European Journal of Drug Metabolism and Pharmacokinetics

02/07/2024

External Evaluation of Population Pharmacokinetic Models of Piperacillin in Preterm and Term Patients from Neonatal Intensive Care

Authors: Frida S. Boer-Pérez, Victoria Lima-Rogel, Ana R. Mejía-Elizondo, Susanna E. Medellín-Garibay, Ana S. Rodríguez-Báez, Cristian J. Rodríguez-Pinal, Rosa del C. Milán-Segovia & Silvia Romano-Moreno

Abstract
Background and Objectives
Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance. This study aimed to evaluate the predictive performance of reported piperacillin population pharmacokinetic models for their application in a model-informed precision dosing strategy in preterm and term Mexican neonatal intensive care patients.

Methods
Published population pharmacokinetic models for piperacillin which included neonates in their study population were identified. From the reference models, structured models, population pharmacokinetic parameters, and interindividual and residual variability data were extracted to be replicated in pharmacokinetic software (NONMEM® version 7.4). For the clinical study, a sampling schedule was designed, and 2–3 blood samples of 250 µL were taken from neonates who met the inclusion criteria. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. The clinical treatment data were collected, and piperacillin plasma concentrations were estimated using reference pharmacokinetic models for an a priori or Bayesian approach. Statistical methods were used in terms of bias and precision to evaluate the differences between observed and estimated neonatal piperacillin plasma concentrations with the different approaches and to identify the pharmacokinetic model that best fits the neonatal data.

Results
A total of 70 plasma samples were collected from 25 neonatal patients, of which 15 were preterm neonates. The overall median value (range) postnatal age, gestational age, body weight, and serum creatinine at the sampling collecting day were 12 (3–26) days, 34.2 (26–41.1) weeks, 1.78 (0.08–3.90) Kg, 0.47 (0.20–0.90) mg/dL, respectively. Three population pharmacokinetic models for piperacillin in infants up to 2 months were identified, and their predictive performance in neonatal data was evaluated. No pharmacokinetic model was suitable for our population using an a priori approach.

The model published by Cohen-Wolkowiez et al. in 2014 with a Bayesian approach showed the best performance of the pharmacokinetic models evaluated in our neonatal data. The procedure requires two blood samples (predose and postdose), and, when applied, it predicted 66.6% of the observations with a relative median absolute predicted error of less than 30%.

Conclusions
The population pharmacokinetic model developed by Cohen-Wolkowiez et al. in 2014 demonstrated superior performance in predicting the plasma concentration of piperacillin in preterm and term Mexican neonatal intensive care patients. The Bayesian approach, including two different piperacillin plasma concentrations, was clinically acceptable regarding bias and precision. Its application for model-informed precision dosing can be an option to optimize the piperacillin dosage in our population.

https://link.springer.com/article/10.1007/s13318-024-00906-3

02/07/2024

Inhibitory Effect of Two Carbonic Anhydrases Inhibitors on the Activity of Major Cytochrome P450 Enzymes

Authors: Fawzy A. Elbarbry, Tamer M. Ibrahim, Mohamed A. Abdelrahman, Claudiu T. Supuran & Wagdy M. Eldehna

Abstract
Background and Objectives
Both AW-9A (coumarin derivative) and WES-1 (sulfonamide derivative) were designed and synthesized as potential selective carbonic anhydrase inhibitors and were tested for anticancer activity. This study was undertaken to investigate their potential inhibitory effects on the major human cytochrome P450 (CYP) drug-metabolizing enzymes.

Methods
Specific CYP probe substrates and validated analytical methods were used to measure the activity of the tested CYP enzymes. Furthermore, in silico simulations were conducted to understand how AW-9A and WES-1 bind to CYP2A6 at a molecular level. Molecular docking experiments were performed using the high-resolution X-ray structure, Protein Data Bank (PDB) ID: 2FDV for CYP2A6.

Results
CYP2E1-catalyzed chlorzoxazone-6′-hydroxylation was strongly inhibited by AW-9A and WES-1 with IC50 values of 0.084 µM and 0.101 µM, respectively. CYP2A6-catalyzed coumarin-7′-hydroxylation was moderately inhibited by AW-9A (IC50 = 4.2 µM). CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were weakly or negligibly inhibited by both agents. Docking studies suggest elevated potential to block the catalytic activity of CYP2A6.

Conclusions
These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes.

https://link.springer.com/article/10.1007/s13318-024-00903-6

20/06/2024

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer

Authors: Niels Westra, Paul D. Kruithof, Sander Croes, Robin M. J. M. van Geel, Lizza E. L. Hendriks, Daan J. Touw, Thijs H. Oude Munnink & Paola Mian

Abstract
Background and Objective
Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature.

Methods
Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort.

Results
The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas.

Conclusion
All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known.

https://link.springer.com/article/10.1007/s13318-024-00904-5

21/05/2024

Model-Informed Clinical Development of 6-Monthly Injection of Paliperidone Palmitate in Patients with Schizophrenia: Dosing Strategies Guided by Population Pharmacokinetic Modeling and Simulation (Part II)

Authors: Huybrecht T’jollyn, Raja Venkatasubramanian, Martine Neyens, Srihari Gopal, Alberto Russu, Partha Nandy, Juan Jose Perez-Ruixo & Oliver Ackaert

Abstract
Background and Objective
Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M.

Methods
The extensive analysis database included 15,932 paliperidone samples from 700 patients receiving gluteal paliperidone palmitate 3-month (PP3M) or PP6M injections in the double-blind phase of a phase-3 noninferiority study (NCT03345342). Exposure parameters for paliperidone appeared to increase dose-proportionally within each dosing schedule (PP3M/PP6M). The range of paliperidone exposures after IM administration of PP6M overlaps with that of corresponding doses of oral paliperidone extended release, PP 1-month (PP1M), and PP3M. Model-based simulations were performed to investigate paliperidone exposures in different PP6M dosing scenarios and relevant subpopulations.

Results
A dosing window of ≤ 2 weeks earlier and ≤ 3 weeks later than the target 6-month interval for maintenance treatment with PP6M dosing maintains paliperidone exposures at levels that are not expected to substantially impact its safety and efficacy. For missed-dose scenarios, tailored re-initiation regimens are proposed that should be applied before resuming PP6M maintenance dosing. Regarding subpopulations, PP6M 700 mg eq. is the highest dose recommended in mild renal-impairment patients; the paliperidone pharmacokinetics after PP6M administration is not affected by s*x, body mass index, or age in a clinically meaningful way.

Conclusion
Paliperidone concentration–time profiles after PP6M and PP3M dosing were adequately described by the popPK model. Model-based simulation results provide guidance for clinicians on initiating PP6M therapy, transitioning between paliperidone formulations, the dosing windows to use for maintenance dosing, and managing missed PP6M doses.

Background and Objective Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M. Methods The....

21/05/2024

Model-Informed Clinical Development of Once-Every-6-Month Injection of Paliperidone Palmitate in Patients with Schizophrenia: A Pharmacometric Bridging Approach (Part I)

Authors: Huybrecht T’jollyn, Alberto Russu, Raja Venkatasubramanian, Srihari Gopal, Partha Nandy, Martine Neyens, Ruben Faelens, Mahesh N. Samtani, Oliver Ackaert & Juan Jose Perez-Ruixo
Abstract
Background and Objective
A model-informed drug development (MIDD) approach was implemented for paliperidone palmitate (PP) 6-month (PP6M) clinical development, using pharmacokinetics and pharmacokinetic/pharmacodynamic model-based simulations.

Methods
PP6M pharmacokinetics were simulated by extending the PP 3-month (PP3M) pharmacokinetic model to account for increased injection volume, and hence dose. Contribution of the MIDD approach to the design of the pivotal PP6M phase-3 study (PP6M/PP3M noninferiority study, NCT03345342) investigating schizophrenia relapse rates was twofold: (1) PP6M dose selection, and (2) hypothesis generation that lower trough concentrations (Ctrough) associated with PP6M, relative to PP3M, were not associated with lower efficacy, which was to be evaluated in the phase-3 study. Moreover, accompanied by an intense sampling scheme to adequately characterize paliperidone pharmacokinetics and to elucidate the potential relationship between concentration and safety/efficacy, the bridging strategy eliminated the need for additional phase-1/phase-2 clinical studies.

Results
Using a MIDD bridging strategy, PP6M doses were selected that, compared with PP3M, were expected to have a similar range of exposures and a noninferior relapse rate and safety profile. Clinical data from PP6M/PP3M noninferiority study confirmed that PP6M, compared with PP3M, had a similar range of exposures (T’jollyn et al. in Eur J Drug Metab Pharmacokinet 2024), as well as a noninferior relapse rate and safety profile (this manuscript).

Conclusions
Consistency of the MIDD approach with observed clinical outcomes confirmed the hypothesis that lower Ctrough did not lead to increased relapse rates at the doses administered. Although higher paliperidone peak concentrations are achieved with corresponding doses of PP6M relative to PP3M in the phase-3 clinical study, types and incidences of treatment-related adverse events were comparable between PP6M and PP3M groups and no new safety concerns emerged for PP6M (Najarian et al. in Int J Neuropsychopharmacol 25(3):238–251, 2022).

Background and Objective A model-informed drug development (MIDD) approach was implemented for paliperidone palmitate (PP) 6-month (PP6M) clinical development, using pharmacokinetics and pharmacokinetic/pharmacodynamic model-based simulations. Methods PP6M pharmacokinetics were simulated by extendin...

16/05/2024

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in Healthy Male Volunteers

Authors: Mohamed T. Khayyal, Mahmoud H. Teaima, Hoda M. Marzouk, Rania M. El -Hazek, Frank Behnam & Dariush Behnam

Abstract
Background and Objective
Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults.

Methods
A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography–diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞], half-life (T½) and time to reach Cmax (Tmax) were calculated.

Results
The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin.

Conclusion
Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

https://link.springer.com/article/10.1007/s13318-024-00898-0

12/05/2024

Prediction of the First-Pass Metabolism of a Drug After Oral Intake Based on Structural Parameters and Physicochemical Properties

Full-text, read-only, sharable link https://rdcu.be/dHJo0

Authors: Mir Amir Hossein Hosseini, Ali Akbar Alizadeh & Ali Shayanfar

Abstract
Background and Objective
The oral first-pass metabolism is a crucial factor that plays a key role in a drug’s pharmacokinetic profile. Prediction of the oral first-pass metabolism based on chemical structural parameters can be useful in the drug-design process. Developing an orally administered drug with an acceptable pharmacokinetic profile is necessary to reduce the cost and time associated with evaluating the extent of the first-pass metabolism of a candidate compound in preclinical studies. The aim of this study is to estimate the first-pass metabolism of an orally administered drug.

Methods
A set of compounds with reported first-pass metabolism data were collected. Moreover, human intestinal absorption percentage and oral bioavailability data were extracted from the literature to propose a classification system that split the drugs up based on their first-pass metabolism extents. Various structural parameters were calculated for each compound. The relations of the structural and physicochemical values of each compound to the class the compound belongs to were obtained using logistic regression.

Results
Initial analysis showed that compounds with logD7.4 > 1 or a rugosity factor of > 1.5 are more likely to have high first-pass metabolism. Four different models that can predict the oral first-pass metabolism with acceptable error were introduced. The overall accuracies of the models were in the range of 72% (for models with simple descriptors) to 78% (for models with complex descriptors). Although the models with simple descriptors have lower accuracies compared to complex models, they are more interpretable and easier for researchers to utilize.

Conclusion
A novel classification of drugs based on the extent of the oral first-pass metabolism was introduced, and mechanistic models were developed to assign candidate compounds to the appropriate proposed classes.

https://link.springer.com/article/10.1007/s13318-024-00892-6

Background and Objective The oral first-pass metabolism is a crucial factor that plays a key role in a drug’s pharmacokinetic profile. Prediction of the oral first-pass metabolism based on chemical structural parameters can be useful in the drug-design process. Developing an orally administered dr...

12/05/2024

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy

Authors: Jing Yang, Jinxingyi Wang, Lijie Ning, Changsong Wu, Yang Liu, Jie Xia, Yanping Guan, Qian Liu & Jianghuan Zheng

Abstract
Background and Objectives
A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy.

Methods
The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency.

Results
This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e−16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658–0.776, p < 0.001; OR = 0.926, 95% CI 0.901–0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690–0.966), 2.70 μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 μg/ml (AUC: 0.807, 95% CI 0.686–0.928) for the adult group, adolescent group, and toddler and school-age group, respectively.

Conclusions
UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.

https://link.springer.com/article/10.1007/s13318-024-00894-4

12/05/2024

Does Sample Size, Sampling Strategy, or Handling of Concentrations Below the Lower Limit of Quantification Matter When Externally Evaluating Population Pharmacokinetic Models?

Authors: Mehdi El Hassani, Uwe Liebchen & Amélie Marsot

Background and Objectives
Precision dosing requires selecting the appropriate population pharmacokinetic model, which can be assessed through external evaluations (EEs). The lack of understanding of how different study design factors influence EE study outcomes makes it challenging to select the most suitable model for clinical use. This study aimed to evaluate the impact of sample size, sampling strategy, and handling of concentrations below the lower limit of quantification (BLQ) on the outcomes of EE for four population pharmacokinetic models using vancomycin and tobramycin as examples.

Methods
Three virtual patient populations undergoing vancomycin or tobramycin therapy were simulated with varying sample size and sampling scenarios. The three approaches used to handle BLQ data were to (1) discard them, (2) impute them as LLOQ/2, or (3) use a likelihood-based approach. EEs were performed with NONMEM and R.

Results
Sample size did not have an important impact on the EE results for a given scenario. Increasing the number of samples per patient did not improve predictive performance for two out of the three evaluated models. Evaluating a model developed with rich sampling did not result in better performance than those developed with regular therapeutic drug monitoring. A likelihood-based method to handle BLQ samples impacted the outcomes of the EE with lower bias for predicted troughs.

Conclusions
This study suggests that a large sample size may not be necessary for an EE study, and models selected based on TDM may be more generalizable. The study highlights the need for guidelines for EE of population pharmacokinetic models for clinical use.

Background and Objectives Precision dosing requires selecting the appropriate population pharmacokinetic model, which can be assessed through external evaluations (EEs). The lack of understanding of how different study design factors influence EE study outcomes makes it challenging to select the mos...

02/05/2024

The Use of Microdosing for In vivo Phenotyping of Cytochrome P450 Enzymes: Where Do We Stand? A Narrative Review
Authors: Lisa T. van der Heijden, Frans L. Opdam, Jos H. Beijnen & Alwin D. R. Huitema

Full-text, Read-only, Sharable link https://rdcu.be/dGAjL

Abstract

Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug–drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC0–24) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1–75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC∞) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC0–10) and AUC from 2 to 4 h (AUC2–4).

https://link.springer.com/article/10.1007/s13318-024-00896-2

Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity coul...

22/04/2024

Uridine 5′-Diphospho-glucuronosyltransferase 1A3 (UGT1A3) Prediction of Hepatic Clearance of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) Substrate Telmisartan by Glucuronidation Using In Vitro–In Vivo Extrapolation (IVIVE)

Authors: Ewelina Gabor-Worwa, Anna Kowal-Chwast, Nilesh Gaud, Dawid Gogola, Peter Littlewood, Marek Smoluch, Krzysztof Brzózka & Kamil Kus

Abstract
Background and Objective
The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro–in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5′-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results.

Methods
Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CLint, in vitro) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CLint, in vitro values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CLint, in vitro data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors.

Results
The in vitro scaled CLint, in vitro by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro–in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC.

Conclusions
The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data.

https://link.springer.com/article/10.1007/s13318-024-00895-3

22/04/2024

Long-Acting Strategies for Antibody Drugs: Structural Modification, Controlling Release, and Changing the Administration Route

Full-text, read-only, sharable link: https://rdcu.be/dFsAX

Authors: Hao Wang, Mengdi Song, Jiaqi Xu, Zhenjing Liu, Mingyue Peng, Haoqiang Qin, Shaoqian Wang, Ziyang Wang & Kehai Liu

Abstract
Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-life and need to be administered frequently, and are often associated with injection-site reactions and local toxicities during use. Increasing attention has been paid to the development of antibody drugs that are long-acting and have fewer side effects. This paper reviews existing strategies to achieve long-acting antibody drugs, including modification of the drug structure, the application of drug delivery systems, and changing their administration route. Among these, microspheres have been studied extensively regarding their excellent tolerance at the injection site, controllable loading and release of drugs, and good material safety. Subcutaneous injection is favored by most patients because it can be quickly self-administered. Subcutaneous injection of microspheres is expected to become the focus of developing long-lasting antibody drug strategies in the near future.

https://link.springer.com/article/10.1007/s13318-024-00891-7

Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-lif...