months cumulative dose over the median of 34 g. The developed model provides essential information on the hazard of positive symptoms improvement after the first clozapine dose administration, including modifiable predictors of high clinical importance. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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12 pages, 857 KiB

Open AccessArticle

The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia

by Robin Michelet, Moreno Ursino, Sandrine Boulet, Sebastian Franck, Fiordiligie Casilag, Mara Baldry, Jens Rolff, Madelé van Dyk, Sebastian G. Wicha, Jean-Claude Sirard, Emmanuelle Comets, Sarah Zohar and Charlotte Kloft

Pharmaceutics 2021, 13(5), 601; https://doi.org/10.3390/pharmaceutics13050601 - 22 Apr 2021

Cited by 1 | Viewed by 2991

Abstract

The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the [...] Read more.

The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia. For this, two case studies of translational modelling and simulation frameworks are introduced for these types of drugs up to clinical use. First, we evaluate the pharmacokinetic/pharmacodynamic relationship of an experimental combination of amoxicillin and a TLR4 agonist, monophosphoryl lipid A, by developing a pharmacometric model accounting for interaction and potential translation to humans. Capitalizing on this knowledge and associating clinical trial extrapolation and statistical modelling approaches, we then investigate the TLR5 agonist flagellin. The resulting workflow combines expert and prior knowledge on the compound with the in vitro and in vivo data generated during exploratory studies in order to construct high-dimensional models considering the pharmacokinetics and pharmacodynamics of the compound. This workflow can be used to refine preclinical experiments, estimate the best doses for human studies, and create an adaptive knowledge-based design for the next phases of clinical development. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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16 pages, 2277 KiB

Open AccessArticle

Matrix Effects of the Hydroethanolic Extract of Calyces of Physalis peruviana L. on Rutin Pharmacokinetics in Wistar Rats Using Population Modeling

by Gina Paola Domínguez Moré, María Isabel Cardona, Paula Michelle Sepúlveda, Sandra Milena Echeverry, Cláudia Maria Oliveira Simões and Diana Marcela Aragón

Pharmaceutics 2021, 13(4), 535; https://doi.org/10.3390/pharmaceutics13040535 - 12 Apr 2021

Cited by 9 | Viewed by 2568

Abstract

Rutin is the rutinose conjugate of quercetin. It presents several biological activities and is the major flavonoid in the hydroalcoholic extract of the calyces of Physalis peruviana L. It also shows hypoglycemic activity after oral administration. The aim of this work was to [...] Read more.

Rutin is the rutinose conjugate of quercetin. It presents several biological activities and is the major flavonoid in the hydroalcoholic extract of the calyces of Physalis peruviana L. It also shows hypoglycemic activity after oral administration. The aim of this work was to study the matrix effects of the extract from P. peruviana calyces on the pharmacokinetics of rutin and its metabolites in Wistar rats, using non-compartmental and population pharmacokinetic analyses. A pharmacokinetic study was performed after intravenous and oral administration of different doses of pure rutin and the extract. In the non-compartmental analysis, it was found that rutin from the extract exhibited higher distribution and clearance, as well as an 11-fold increase in the bioavailability of its active metabolites. A population pharmacokinetic model was also carried out with two compartments, double absorption and linear elimination, in which the extract and the doses were the covariates involved. This model correctly described the differences observed between rutin as a pure compound and rutin from the extract, including the dose dependency. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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15 pages, 2303 KiB

Open AccessArticle

Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total

by John Hood, Ignacio González-García, Nicholas White, Leeron Marshall, Vincent F. S. Dubois, Paolo Vicini and Paul G. Baverel

Pharmaceutics 2021, 13(4), 519; https://doi.org/10.3390/pharmaceutics13040519 - 9 Apr 2021

Cited by 3 | Viewed by 3333

Abstract

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce [...] Read more.

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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14 pages, 1141 KiB

Open AccessArticle

A Model-Informed Drug Development (MIDD) Approach for a Low Dose of Empagliflozin in Patients with Type 1 Diabetes

by Curtis K. Johnston, Rena J. Eudy-Byrne, Ahmed Elmokadem, Valerie Nock, Jan Marquard, Nima Soleymanlou, Matthew M. Riggs and Karl-Heinz Liesenfeld

Pharmaceutics 2021, 13(4), 485; https://doi.org/10.3390/pharmaceutics13040485 - 2 Apr 2021

Cited by 4 | Viewed by 3540

Abstract

In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, [...] Read more.

In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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11 pages, 1013 KiB

Open AccessArticle

A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

by Sebastian Franck, Robin Michelet, Fiordiligie Casilag, Jean-Claude Sirard, Sebastian G. Wicha and Charlotte Kloft

Pharmaceutics 2021, 13(4), 469; https://doi.org/10.3390/pharmaceutics13040469 - 30 Mar 2021

Cited by 4 | Viewed by 3726

Abstract

Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response [...] Read more.

Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival. Antibiotic serum concentrations, bacterial numbers in lung and spleen and survival data of mice being untreated or treated with amoxicillin (four dose levels), MPLA, or their combination were analyzed by nonlinear mixed-effects modelling and time-to-event analysis using NONMEM^® to characterize these treatment regimens. On top of a pharmacokinetic interaction, regarding the pharmacodynamic effects the combined treatment was superior to both monotherapies: The amoxicillin efficacy at highest dose was increased by a bacterial reduction of 1.74 log10 CFU/lung after 36 h and survival was increased 1.35-fold to 90.3% after 14 days both compared to amoxicillin alone. The developed pharmacometric pharmacokinetic/pharmacodynamic disease-treatment-survival models provided quantitative insights into a novel treatment option against pneumonia revealing a pharmacokinetic interaction and enhanced activity of amoxicillin and the immune system stimulator MPLA in combination. Further development of this drug combination flanked with pharmacometrics towards the clinical setting seems promising. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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16 pages, 2790 KiB

Open AccessArticle

Population Pharmacokinetics and Dose Optimization of Ceftazidime and Imipenem in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease

by Thu-Minh Nguyen, Thu-Hue Ngo, Anh-Quan Truong, Dinh-Hoa Vu, Dinh-Chi Le, Ngan-Binh Vu, Tuyet-Nga Can, Hoang-Anh Nguyen, Thu-Phuong Phan, Françoise Van Bambeke, Céline Vidaillac and Quy-Chau Ngo

Pharmaceutics 2021, 13(4), 456; https://doi.org/10.3390/pharmaceutics13040456 - 27 Mar 2021

Cited by 2 | Viewed by 4971

Abstract

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and [...] Read more.

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and imipenem in patients with AECOPD. Methods: We conducted a prospective PK study at Bach Mai Hospital (Viet Nam). A total of 50 (ceftazidime) and 44 (imipenem) patients with AECOPD were enrolled. Population PK analysis was performed using Monolix 2019R1 and Monte Carlo simulations were conducted to determine the optimal dose regimen with respect to the attainment of 60% and 40% fT>MIC for ceftazidime and imipenem, respectively. A dosing algorithm was developed to identify optimal treatment doses. Results: Ceftazidime and imipenem PK was best described by a one-compartment population model with a volume of distribution and clearance of 23.7 L and 8.74 L/h for ceftazidime and 15.1 L and 7.88 L/h for imipenem, respectively. Cockcroft–Gault creatinine clearance represented a significant covariate affecting the clearance of both drugs. Increased doses with prolonged infusion were found to cover pathogens with reduced susceptibility. Conclusions: This study describes a novel and versatile three-level dosing algorithm based on patients’ renal function and characteristic of the infective pathogen to explore ceftazidime and imipenem optimal regimen for AECOPD. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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13 pages, 2523 KiB

Open AccessArticle

Evaluation of Current Amikacin Dosing Recommendations and Development of an Interactive Nomogram: The Role of Albumin

by Jonás Samuel Pérez-Blanco, Eva María Sáez Fernández, María Victoria Calvo, José M. Lanao and Ana Martín-Suárez

Pharmaceutics 2021, 13(2), 264; https://doi.org/10.3390/pharmaceutics13020264 - 15 Feb 2021

Cited by 6 | Viewed by 4392

Abstract

This study aimed to evaluate the potential efficacy and safety of the amikacin dosage proposed by the main guidelines and to develop an interactive nomogram, especially focused on the potential impact of albumin on initial dosage recommendation. The probability of target attainment (PTA) [...] Read more.

This study aimed to evaluate the potential efficacy and safety of the amikacin dosage proposed by the main guidelines and to develop an interactive nomogram, especially focused on the potential impact of albumin on initial dosage recommendation. The probability of target attainment (PTA) for each of the different dosing recommendations was calculated through stochastic simulations based on pharmacokinetic/pharmacodynamic (PKPD) criteria. Large efficacy and safety differences were observed for the evaluated amikacin dosing guidelines together with a significant impact of albumin concentrations on efficacy and safety. For all recommended dosages evaluated, efficacy and safety criteria of amikacin dosage proposed were not achieved simultaneously in most of the clinical scenarios evaluated. Furthermore, a significant impact of albumin was identified: The higher is the albumin, (i) the higher will be the PTA for maximum concentration/minimum inhibitory concentration (Cmax/MIC), (ii) the lower will be the PTA for the time period with drug concentration exceeding MIC (T_>MIC) and (iii) the lower will be the PTA for toxicity (minimum concentration). Thus, accounting for albumin effect might be of interest for future amikacin dosing guidelines updates. In addition, AMKnom, an amikacin nomogram builder based on PKPD criteria, has been developed and is freely available to help evaluating dosing recommendations. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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17 pages, 1933 KiB

Open AccessArticle

Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico

by Darlene Santiago, Victor Mangas-Sanjuan, Kyle Melin, Jorge Duconge, Wenchen Zhao and Raman Venkataramanan

Pharmaceutics 2020, 12(12), 1226; https://doi.org/10.3390/pharmaceutics12121226 - 18 Dec 2020

Cited by 4 | Viewed by 2872

Abstract

Background: The aim of this analysis was to characterize the pharmacokinetics (PK) of sublingual buprenorphine (BUP) and its metabolites (buprenorphine glucuronide; BUP-g, norbuprenorphine; Nor-BUP, and norbuprenorphine glucuronide; Nor-BUP-g) in opioid use disorder (OUD) patients in Puerto Rico (PR) as a first step of [...] Read more.

Background: The aim of this analysis was to characterize the pharmacokinetics (PK) of sublingual buprenorphine (BUP) and its metabolites (buprenorphine glucuronide; BUP-g, norbuprenorphine; Nor-BUP, and norbuprenorphine glucuronide; Nor-BUP-g) in opioid use disorder (OUD) patients in Puerto Rico (PR) as a first step of evidence-based BUP dosing strategies in this population. Methods: BUP and metabolites concentrations were measured from 0 to 8 h after the administration of sublingual buprenorphine/naloxone films in 12 stable OUD subjects. Results: PK non-compartmental characteristics showed considerable variability in parameters between the subjects over the 8-h sampling time (t_max = 1.5 ± 0.7 h, C_o = 1.6 ± 1.4 ng/mL, C_max= 7.1 ± 6 ng/mL, and AUC_0–8h = 26.8 ± 17.8 h·ng/mL). Subjects had a significantly higher tendency towards CYP-mediated N-demethylation, with the AUC_0–8h ratios of the molar concentrations of [Nor-BUP + Nor-BUP-g] to BUP being (3.4 ± 1.9) significantly higher compared with BUP-g to BUP (0.19 ± 0.2). A two-compartment population-PK model with linear absorption (k_a = 2.54 h⁻¹), distribution (k₁₂= 2.34 h⁻¹, k₁₄ = 1.29 h⁻¹), metabolism (k₂₄ = 1.28 × 10⁻¹ h⁻¹, k₂₃ = 6.43 × 10⁻² h⁻¹, k₃₅ = 1.23 × 10⁻¹ h⁻¹, k₄₅ = 8.73 × 10⁻¹ h⁻¹), and elimination (k₃₀ = 3.81 × 10⁻³ h⁻¹, k₅₀ = 1.27 × 10⁻¹ h⁻¹) adequately described the time-course of BUP and its metabolites, which has been externally validated using published data. Conclusions: Although limited in sampling time and number of recruited subjects, this study presents specific BUP PK characteristics that evidenced the need for additional PK studies and subsequent modeling of the data for the development of evidence-based dosing approaches in Puerto Rico. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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14 pages, 1570 KiB

Open AccessArticle

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease

by Niurys de Castro-Suárez, Mirjam N. Trame, Mayra Ramos-Suzarte, José M. Dávalos, Raymed A. Bacallao-Mendez, Anaelys R. Maceo-Sinabele, Víctor Mangas-Sanjuán, Gledys Reynaldo-Fernández and Leyanis Rodríguez-Vera

Pharmaceutics 2020, 12(12), 1147; https://doi.org/10.3390/pharmaceutics12121147 - 26 Nov 2020

Viewed by 2935

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM^®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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17 pages, 11139 KiB

Open AccessArticle

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

by Javier Reig-López, María del Mar Maldonado, Matilde Merino-Sanjuan, Ailed M. Cruz-Collazo, Jean F. Ruiz-Calderón, Victor Mangas-Sanjuán, Suranganie Dharmawardhane and Jorge Duconge

Pharmaceutics 2020, 12(10), 975; https://doi.org/10.3390/pharmaceutics12100975 - 15 Oct 2020

Cited by 7 | Viewed by 3848

Abstract

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim [...] Read more.

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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18 pages, 1031 KiB

Open AccessReview

The Role of Mathematical Models in Immuno-Oncology: Challenges and Future Perspectives

by Aymara Sancho-Araiz, Victor Mangas-Sanjuan and Iñaki F. Trocóniz

Pharmaceutics 2021, 13(7), 1016; https://doi.org/10.3390/pharmaceutics13071016 - 2 Jul 2021

Cited by 10 | Viewed by 3835

Abstract

Immuno-oncology (IO) focuses on the ability of the immune system to detect and eliminate cancer cells. Since the approval of the first immune checkpoint inhibitor, immunotherapies have become a major player in oncology treatment and, in 2021, represented the highest number of approved [...] Read more.

Immuno-oncology (IO) focuses on the ability of the immune system to detect and eliminate cancer cells. Since the approval of the first immune checkpoint inhibitor, immunotherapies have become a major player in oncology treatment and, in 2021, represented the highest number of approved drugs in the field. In spite of this, there is still a fraction of patients that do not respond to these therapies and develop resistance mechanisms. In this sense, mathematical models offer an opportunity to identify predictive biomarkers, optimal dosing schedules and rational combinations to maximize clinical response. This work aims to outline the main therapeutic targets in IO and to provide a description of the different mathematical approaches (top-down, middle-out, and bottom-up) integrating the cancer immunity cycle with immunotherapeutic agents in clinical scenarios. Among the different strategies, middle-out models, which combine both theoretical and evidence-based description of tumor growth and immunological cell-type dynamics, represent an optimal framework to evaluate new IO strategies. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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27 pages, 17584 KiB

Open AccessReview

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

by Alicia Rodríguez-Gascón, María Ángeles Solinís and Arantxa Isla

Pharmaceutics 2021, 13(6), 833; https://doi.org/10.3390/pharmaceutics13060833 - 3 Jun 2021

Cited by 60 | Viewed by 9124

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) analysis has proved to be very useful to establish rational dosage regimens of antimicrobial agents in human and veterinary medicine. Actually, PK/PD studies are included in the European Medicines Agency (EMA) guidelines for the evaluation of medicinal products. The PK/PD approach [...] Read more.

Pharmacokinetic/pharmacodynamic (PK/PD) analysis has proved to be very useful to establish rational dosage regimens of antimicrobial agents in human and veterinary medicine. Actually, PK/PD studies are included in the European Medicines Agency (EMA) guidelines for the evaluation of medicinal products. The PK/PD approach implies the use of in vitro, ex vivo, and in vivo models, as well as mathematical models to describe the relationship between the kinetics and the dynamic to determine the optimal dosing regimens of antimicrobials, but also to establish susceptibility breakpoints, and prevention of resistance. The final goal is to optimize therapy in order to maximize efficacy and minimize side effects and emergence of resistance. In this review, we revise the PK/PD principles and the models to investigate the relationship between the PK and the PD of antibiotics. Additionally, we highlight the outstanding role of the PK/PD analysis at different levels, from the development and evaluation of new antibiotics to the optimization of the dosage regimens of currently available drugs, both for human and animal use. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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28 pages, 3099 KiB

Open AccessReview

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

by Yu Tang and Yanguang Cao

Pharmaceutics 2021, 13(3), 422; https://doi.org/10.3390/pharmaceutics13030422 - 21 Mar 2021

Cited by 19 | Viewed by 7450

Abstract

With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing many therapeutic advantages such as long half-life and highly selective actions, therapeutic antibodies [...] Read more.

With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing many therapeutic advantages such as long half-life and highly selective actions, therapeutic antibodies still face many outstanding issues associated with their pharmacokinetics (PK) and pharmacodynamics (PD), including high variabilities, low tissue distributions, poorly-defined PK/PD characteristics for novel antibody formats, and high rates of treatment resistance. We have witnessed many successful cases applying PK/PD modeling to answer critical questions in therapeutic antibodies’ development and regulations. These models have yielded substantial insights into antibody PK/PD properties. This review summarized the progress, challenges, and future directions in modeling antibody PK/PD and highlighted the potential of applying mechanistic models addressing the development questions. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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