The Role of Pharmacometrics in Drug Discovery and Development Process (Volume II)

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 37885

Special Issue Editors

Department of Pharmacy and Pharmaceutical Technology and Parasitology, School of Pharmacy, University of Valencia, Valencia, Spain
Interests: pharmacokinetics; biopharmaceutics; oral absorption; dissolution methods
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, Universidad de Navarra, Pamplona, Spain
Interests: population analysis; pharmacokinetics/pharmacodynamics/disease modeling; pharmacometrics; systems pharmacology; model-based-drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmacometrics is the science that integrates information on drug behavior, pharmacological response, and disease progression using mathematical models based on biology, pharmacology, and pathophysiology, along with statistical models that allow describing and explaining the sources of variability in the studied populations. Its quantitative, integrative, and translational capacity helps not only describe the observed behavior (prediction) but evaluate (simulation) with a greater degree of certainty unknown situations and scenarios. Model-informed approaches have revolutionized drug development and therapeutic use paradigm due to a more rational and efficient decision making, achieving significant support from the main regulatory agencies (FDA, EMA, PMDA).

This Special Issue is focused on new modeling strategies and methodologies, applications in the preclinical and clinical field that can highlight the relevance of pharmacometrics in the PK or PK/PD characterization, identification of relevant sources of variability, inter-species scaling, optimization of dosing schedules in special sub-groups of populations, optimal design, QTc prolongation, placebo and disease models, and exposure-response analysis using continuous or categorical data.

Dr. Victor Mangas Sanjuán
Prof. Dr. Inaki F. Troconiz
Guest Editors

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Keywords

  • pharmacometrics
  • population analysis
  • pharmacokinetics
  • pharmacodynamics
  • modeling

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Published Papers (16 papers)

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Research

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15 pages, 2165 KiB  
Article
Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice
by Christos Kaikousidis, Paraskevi Papakyriakopoulou, Aristides Dokoumetzidis and Georgia Valsami
Pharmaceutics 2023, 15(5), 1409; https://doi.org/10.3390/pharmaceutics15051409 - 05 May 2023
Cited by 1 | Viewed by 1585
Abstract
Intranasal delivery is a non-invasive mode of administration, gaining popularity due to its potential for targeted delivery to the brain. The anatomic connection of the nasal cavity with the central nervous system (CNS) is based on two nerves: olfactory and trigeminal. Moreover, the [...] Read more.
Intranasal delivery is a non-invasive mode of administration, gaining popularity due to its potential for targeted delivery to the brain. The anatomic connection of the nasal cavity with the central nervous system (CNS) is based on two nerves: olfactory and trigeminal. Moreover, the high vasculature of the respiratory area enables systemic absorption avoiding possible hepatic metabolism. Due to these physiological peculiarities of the nasal cavity, compartmental modeling for nasal formulation is considered a demanding process. For this purpose, intravenous models have been proposed, based on the fast absorption from the olfactory nerve. However, most of the sophisticated approaches are required to describe the different absorption events occurring in the nasal cavity. Donepezil was recently formulated in the form of nasal film ensuring drug delivery in both bloodstream and the brain. In this work, a three-compartment model was first developed to describe donepezil oral brain and blood pharmacokinetics. Subsequently, using parameters estimated by this model, an intranasal model was developed dividing the administered dose into three fractions, corresponding to absorption directly to the bloodstream and brain, as well as indirectly to the brain expressed through transit compartments. Hence, the models of this study aim to describe the drug flow on both occasions and quantify the direct nose-to-brain and systemic distribution. Full article
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13 pages, 3454 KiB  
Article
Evaluation of a Cardiovascular Systems Model for Design and Analysis of Hemodynamic Safety Studies
by Yu Fu, Nelleke Snelder, Tingjie Guo, Piet H. van der Graaf and Johan. G. C. van Hasselt
Pharmaceutics 2023, 15(4), 1175; https://doi.org/10.3390/pharmaceutics15041175 - 07 Apr 2023
Viewed by 1035
Abstract
Early prediction, quantification and translation of cardiovascular hemodynamic drug effects is essential in pre-clinical drug development. In this study, a novel hemodynamic cardiovascular systems (CVS) model was developed to support these goals. The model consisted of distinct system- and drug-specific parameter, and uses [...] Read more.
Early prediction, quantification and translation of cardiovascular hemodynamic drug effects is essential in pre-clinical drug development. In this study, a novel hemodynamic cardiovascular systems (CVS) model was developed to support these goals. The model consisted of distinct system- and drug-specific parameter, and uses data for heart rate (HR), cardiac output (CO), and mean atrial pressure (MAP) to infer drug mode-of-action (MoA). To support further application of this model in drug development, we conducted a systematic analysis of the estimation performance of the CVS model to infer drug- and system-specific parameters. Specifically, we focused on the impact on model estimation performance when considering differences in available readouts and the impact of study design choices. To this end, a practical identifiability analysis was performed, evaluating model estimation performance for different combinations of hemodynamic endpoints, drug effect sizes, and study design characteristics. The practical identifiability analysis showed that MoA of drug effect could be identified for different drug effect magnitudes and both system- and drug-specific parameters can be estimated precisely with minimal bias. Study designs which exclude measurement of CO or use a reduced measurement duration still allow the identification and quantification of MoA with acceptable performance. In conclusion, the CVS model can be used to support the design and inference of MoA in pre-clinical CVS experiments, with a future potential for applying the uniquely identifiable systems parameters to support inter-species scaling. Full article
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16 pages, 4513 KiB  
Article
Leveraging Physiologically Based Modelling to Provide Insights on the Absorption of Paliperidone Extended-Release Formulation under Fed and Fasting Conditions
by Saima Subhani, Viera Lukacova, Chaejin Kim, Leyanis Rodriguez-Vera, Paula Muniz, Monica Rodriguez, Rodrigo Cristofoletti, Sandra Van Os, Elena Suarez, Stephan Schmidt and Valvanera Vozmediano
Pharmaceutics 2023, 15(2), 629; https://doi.org/10.3390/pharmaceutics15020629 - 13 Feb 2023
Cited by 1 | Viewed by 2413
Abstract
Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega®) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing [...] Read more.
Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega®) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively. Food has various effects on gastrointestinal (GI) physiology, including changed transit times, changed volumes, altered pH in different GI compartments, secretion of bile salts, and increased hepatic blood flow. This may affect solubility, the dissolution rate, absorption, and the pharmacokinetics. The aim of this study was to apply physiologically based absorption modeling (PBAM) to provide insights on paliperidone ER absorption under fed and fasting conditions. The PBAM adequately predicted absorption from the OROS formulation under both conditions. Absorption primarily occurs in the ascending colon and caecum. After a high-fat/high-calorie meal, absorption is increased through the jejunum, ileum, and colon due to either increased solubilization or the better efficiency of the OROS technology. PBAM-guided approaches can improve the understanding of branded drugs and thereby aid in guiding the development of generic formulations or formulation alternatives. Full article
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16 pages, 2484 KiB  
Article
Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia
by Xiaoqing Fan, Wojciech Krzyzanski, Dongyang Liu, Raymond S. M. Wong and Xiaoyu Yan
Pharmaceutics 2023, 15(2), 344; https://doi.org/10.3390/pharmaceutics15020344 - 19 Jan 2023
Viewed by 1304
Abstract
Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce [...] Read more.
Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance. We further found that the combination of EPO with romiplostim, a thrombopoietin receptor agonist that can stimulate the expansion of hematopoietic stem cells, can treat EPO-resistance. In this study, we performed interspecies pharmacodynamic (PD) scaling of this combination therapy for human dose prediction. The pharmacokinetic parameters of both rHuEPO and romiplostim in humans were obtained from previous studies. The PD parameters obtained in rats were scaled to humans using allometric equations. The relationship between PD parameters of the megakaryocyte lineage from rats, monkeys, and humans was in agreement with those from the literature on allometric scaling. The PD response was translated to humans based on allometric scaling and agreed with the observed data. These parameters were used to simulate hemoglobin and platelet response in humans. RHuEPO 50 IU/kg thrice weekly and romiplostim 1 μg/kg once every 4 weeks from the second week is the recommended combination dosing regimen according to the model prediction. Our work successfully scaled the PD of rHuEPO and romiplostim monotherapy from rats to humans. The predicted dosing regimen of each drug in the combination therapy is less intensive than the approved starting dose of each drug, which supports additional evaluations of the combination therapy in humans. Full article
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13 pages, 4120 KiB  
Article
Fractal Kinetic Implementation in Population Pharmacokinetic Modeling
by Woojin Jung, Hyo-jeong Ryu, Jung-woo Chae and Hwi-yeol Yun
Pharmaceutics 2023, 15(1), 304; https://doi.org/10.3390/pharmaceutics15010304 - 16 Jan 2023
Viewed by 2012
Abstract
Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, [...] Read more.
Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, as novel drugs are increasingly characterized by physiological or physical features. Alternative approaches have focused on fractal kinetics, but evaluations of their application are lacking. Thus, in this study, a simulation was performed to identify desirable fractal-kinetics applications in conventional modeling. Visible changes in the profiles were then investigated. Five cases of finalized population models were collected for implementation. For model diagnosis, the objective function value (OFV), Akaike’s information criterion (AIC), and corrected Akaike’s information criterion (AICc) were used as performance metrics, and the goodness of fit (GOF), visual predictive check (VPC), and normalized prediction distribution error (NPDE) were used as visual diagnostics. In most cases, model performance was enhanced by the fractal rate, as shown in a simulation study. The necessary parameters of the fractal rate in the model varied and were successfully estimated between 0 and 1. GOF, VPC, and NPDE diagnostics show that models with the fractal rate described the data well and were robust. In the simulation study, the fractal absorption process was, therefore, chosen for testing. In the estimation study, the rate application yielded improved performance and good prediction–observation agreement in early sampling points, and did not cause a large shift in the original estimation results. Thus, the fractal rate yielded explainable parameters by setting only the heterogeneity exponent, which reflects true physiological behavior well. This approach can be expected to provide useful insights in pharmacological decision making. Full article
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27 pages, 5120 KiB  
Article
A Mechanistic Pharmacodynamic Modeling Framework for the Assessment and Optimization of Proteolysis Targeting Chimeras (PROTACs)
by Robin Thomas Ulrich Haid and Andreas Reichel
Pharmaceutics 2023, 15(1), 195; https://doi.org/10.3390/pharmaceutics15010195 - 05 Jan 2023
Cited by 7 | Viewed by 5084
Abstract
The field of targeted protein degradation is growing exponentially. Yet, there is an unmet need for pharmacokinetic/pharmacodynamic models that provide mechanistic insights, while also being practically useful in a drug discovery setting. Therefore, we have developed a comprehensive modeling framework which can be [...] Read more.
The field of targeted protein degradation is growing exponentially. Yet, there is an unmet need for pharmacokinetic/pharmacodynamic models that provide mechanistic insights, while also being practically useful in a drug discovery setting. Therefore, we have developed a comprehensive modeling framework which can be applied to experimental data from routine projects to: (1) assess PROTACs based on accurate degradation metrics, (2) guide compound optimization of the most critical parameters, and (3) link degradation to downstream pharmacodynamic effects. The presented framework contains a number of first-time features: (1) a mechanistic model to fit the hook effect in the PROTAC concentration-degradation profile, (2) quantification of the role of target occupancy in the PROTAC mechanism of action and (3) deconvolution of the effects of target degradation and target inhibition by PROTACs on the overall pharmacodynamic response. To illustrate applicability and to build confidence, we have employed these three models to analyze exemplary data on various compounds from different projects and targets. The presented framework allows researchers to tailor their experimental work and to arrive at a better understanding of their results, ultimately leading to more successful PROTAC discovery. While the focus here lies on in vitro pharmacology experiments, key implications for in vivo studies are also discussed. Full article
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16 pages, 2911 KiB  
Article
Development of a Physiologically Based Pharmacokinetic Model for Tegoprazan: Application for the Prediction of Drug–Drug Interactions with CYP3A4 Perpetrators
by Lien Thi Ngo, Jaeyeon Lee, Hwi-yeol Yun and Jung-woo Chae
Pharmaceutics 2023, 15(1), 182; https://doi.org/10.3390/pharmaceutics15010182 - 04 Jan 2023
Cited by 3 | Viewed by 2555
Abstract
Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) developed by CJ Healthcare (Korea) for the treatment of gastroesophageal reflux disease and helicobacter pylori infections. Tegoprazan is mainly metabolized by cytochrome P450 (CYP) 3A4. Considering the therapeutic indications, tegoprazan is likely to be administered [...] Read more.
Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) developed by CJ Healthcare (Korea) for the treatment of gastroesophageal reflux disease and helicobacter pylori infections. Tegoprazan is mainly metabolized by cytochrome P450 (CYP) 3A4. Considering the therapeutic indications, tegoprazan is likely to be administered in combination with various drugs. Therefore, the investigation of drug–drug interactions (DDI) between tegoprazan and CYP3A4 perpetrators is imperative. In the present study, we first aimed to develop a physiologically based pharmacokinetic (PK) model for tegoprazan and its major metabolite, M1, using PK-Sim®. This model was applied to predict the DDI between tegoprazan and CYP3A4 perpetrators. Clarithromycin, a potent inhibitor of CYP3A4, and rifampicin, a strong inducer of CYP3A4, were selected as case studies. Our results show that clarithromycin significantly increased the exposure of tegoprazan. The area under the concentration–time curve (AUC) and Cmax of tegoprazan in the steady state increased up to 4.54- and 2.05-fold, respectively, when tegoprazan (50 mg, twice daily) was coadministered with clarithromycin (500 mg, three times daily). Rifampicin significantly reduced the exposure of tegoprazan. The AUC and Cmax of tegoprazan were reduced by 5.71- and 3.51-fold when tegoprazan was coadministered with rifampicin (600 mg, once daily). Due to the high DDI potential, the comedication of tegoprazan with CYP3A4 perpetrators should be controlled. The dosage adjustment for each individual is suggested. Full article
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15 pages, 3551 KiB  
Article
Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment
by Teresa García-Martínez, María Dolores Bellés-Medall, Maria García-Cremades, Raúl Ferrando-Piqueres, Victor Mangas-Sanjuán and Matilde Merino-Sanjuan
Pharmaceutics 2022, 14(10), 2226; https://doi.org/10.3390/pharmaceutics14102226 - 18 Oct 2022
Cited by 1 | Viewed by 1536
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 [...] Read more.
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 m2) and body weight (50–100 kg). The final dataset included 46 patients and 157 daptomycin observations. A two-compartment model with first-order peripheral distribution and elimination kinetics assuming non-linear protein-binding kinetics was selected. The bactericidal effect for Gram+ strains with MIC ≤ 0.5 mg/L could be achieved with 5–12 mg/kg daily daptomycin based on body weight and renal function. The administration of 10–17 mg/kg q48 h daptomycin allows to achieve bactericidal effect for Gram+ strains with MIC ≤ 1 mg/L. Four PK samples were selected as the optimal sampling strategy for an accurate AUC estimation. A quantitative framework has served to characterize the non-linear binding kinetics of daptomycin in patients with normal and impaired renal function. The impact of different dosing regimens on the efficacy and safety outcomes of daptomycin treatment based on the unbound exposure of daptomycin and individual patient characteristics has been evaluated. Full article
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15 pages, 3500 KiB  
Article
Pharmacometric Modeling of the Impact of Azelastine Nasal Spray on SARS-CoV-2 Viral Load and Related Symptoms in COVID-19 Patients
by Christiane Dings, Peter Meiser, Frank Holzer, Michael Flegel, Dominik Selzer, Eszter Nagy, Ralph Mösges, Jens Peter Klussmann and Thorsten Lehr
Pharmaceutics 2022, 14(10), 2059; https://doi.org/10.3390/pharmaceutics14102059 - 27 Sep 2022
Cited by 2 | Viewed by 1989
Abstract
The histamine-1 receptor antagonist azelastine was recently found to impact SARS-CoV-2 viral kinetics in a Phase 2 clinical trial (CARVIN). Thus, we investigated the relationship between intranasal azelastine administrations and viral load, as well as symptom severity in COVID-19 patients and analyzed the [...] Read more.
The histamine-1 receptor antagonist azelastine was recently found to impact SARS-CoV-2 viral kinetics in a Phase 2 clinical trial (CARVIN). Thus, we investigated the relationship between intranasal azelastine administrations and viral load, as well as symptom severity in COVID-19 patients and analyzed the impact of covariates using non-linear mixed-effects modeling. For this, we developed a pharmacokinetic (PK) model for the oral and intranasal administration of azelastine. A one-compartment model with parallel absorption after intranasal administration described the PK best, covering both the intranasal and the gastro-intestinal absorption pathways. For virus kinetic and symptoms modeling, viral load and symptom records were gathered from the CARVIN study that included data of 82 COVID-19 patients receiving placebo or intranasal azelastine. The effect of azelastine on viral load was described by a dose–effect model targeting the virus elimination rate. An extension of the model revealed a relationship between COVID-19 symptoms severity and the number of infected cells. The analysis revealed that the intranasal administration of azelastine led to a faster decline in viral load and symptoms severity compared to placebo. Moreover, older patients showed a slower decline in viral load compared to younger patients and male patients experienced higher peak viral loads than females. Full article
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13 pages, 1277 KiB  
Article
Modeling the Probability of HIV Infection over Time in High-Risk Seronegative Participants Receiving Placebo in Five Randomized Double-Blind Placebo-Controlled HIV Pre-Exposure Prophylaxis Trials: A Patient-Level Pooled Analysis
by Maria Garcia-Cremades, Craig W. Hendrix, Priya Jayachandran, Natasha Strydom, Leah Jarlsberg, Robert Grant, Connie L. Celum, Michael Martin, Jared M. Baeten, Jeanne Marrazzo, Peter Anderson, Kachit Choopanya, Suphak Vanichseni, David V. Glidden and Radojka M. Savic
Pharmaceutics 2022, 14(9), 1801; https://doi.org/10.3390/pharmaceutics14091801 - 27 Aug 2022
Cited by 1 | Viewed by 1574
Abstract
The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. The aim of this analysis is to quantify the individual risk of HIV infection over time, using a large database of high-risk individuals (n = 5583). [...] Read more.
The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. The aim of this analysis is to quantify the individual risk of HIV infection over time, using a large database of high-risk individuals (n = 5583). We used data from placebo recipients in five phase III PrEP trials: iPrEx, conducted in men who have sex with men and transgender women; VOICE, conducted in young women at high sexual risk; Partners PrEP, conducted in HIV serodiscordant heterosexual couples; TDF2, conducted in high-risk heterosexual men and women; and BTS, conducted in persons who inject drugs. The probability of HIV infection over time was estimated using NONMEM7.4. We identified predictors of HIV risk and found a substantial difference in the risk of infection among and within trial populations, with each study including a mix of low, moderate, and high-risk individuals (p < 0.05). Persons who were female at birth were at a higher risk of HIV infection than people who were male at birth. Final models were integrated in a tool that can assess person-specific risk and simulate cumulative HIV risk over time. These models can be used to optimize future PrEP clinical trials by identifying potential participants at highest risk. Full article
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17 pages, 1909 KiB  
Article
Novel αO-conotoxin GeXIVA[1,2] Nonaddictive Analgesic with Pharmacokinetic Modelling-Based Mechanistic Assessment
by Xiaoyu Zhu, Mei Yuan, Huanbai Wang, Dongting Zhangsun, Gang Yu, Jinjing Che and Sulan Luo
Pharmaceutics 2022, 14(9), 1789; https://doi.org/10.3390/pharmaceutics14091789 - 26 Aug 2022
Cited by 3 | Viewed by 1251
Abstract
αO-conotoxin GeXIVA[1,2] was isolated in our laboratory from Conus generalis, a snail native to the South China Sea, and is a novel, nonaddictive, intramuscularly administered analgesic targeting the α9α10 nicotinic acetylcholine receptor (nAChR) with an IC50 of 4.61 nM. However, its [...] Read more.
αO-conotoxin GeXIVA[1,2] was isolated in our laboratory from Conus generalis, a snail native to the South China Sea, and is a novel, nonaddictive, intramuscularly administered analgesic targeting the α9α10 nicotinic acetylcholine receptor (nAChR) with an IC50 of 4.61 nM. However, its pharmacokinetics and related mechanisms underlying the analgesic effect remain unknown. Herein, pharmacokinetics and multiscale pharmacokinetic modelling in animals were subjected systematically to mechanistic assessment for αO-conotoxin GeXIVA[1,2]. The intramuscular bioavailability in rats and dogs was 11.47% and 13.37%, respectively. The plasma exposure of GeXIVA[1,2] increased proportionally with the experimental dose. The plasma protein binding of GeXIVA[1,2] differed between the tested animal species. The one-compartment model with the first-order absorption population pharmacokinetics model predicted doses for humans with bodyweight as the covariant. The pharmacokinetics-pharmacodynamics relationships were characterized using an inhibitory loss indirect response model with an effect compartment. Model simulations have provided potential mechanistic insights into the analgesic effects of GeXIVA[1,2] by inhibiting certain endogenous substances, which may be a key biomarker. This report is the first concerning the pharmacokinetics of GeXIVA[1,2] and its potential analgesic mechanisms based on a top-down modelling approach. Full article
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13 pages, 3693 KiB  
Communication
Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue
by Laura Else, Sujan D. Penchala, Azure-Dee Pillay, Thabiso B. Seiphetlo, Limakatso Lebina, Christian Callebaut, Suks Minhas, Roland Morley, Tina Rashid, Neil Martinson, Julie Fox, Saye Khoo and Carolina Herrera
Pharmaceutics 2022, 14(6), 1285; https://doi.org/10.3390/pharmaceutics14061285 - 16 Jun 2022
Cited by 3 | Viewed by 2016
Abstract
Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic–pharmacodynamic (PK–PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. [...] Read more.
Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic–pharmacodynamic (PK–PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. Methods: Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1BaL at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV–diphosphate (TFV–DP) concentrations were measured in tissues, culture supernatants and dosing and washing solutions. Results: Dose–response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV–DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV–DP and p24 concentrations following HVT. Conclusions: Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding. Full article
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20 pages, 4328 KiB  
Article
Pharmacokinetics of Curative Tranexamic Acid in Parturients Undergoing Cesarean Delivery
by Sixtine Gilliot, Anne-Sophie Ducloy-Bouthors, Florence Loingeville, Benjamin Hennart, Delphine Allorge, Gilles Lebuffe and Pascal Odou
Pharmaceutics 2022, 14(3), 578; https://doi.org/10.3390/pharmaceutics14030578 - 06 Mar 2022
Cited by 6 | Viewed by 2026
Abstract
The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic cesarean delivery and to evaluate the influence of patient variables on TXA [...] Read more.
The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic cesarean delivery and to evaluate the influence of patient variables on TXA pharmacokinetics. Subjects from three recruiting centers were included in this PK sub-study if randomized in the experimental group (i.v TXA 0.5 g or 1 g over one minute) of the TRACES study. Blood samples and two urinary samples were collected within 6 h after TXA injection. Parametric non-linear mixed-effect modeling (Monolix v2020R1) was computed. The final covariate model building used 315 blood and 117 urinary concentrations from seventy-nine patients. A two-compartment model with a double first-order elimination from the central compartment best described the data. The population estimates of clearance (CL), central volume of distribution (V1), and half-life for a typical 70 kg patient with an estimated renal clearance of 150 mL/min (Cockroft–Gault) were 0.14 L/h, 9.25 L, and 1.8 h. A correlation between estimated creatinine clearance and CL, body weight before pregnancy, and V1 was found and partly explained the PK variability. The final model was internally validated using a 500-run bootstrap. The first population pharmacokinetic model of TXA in active hemorrhagic caesarean section was successfully developed and internally validated. Full article
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Review

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20 pages, 1418 KiB  
Review
Understanding the Mechanisms and Treatment of Heart Failure: Quantitative Systems Pharmacology Models with a Focus on SGLT2 Inhibitors and Sex-Specific Differences
by Jean François Ndiaye, Fahima Nekka and Morgan Craig
Pharmaceutics 2023, 15(3), 1002; https://doi.org/10.3390/pharmaceutics15031002 - 20 Mar 2023
Cited by 1 | Viewed by 2284
Abstract
Heart failure (HF), which is a major clinical and public health challenge, commonly develops when the myocardial muscle is unable to pump an adequate amount of blood at typical cardiac pressures to fulfill the body’s metabolic needs, and compensatory mechanisms are compromised or [...] Read more.
Heart failure (HF), which is a major clinical and public health challenge, commonly develops when the myocardial muscle is unable to pump an adequate amount of blood at typical cardiac pressures to fulfill the body’s metabolic needs, and compensatory mechanisms are compromised or fail to adjust. Treatments consist of targeting the maladaptive response of the neurohormonal system, thereby decreasing symptoms by relieving congestion. Sodium–glucose co-transporter 2 (SGLT2) inhibitors, which are a recent antihyperglycemic drug, have been found to significantly improve HF complications and mortality. They act through many pleiotropic effects, and show better improvements compared to others existing pharmacological therapies. Mathematical modeling is a tool used to describe the pathophysiological processes of the disease, quantify clinically relevant outcomes in response to therapies, and provide a predictive framework to improve therapeutic scheduling and strategies. In this review, we describe the pathophysiology of HF, its treatment, and how an integrated mathematical model of the cardiorenal system was built to capture body fluid and solute homeostasis. We also provide insights into sex-specific differences between males and females, thereby encouraging the development of more effective sex-based therapies in the case of heart failure. Full article
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16 pages, 2521 KiB  
Review
A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability
by Douglas Chung, Suruchi Bakshi and Piet H. van der Graaf
Pharmaceutics 2023, 15(3), 918; https://doi.org/10.3390/pharmaceutics15030918 - 11 Mar 2023
Cited by 3 | Viewed by 3571
Abstract
Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the [...] Read more.
Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the interactions between proteases, cofactors, regulators, fibrin, and therapeutic responses under different clinical scenarios. We aim to review the literature on QSP models to assess the unique capabilities and reusability of these models. We systematically searched the literature and BioModels database reviewing systems biology (SB) and QSP models. The purpose and scope of most of these models are redundant with only two SB models serving as the basis for QSP models. Primarily three QSP models have a comprehensive scope and are systematically linked between SB and more recent QSP models. The biological scope of recent QSP models has expanded to enable simulations of previously unexplainable clotting events and the drug effects for treating bleeding or thrombosis. Overall, the field of coagulation appears to suffer from unclear connections between models and irreproducible code as previously reported. The reusability of future QSP models can improve by adopting model equations from validated QSP models, clearly documenting the purpose and modifications, and sharing reproducible code. The capabilities of future QSP models can improve from more rigorous validation by capturing a broader range of responses to therapies from individual patient measurements and integrating blood flow and platelet dynamics to closely represent in vivo bleeding or thrombosis risk. Full article
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Review
Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis
by Karine Rodríguez-Fernández, Víctor Mangas-Sanjuán, Matilde Merino-Sanjuán, Antonio Martorell-Calatayud, Almudena Mateu-Puchades, Mónica Climente-Martí and Elena Gras-Colomer
Pharmaceutics 2022, 14(3), 654; https://doi.org/10.3390/pharmaceutics14030654 - 16 Mar 2022
Cited by 10 | Viewed by 4051
Abstract
The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have [...] Read more.
The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis. Full article
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