BACKGROUND: Amoxicillin is frequently prescribed to peripartum women as prophylaxis and treatment for infection. Despite frequent usage of amoxicillin in lactating women, quantitative evidence regarding its transfer betw...BACKGROUND: Amoxicillin is frequently prescribed to peripartum women as prophylaxis and treatment for infection. Despite frequent usage of amoxicillin in lactating women, quantitative evidence regarding its transfer between systemic circulation and breastmilk remains limited. However, such data is fundamentally essential for assessing the safety risk of medicine usage during breastfeeding. OBJECTIVE: This research performed population pharmacokinetic (PopPK) modeling and simulation to characterize the pharmacokinetics of amoxicillin in plasma and breastmilk in lactating Göttingen Minipigs, a physiologically relevant animal model to humans that enables studying medication transfer during lactation. METHODS: Demographic characteristics and amoxicillin concentrations in plasma and breastmilk following daily intramuscular doses (7 mg/kg) in 9 minipigs from two studies were included in the PopPK analysis. The milk-to-plasma (M/P) ratio, daily infant dosage (DID), and relative infant dose (RID) were calculated based on the simulated steady-state exposure. RESULTS: The final model consisted of a two-compartment distribution with zero-order absorption and linear elimination. The central compartment was deemed as the plasma compartment with time-varying volume of distribution, and linked to the breastmilk compartment via bidirectional first-order transfer. No covariate was included. The developed PopPK model well described amoxicillin in plasma and breastmilk in the lactating Göttingen Minipigs. The predicted M/P ratio, DID, and RID of amoxicillin following the maximal doses were approximately 0.25, 0.11 mg·kg·day, and 1.6% for Göttingen Minipigs, respectively. CONCLUSIONS: The model-based simulation indicated minimal amoxicillin exposure to the breastfed piglets, suggesting a low safety risk, which was reinforced by the absence of adverse events in the piglets.
Direct compression (DC) remains a popular manufacturing technology for producing solid dosage forms. However, the formulation optimisation is a laborious process, costly and time-consuming. The aim of this study was to d...Direct compression (DC) remains a popular manufacturing technology for producing solid dosage forms. However, the formulation optimisation is a laborious process, costly and time-consuming. The aim of this study was to determine whether machine learning (ML) can be used to accelerate developments by predicting the drug release profiles under dynamic conditions given the composition of formulations. A total of 377 formulations were produced in-house and their release profile under dynamic dissolution conditions was measured from 0 to 480 min across 11 time points. A subsequent ML analysis involved predicting the entire release profile. Six different ML techniques were explored, where random forest (RF) and extreme gradient boosting (XGB) were found to achieve a fivefold cross-validation R of 0.635 ± 0.047 and 0.601 ± 0.091, respectively. A second ML strategy was developed, where the ML techniques predict the kinetic parameters of the Weibull and a modified first-order kinetic release model and subsequently use the predicted parameters to fit the release profiles. The R results using RF were comparable to the first strategy. These findings demonstrate that ML can be used to predict entire drug release profiles during dynamic dissolution studies, whilst simultaneously providing insight into kinetic parameters, thus making the modelling process more informative for pharmaceutical researchers. Future work will seek to investigate more 'kinetic-informed' ML models.
The human cytochrome P450 3A4 (CYP3A4) enzyme, which is expressed in the liver and the intestines, catalyzes the metabolism of numerous drugs. The induction of CYP3A4 by the pregnane X receptor (PXR) represents a signifi...The human cytochrome P450 3A4 (CYP3A4) enzyme, which is expressed in the liver and the intestines, catalyzes the metabolism of numerous drugs. The induction of CYP3A4 by the pregnane X receptor (PXR) represents a significant problem in pharmacotherapy. Since the metabolic properties of CYP3A substrates and the recognition of PXR ligands differ between humans and rats, there are limitations to reproducing human CYP3A4 induction in rat studies. Here, we developed a double-humanized rat model for CYP3A and PXR to mimic drug-drug interactions in humans using a rat model. The model was created using a combination of mammalian artificial chromosome-based chromosome engineering, bacterial artificial chromosome-based transgenic technology, and genome editing. The resulting double-humanized rat model for CYP3A and PXR (huCYP3A-PXR rat) was treated with rifampicin, a human PXR ligand. This treatment increased CYP3A4 mRNA expression in the liver and intestine and enhanced the hydroxylation activities of triazolam, a CYP3A4 substrate. Pretreatment with rifampicin resulted in a reduction of triazolam plasma concentrations and an increase in its metabolites after oral administration. Furthermore, ketoconazole, a CYP3A4 inhibitor, led to an increase in triazolam plasma concentrations and a decrease in its metabolites in huCYP3A-PXR rats regardless of pretreatment with rifampicin. These results suggest that huCYP3A-PXR rats could predict human CYP3A4 induction and inhibition in vivo. This innovative model, in which PXR and CYP3A are humanized, is expected to be a valuable tool for studying drug-drug interactions, including a combination of inducers and inhibitors, and to be integrated into the preclinical drug-development pipeline in future.
Difluprednate is marketed as an emulsion due to its poor aqueous solubility. Emulsions are known to cause ocular discomfort and require frequent dosing to show therapeutic activity. Nanomicelles are well known to improve...Difluprednate is marketed as an emulsion due to its poor aqueous solubility. Emulsions are known to cause ocular discomfort and require frequent dosing to show therapeutic activity. Nanomicelles are well known to improve the solubility and permeation of water-insoluble drugs. Therefore, to enhance the water solubility and reduce the dosing frequency by improving difluprednate permeation across the cornea, we formulated nanomicelles. Difluprednate loaded nanomicelles (Dicel) was prepared by thin film hydration method and optimized using Box-Behnken design. The Dicel formulated had a particle size, polydispersity index, zeta potential and entrapment efficiency of 21.9 nm, 0.15, -7.55 mV and 75.4%, respectively. Transmission electron microscopy analysis showed spherical nanomicelles. The Dicel showed a sustained release profile for 48 h. The difluprednate permeation across the cornea from Dicel was enhanced by twofold compared to commercially available emulsion. Also, it was found to be stable upon dilution with simulated tear fluid and was biocompatible. Further, Dicel improved the anti-inflammatory activity of difluprednate at one and two times a day administration compared to four times a day administration of difluprednate emulsion. The present study highlights the role of topical nanomicelles in delivering difluprednate, which is better than the existing marketed emulsion in the management of ocular inflammation.
Gastric emptying plays a crucial role in the dissolution and absorption of oral drugs, particularly those with pH-dependent solubility, such as dipyridamole. This study evaluates the impact of gastric emptying kinetics o...Gastric emptying plays a crucial role in the dissolution and absorption of oral drugs, particularly those with pH-dependent solubility, such as dipyridamole. This study evaluates the impact of gastric emptying kinetics on dipyridamole dissolution using a Gastrointestinal Simulator. A dynamic dissolution model incorporating first-order and Weibull kinetics was applied to simulate different gastric emptying profiles. Results indicate that dissolution behavior is significantly influenced by the rate and pattern of gastric emptying, affecting drug solubility and potential bioavailability. The Weibull model provided a more flexible fit to experimental data, but the external control shows that significant differences exist between theorical and experimental gastric volumes. These findings highlight the importance of integrating physiologically relevant gastric emptying models into biopharmaceutical assessments to improve the prediction of in vivo drug performance. This approach could enhance the design of oral formulations by optimizing dissolution profiles for weak base drugs.
Cardiovascular diseases (CVDs) have become one of the leading threats to human health due to their high incidence and mortality rates. Their pathological mechanisms are complex, involving inflammation, oxidative stress,...Cardiovascular diseases (CVDs) have become one of the leading threats to human health due to their high incidence and mortality rates. Their pathological mechanisms are complex, involving inflammation, oxidative stress, energy metabolism, and other factors. Catechins are a group of flavanol derivatives originally extracted from the traditional Chinese medicine Acacia catechu (L.f.) Willd. Their unique polyhydroxy chemical structure endows catechins with a range of biological activities, such as anti-inflammatory properties, antioxidant properties, and the regulation of nutrient homeostasis. Recent studies have shown the beneficial effects of catechins in atherosclerosis, hypertension, heart failure, cardiomyopathy, and other cardiovascular conditions. Therefore, catechins present significant potential as a therapeutic approach for CVDs. This review provides an overview of the structure, pharmacological mechanisms, and recent research developments of catechins in cardiovascular diseases, with the goal of offering insights for the future medicinal study of catechins.
As process analytical technology (PAT) and real-time release testing (RTRT) are gaining momentum in the pharmaceutical industry, there is an increasing need for developing methods for the non-destructive and real-time ch...As process analytical technology (PAT) and real-time release testing (RTRT) are gaining momentum in the pharmaceutical industry, there is an increasing need for developing methods for the non-destructive and real-time characterization of the in vitro dissolution of pharmaceuticals. In recent years, several surrogate models relying on PAT measurements and advanced chemometric techniques have been published addressing this task. Nevertheless, methodologies for the fair comparison of the model performance and setting relevant acceptance criteria are still not well established. Therefore, this study aims to draw attention to appropriate model comparison when developing and applying surrogate dissolution models and highlight the limitations of the widely used dissolution curve comparison metrics, including the f similarity value. A set of 10 different artificial neural network (ANN) models were developed for the prediction of the dissolution profiles of clopidogrel tablets produced through hot-melt granulation and tableting. Models were fitted with diverse input data, including granulation nominal experiment settings and real recorded process parameters (e.g., air and material temperature, humidity, granulation and lubrication time, tableting pressure) and near-infrared spectra. The models' goodness was compared using the f factor, coefficient of determination (R) and root mean square error (RMSE). The results demonstrated that these measures do not sufficiently reflect the discriminating ability of the models. We proposed for the first time the use of the sum of ranking differences (SRD) method for the comparison of the prediction models, which proved to be an effective tool to assess the discriminatory power of surrogate dissolution models during model development.
Human health and the environment are continuously impacted by anthropogenic activities, particularly those involving emerging compounds. As these compounds are newly identified or not yet fully documented in the literatu...Human health and the environment are continuously impacted by anthropogenic activities, particularly those involving emerging compounds. As these compounds are newly identified or not yet fully documented in the literature, comprehensive knowledge of their specific toxicities remains limited. Among these, pharmaceutical compounds are of particular concern, as their mechanisms of action and the effects of their pharmaceutical impurities remain insufficiently understood. In this context, this study aimed to evaluate the behavior of the antineoplastic pharmaceutical doxorubicin (DOX) under stress conditions, including acid and base hydrolysis, oxidation, photolysis, and temperature variations. The goal was to identify the major degradation pathways and elucidate the structures of the main degradation products. A stability-indicating HPLC-DAD-MS method was developed and validated for this purpose. Throughout method development, several degradation products were identified, including 7-deoxydehydrodoxorubicinone, formed through acid hydrolysis, and a major thermal degradation product with a mass-to-charge ratio (m/z) of 530. This thermal degradation product was also detected in analyses of expired pharmaceutical formulations. Furthermore, the in vitro toxicity assessment of samples containing degradation products from thermal decomposition revealed cytotoxic effects on mononuclear cells. These findings underscore the importance of not only understanding the degradation pathways of pharmaceutical compounds but also evaluating the potential environmental and human health impacts of these degradation products.
Over the past three years, we have published a series of nine manuscripts demonstrating that all relevant pharmacokinetic relationships may be simply derived independent of differential equations, offering an alternative...Over the past three years, we have published a series of nine manuscripts demonstrating that all relevant pharmacokinetic relationships may be simply derived independent of differential equations, offering an alternative to traditional pharmacokinetic analyses. These derivations are based on an understanding of parallel and in series rate-defining processes, and account for all relevant drivers, including organ blood flow and drug delivery clearance kinetics, across both linear and nonlinear scenarios. In this tutorial, we present the simple derivation of renal clearance and hepatic clearance directly relevant to clinical pharmacokinetics, as applied to making drug dosing decisions based on measures of systemic exposure. We further advocate for a more streamlined and practical approach to teaching and applying clinical pharmacokinetics, noting that compartmental modeling, protein binding in hypothetical compartments, trapezoidal AUC calculations, and alternative volume of distribution parameters, aside from (the unfortunately misnamed) volume of distribution steady-state, often overcomplicate pharmacokinetics in practice. The key advantage of this simplified methodology is the ability to directly incorporate clearance from the drug delivery site into systemic pharmacokinetic relationships. This enables a clear understanding of how entering clearance can influence systemic AUC, helping explain: enhanced pharmacodynamic outcomes of slow drug delivery versus immediate-release formulations; systemic bioavailability measures exceeding unity, statistically significant discrepancies between urinary and systemic bioavailability measures; and changes in renal clearance as a function of drug clearance from the delivery site. These key concepts are illustrated by applying the proposed methodology to an example drug, analyzing all relevant clinical pharmacokinetic relationships required for dosing decisions.
In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming....In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.
The six-minute walk test (6MWT) is a common method to assess submaximal exercise capacity in children and adults with pulmonary arterial hypertension (PAH) and other chronic diseases. There is no guideline specifically f...The six-minute walk test (6MWT) is a common method to assess submaximal exercise capacity in children and adults with pulmonary arterial hypertension (PAH) and other chronic diseases. There is no guideline specifically for 6MWT in children. In this observational pilot study, we evaluated the impact of procedural variations on the outcome of the 6MWT in the real-world clinical setting at pediatric PAH programs. We collected 6MWT data from 33 children with PAH participating in a multicenter, prospective, non-interventional study. Data range/quantiles and standard deviation (SD) were used to describe distribution of the six-minute walk distance (6MWD) and data variability. Levene's test was used to test for heterogeneity of variance with the two sites of similar altitude and their age/height/weight-matched Panama Function Class II participants. We analyzed all 33 eligible participants and their qualified first walks at five centers (A-E) with 6MWD ranges of 420-570, 357-683, 418-481, 400-700, 377-549 m, respectively. Site D performed the 6MWT in a busy hallway and allowed parental/caregiver's cheering, while Site E performed the 6MWT in a secluded area with no parental/caregiver involvement. Mean 6MWD and SD for Sites D and E were 547 (125) and 432 (67.5) meters, respectively (p = 0.03). In conclusion, procedural variations seem to associate with 6MWD data variability. Although interpretation of our results is limited by the small sample size, our findings suggest that standardizing pediatric 6MWT procedures are needed.
Herein, we report a new modified nanoprecipitation method for the fabrication of water-dispersible Poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating three poorly water-soluble anticancer agents as model dr...Herein, we report a new modified nanoprecipitation method for the fabrication of water-dispersible Poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating three poorly water-soluble anticancer agents as model drugs: paclitaxel (PTX), docetaxel (DTX) or curcumin (Cur). These nanoparticles were water dispersible with favourable size for anticancer applications (below 200 nm) and relatively high drug loading (6.3-8.9%). These nanoparticles were stable for four weeks in solid state and up to 48 h when dispersed in water. PTX and Cur nanoparticles showed a very minimal release of the payload during a 72-h in vitro release study. The new method also yielded reproducible results across three different batches of each type of nanoparticles and following three times upscaling of PTX nanoparticles. PTX and Cur nanoparticles were more effective than the free drugs against MDA-MB-231 cells (p < 0.05). In addition, PTX nanoparticles showed a significant enhanced induction of early apoptosis in MDA-MB-231 cells (42.3%) in comparison to free PTX (23.7%, p < 0.05). Both flow cytometry and confocal microscopy confirmed the uptake of the nanoparticles by MDA-MB-231 cells. In conclusion, our modified nanoprecipitation method produces PLGA nanoparticles loaded with different anticancer agents and suitable for cancer therapy.
Nomlabofusp is a cell penetrant peptide-based recombinant fusion protein designed to enter cells and deliver human frataxin into the mitochondria of adults and children with Friedreich's ataxia. In this article we presen...Nomlabofusp is a cell penetrant peptide-based recombinant fusion protein designed to enter cells and deliver human frataxin into the mitochondria of adults and children with Friedreich's ataxia. In this article we present non-clinical studies evaluating the pharmacology of nomlabofusp, including in a murine striated muscle tissue frataxin knockout model of Friedreich's ataxia. We demonstrate that subcutaneous administration of nomlabofusp distributes in a dose-dependent manner to several organs including the dorsal root ganglion, heart, and skeletal muscle, which are known to be predominantly affected in Friedreich's ataxia, as well as to other tissues, including skin. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. In the knockout mice, we show that the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and that treatment with nomlabofusp halts the progression of cardiac dysfunction and significantly increased survival. Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increases human frataxin in Friedreich's ataxia-relevant tissues and provide evidence of pharmacologic effects.
Alternative administrations methods, such as chewing or crushing tablets, have been proposed to improve P2Y receptor inhibitors' absorption in acute and chronic coronary syndromes. This study aimed to evaluate the impact...Alternative administrations methods, such as chewing or crushing tablets, have been proposed to improve P2Y receptor inhibitors' absorption in acute and chronic coronary syndromes. This study aimed to evaluate the impact of these alternative strategies on the pharmacokinetics and pharmacodynamics of clopidogrel, ticagrelor, and prasugrel. PubMed, the Cochrane Library, and Web of Science were searched until March 07, 2025 for trials comparing at least one P2Y receptor inhibitor alternative administration method to the standard administration (swallowed integral tablets). Drug concentrations, platelet reactivity, and rates of high on-treatment platelet reactivity (HPR) were evaluated by standardized mean differences (SMD) or odds ratios (OR) with 95% confidence interval (CI) using random-effects models. The effects of specific P2Y inhibitors and administration methods were assessed using meta-regression. Eleven studies (1,735 patients) were included. Administration of crushed or chewed tablets led to an increase in drug concentrations (SMD at 1 h 0.48, 95% CI 0.001 to 0.95, p < 0.05), resulting in a significant improvement in platelet inhibition (SMD at 1 h -0.53, 95% CI -0.67 to -0.39, p < 0.001) and a reduction in HPR rates (OR 0.29, 95% CI 0.16 to 0.54, p < 0.001) as early as 30 min and during the first 4 h after administration. No differences were found between prasugrel and ticagrelor or between crushed and chewed tablets in the pharmacodynamic outcomes, providing flexibility in clinical practice. Further research is needed to confirm the clinical relevance of these findings.
Small molecule activators of the mitochondrial caseinolytic protease P (ClpP agonists) can disrupt tumor metabolism and deprive tumors of their energy needs. The imipridone, ONC201, is a ClpP agonist currently undergoing...Small molecule activators of the mitochondrial caseinolytic protease P (ClpP agonists) can disrupt tumor metabolism and deprive tumors of their energy needs. The imipridone, ONC201, is a ClpP agonist currently undergoing clinical evaluation across multiple cancer types, while additional analogs with improved potency and selectivity are in preclinical development. Preclinical studies in mice have demonstrated a unique pharmacokinetic-pharmacodynamic (PK-PD) relationship for ONC201 characterized by prolonged pharmacology following a single dose. This motivated the selection of an initial human dosing regimen of every three weeks, and subsequent dose exploration studies in mice led to dose intensification in human patients. However, a systematic analysis of ClpP agonist PK-PD relationships has not been performed, and the optimal exposure profile for ClpP agonists remains undefined. To address this gap, we combined PK-PD modeling with a microfluidic perfusion platform as an animal-alternative approach for translational PK-PD of ClpP agonists. We demonstrate that the anti-proliferative effect on triple negative breast cancer cells correlates with the magnitude and duration of ClpP agonist exposure above a threshold concentration required for ClpP activation. Moreover, we demonstrate that PK-PD model simulations using parameters derived from microfluidic perfusion datasets can successfully predict the anti-tumor efficacy of a ClpP agonist in a mouse tumor xenograft study. These studies support the translational relevance of the animal-alternative in vitro PK-PD platform and its utility to help guide dose optimization of ClpP agonists as cancer therapeutics.
Ulcerative colitis (UC) and Crohn's disease (CD), pose a substantial burden, necessitating effective therapies. Etrolizumab, a unique monoclonal antibody targeting integrins, initially showed promise but was terminated d...Ulcerative colitis (UC) and Crohn's disease (CD), pose a substantial burden, necessitating effective therapies. Etrolizumab, a unique monoclonal antibody targeting integrins, initially showed promise but was terminated due to lack of efficacy in PhIII studies. The immune responses elicited by patients towards etrolizumab make it a compelling subject for further in-depth investigation. This study delves into immunogenic responses to etrolizumab, examining factors contributing to such responses, including anti-drug antibody (ADA) assay format, patient baseline characteristics, immunosuppressive (IS) medication use, human leukocyte antigen (HLA) allelic expression, and the clinical impact of ADA responses on safety and efficacy endpoints. Logistic regression was used to test for association between the presence of ADA & (neutralizing antibody) NAb and HLA alleles with carrier frequencies of at least 2%, alongside age, sex, and IS use. We identified two class-II HLA alleles, HLA-DQB1*06:03 and HLADQA1* 03:03, associated with the development of ADA and NAb. However, there was minimal impact of ADA on clinical parameters, such as pharmacokinetics (PK), safety, and efficacy. The findings enhance our understanding of etrolizumab immunogenicity, in the context of clinical impact, providing insights that may inform future biologic development strategies and patient selection criteria in IBD clinical trials.
The administration of biotherapeutics has the potential to induce potent immune responses, including the induction of anti-drug antibodies (ADA) (1). Detection and characterization of ADA in clinical trials is an importa...The administration of biotherapeutics has the potential to induce potent immune responses, including the induction of anti-drug antibodies (ADA) (1). Detection and characterization of ADA in clinical trials is an important component of a comprehensive immunogenicity program (2). ADA testing is mostly accomplished with ligand-binding assays (LBA). While LBA can be robust and specific, they are susceptible to various sources of interference (3). Of particular concern, interference from residual drug present in patient samples may lead to loss of ADA detection, producing false negative results. To mitigate drug interference, sample pretreatment procedures have been developed to enrich ADA from samples with high drug concentrations (4, 5). The pretreatment procedures can vary considerably but typically involve an initial step to liberate ADA from ADA-drug complexes and a subsequent step to affinity capture ADA and acid elute for detection. While these procedures can be highly effective, they have certain drawbacks when performed manually. First, the procedures are time-consuming and require near constant attention. Second, because of the manual workflow, the procedures can produce variable results between experiments and between different analysts with negative consequences for assay robustness. To address these drawbacks, we developed an automated procedure to enrich ADA by leveraging dual flow chromatography (DFC) and Streptavidin PhyTip® columns on a liquid-handling system (6). The enriched ADA were then tested in an LBA to evaluate the effectiveness of the automated enrichment procedure.
The Pharmaceuticals and Medical Devices Agency (PMDA) is a Japanese authority responsible for reviewing the quality, efficacy, and safety of drugs and medical devices to be marketed for public health protection. This stu...The Pharmaceuticals and Medical Devices Agency (PMDA) is a Japanese authority responsible for reviewing the quality, efficacy, and safety of drugs and medical devices to be marketed for public health protection. This study investigated the approval numbers of monoclonal antibodies (mAbs). In addition, it classified canonical and modified antibodies, such as antibody-drug conjugates (ADCs), antibody fragments, and bispecific antibodies (bsAb), excluding the biosimilar versions of mAbs in each fiscal year (FY) based on the PMDA website (1). Moreover, the approval FY data, brand names, international nonproprietary names, cell substrates, targets, disease areas at initial approval, and regulatory pathways were compiled (Supplement Document 1).