Expert Opinion on Drug Metabolism & Toxicology

Introduction: Optimizing drug therapy during pregnancy is crucial for ensuring the safety of mothers and babies. Physiological changes that occur during pregnancy can significantly alter the pharmacokinetics of medications. Population pharmacokinetic (PopPK) modeling is a valuable tool to guide drug dosing regimens in pregnant women. Areas covered: This narrative review summarizes the current literature on the application of PopPK modeling to optimize drug therapy during human pregnancy. It provides an overview of the physiological changes affecting drug disposition in pregnancy and the basic concepts of PopPK modeling including structural, stochastic, and covariate models. We have conducted an exhaustive literature search (PubMed, Web of Science) spanning May 2014-May 2024 to identify PopPK models in the pregnant population. We have highlighted strategies for model building, evaluation, and interpretation with a focus on identifying clinically relevant covariates that inform dose individualization. Case studies illustrating the utility of PopPK models in guiding dosing recommendations for specific drugs are discussed. Expert opinion: Covariate identification can lead to improved mechanistic understanding of drug disposition and establishment of improved dosing regimens during pregnancy. Insufficient data across trimesters may limit the ability of PopPK models to capture time-varying gestational effects.

Introduction: Adverse drug reactions (ADRs) pose a significant challenge in clinical practice, impacting patient safety and treatment outcomes. Genetic variations in drug-metabolizing enzymes, particularly glutathione S-transferases (GSTs), have been implicated in modulating individual susceptibility to ADRs. Areas covered: This overview aims to explore the association between GSTs genetic polymorphisms and ADRs across diverse drug categories documented in current literature. Here we cover antiepileptic, immunosuppressive, chemotherapeutic agents, analgesics, antivirals, and antibiotics. Expert opinion: According to the existing literature, the association between genetic polymorphisms in GST theta (GSTT1), GST mu (GSTM1), and GST pi (GSTP1) and adverse drug reaction occurrence has been frequently reported. However, the strength of these associations varies considerably among studies, with some showing inconsistent or contradictory results, underscoring the need for further investigations.

Introduction: Optimizing drug dosage in critically ill children undergoing Continuous Renal Replacement Therapy (CRRT) is mandatory and challenging, given the many factors impacting pharmacokinetics and pharmacodynamics coupled with the vulnerability of this population. Areas covered: A good understanding of the mechanisms that determine drug elimination via the CRRT technique is useful to avoid prescription pitfalls, however limited by the high between and within subject variability. The developments of population pharmacokinetic and physiologically based pharmacokinetic models derived from in-vivo and in-vitro studies, are challenging, but remain the most appropriate tool to suggest adjusted dosage regimens for every patient, throughout treatment. We searched PubMed using the search string: 'pediatrics OR children' AN 'continuous renal replacement therapy' AND 'pharmacokinetics' AND 'model informed precision dosing' AND, 'physiologically based pharmacokinetics,' AND 'therapeutic drug monitoring' until January 2024, regardless of language or publication status. Expert opinion: Familiarizing the pediatric intensivists with the therapeutic drug monitoring and providing clinicians the individualized prescribing software such as Model Informed Precision Dosing would be a significant step forward. The clinical benefit for patients remains to be demonstrated.

Introduction: Lenacapavir is the first HIV-1 capsid inhibitor administered subcutaneously twice yearly. While lenacapavir is currently only indicated as salvage therapy, it has the potential to become a foundation of future treatments and to revolutionize HIV prevention. Areas covered: This review summarizes the pharmacology of lenacapavir with particular emphasis placed on its drug-drug interaction (DDI) potential as it is used in treatment-experienced individuals who often present multiple comorbidities and polypharmacy. The effect of lenacapavir on drug metabolizing enzymes and transporters as well as findings of DDI studies are summarized. These data were used to predict DDIs with 1073 comedications. Finally, the management of selected DDIs is discussed. Conferences/workshops abstracts (i.e. CROI, IAS, EACS, HIV Glasgow, PK workshop) were screened using the terms: 'lenacapavir,' 'capsid inhibitor,' 'GS-6207,' and a PubMed search was used to compile data until September 2024. Expert opinion: Lenacapavir has a favorable DDI profile with 80% of evaluated comedications estimated to have no clinically significant DDIs. More studies are needed to address pharmacological gaps including the pharmacokinetics of lenacapavir in special populations, its transfer across the blood-brain barrier or the placenta as well as the possibility to manage DDIs with moderate/strong inducers by reducing lenacapavir dosing interval.

Introduction: Cangrelor, the only intravenous platelet P2Y12 receptor inhibitor, is characterized by a prompt and potent platelet inhibition, with a rapid offset of action. Large-scale clinical trials have shown that cangrelor reduce peri-procedural thrombotic events among patients undergoing percutaneous coronary interventions and not pre-treated with an oral P2Y12 receptor inhibitor. However, high P2Y12 receptor occupancy provided by cangrelor raises concerns for drug-drug interactions (DDIs) when transitioning to oral P2Y12 inhibitors. Areas covered: An understanding of the pharmacology of cangrelor and oral P2Y12 inhibitors is essential to define the optimal approach to transition to oral P2Y12 inhibitors without incurring the risk of DDIs. This review, based on a thorough literature search in major scientific databases (PubMed, Cochrane Library, Web of Science), synthesizes the pharmacology of cangrelor and the oral P2Y12 receptor inhibitors, providing the rationale for the occurrence of DDIs and strategies to avoid such risk. Expert opinion: The timing of transition from cangrelor to oral P2Y12 inhibitors plays a crucial role in the occurrence of DDIs, especially with clopidogrel and prasugrel. Currently, no evidence suggests a DDI when transitioning to ticagrelor. Adhering to product labels and guideline recommendations is crucial for optimizing safety and efficacy of cangrelor.

Introduction: Vasomotor symptoms (VMS) affect the majority of menopausal women, with possible negative impact on several domains of quality of life (QoL). Although menopausal hormone therapy (MHT) represents an effective treatment, the risk-benefit profile is not favorable for every woman. Non-hormonal options are limited in number and efficacy. Areas covered: Fezolinetant is a novel oral non-hormonal drug recently approved for treatment of moderate-severe VMS. It acts as an antagonist of neurokinin 3 receptor (NK3R), the main target of neurokinin B (a tachykinin over-expressed by kisspeptin/neurokinin B/dynorphin [KNDy] neurons after menopausal hypoestrogenism), involved in modulation of thermoregulatory hypothalamic center. In here, we report pharmacodynamics and pharmacokinetic properties of fezolinetant as well efficacy and safety data from available clinical trials. Expert opinion: Fezolinetant has shown efficacy in reducing frequency and severity of VMS with a positive impact on sleep and health related QoL and acceptable safety and tolerability profile. Given the limited availability of effective non-hormonal options for VMS, fezolinetant could potentially represent a game-changer for care of menopausal women, especially when relative or absolute contraindications to MHT use are present. Further studies to gain more information about safety profile and potential extra-VMS benefits or disadvantages are warranted in real-life clinical practice.

Introduction: Due to its role in absorption and metabolism, the kidney is an important target for drug toxicity. Drug-induced nephrotoxicity (DIN) presents a significant challenge in clinical practice and drug development. Conventional methods for assessing nephrotoxicity have limitations, highlighting the need for innovative approaches. In recent years, in silico methods have emerged as promising tools for predicting DIN. Areas covered: A literature search was performed using PubMed and Web of Science, from 2013 to February 2023 for this review. This review provides an overview of the current progress and pitfalls in the in silico prediction of DIN, which discusses the principles and methodologies of computational models. Expert opinion: Despite significant advancements, this review identified issues accentuates the pivotal imperatives of data fidelity, model optimization, interdisciplinary collaboration, and mechanistic comprehension in sculpting the vista of DIN prediction. Integration of multiple data sources and collaboration between disciplines are essential for improving predictive models. Ultimately, a holistic approach combining computational, experimental, and clinical methods will enhance our understanding and management of DIN.

Introduction: Blood coagulation factor (F)VIII functions as a cofactor in the tenase complex responsible for phospholipid-dependent FIXa-mediated activation of FX in plasma. Congenital defect of FVIII causes severe bleeding disorder, hemophilia (H) A. Intravenous FVIII replacement therapy is the gold standard therapy in patients with HA (PwHA) but requirement for frequent dosing of FVIII owing to pharmacokinetics burdens PwHA a lot. Efanesoctocog alfa is a new class of recombinant FVIII and has the ability to overcome conceivable unmet needs in treatment for PwHA. Areas covered: Efanesoctocog alfa is a B domain-deleted single-chain fusion FVIII connected to the Fc-region of human immunoglobulin G1, D'D3-fragment of von Willebrand factor (VWF), and unstructured hydrophilic recombinant polypeptides (XTEN). Owing to its novel design, it can function independently of endogenous VWF and elicits 2 to 4 times longer half-life compared to other existing FVIII products. The prolonged half-life contributes to maintain high level of FVIII activity for most of the week and has led to excellent hemostatic effect by once-weekly administration in phase 3 clinical trials. Expert opinion: Efanesoctocog alfa with outstanding pharmacological properties, well tolerated in the clinical trials, is a promising FVIII therapy for PwHA. Future studies should include long-term safety, especially in previously untreated patients.

Background: p-cresol and indole are uremic compounds which undergo sulfonation to generate the highly toxic p-cresol sulfate (pCS) and indoxyl sulfate (IxS). They are also subjected to glucuronidation to produce the less toxic p-cresol glucuronide (pCG) and indoxyl glucuronide (IG). We developed and validated an assay to quantify these metabolites in HepaRG cells. We also tested the effects of mefenamic acid on their in-situ formations in relation to the development of cellular necrosis. Research design and methods: HepaRG cells were exposed to p-cresol or indole (0-1 mM) with mefenamic acid (0-3000 nM) for 24 hours to generate uremic metabolites. Cells were also exposed to 0.5 mM p-cresol or indole with/without 30 nM mefenamic acid to characterize lactate dehydrogenase (LDH) release. Results: The assay exhibited high sensitivity and wide calibration ranges covering human concentrations. HepaRG cells also generated physiologically-relevant concentrations of each metabolite. Mefenamic acid inhibited pCS formation in a concentration-dependent manner without affecting pCG, IxS, or IG. Mefenamic acid also reduced LDH release from p-cresol (by 50.12±5.86%) or indole (56.26±3.58%). Conclusions: This novel assay is capable of quantifying these metabolites in HepaRG cells. Our novel findings suggest that mefenamic acid can be potentially utilized therapeutically to attenuate pCS-associated toxicities.

Background: The gene polymorphisms of the CYP2C9, as well as the substrate specificity of the enzyme, result in different clearances for different substrates by CYP2C9 variants. Research designand methods: The CYP2C9 wild type and 38 CYP2C9 variants, expressed in insectmicrosomes, were incubated with azilsartan. The resulting metabolite,O-desethyl azilsartan, was determined by HPLC-MS/MS. The enzyme kineticparameters of the 38 variants were calculated and compared with the wild type.Subsequently, we selected CYP2C9*1, *2, and *3 as target proteins for molecular docking with azilsartan to elucidate the mechanisms underlying changes in enzyme function. Results: Compared with CYP2C9*1, three variants (CYP2C9*29, *39, and *49) exhibited markedlyincreased CLint values (from 170%-275%, *p < 0.05), whereas 28 variants exhibited significantly decreased CLint values (from 3-63%,*p < 0.05). The molecular docking results showed that the binding energy of CYP2C9*2 and *3 was lower than that of the wild type. Conclusion: Thisassessment revealed the effect of CYP2C9 gene polymorphisms on azilsartan metabolism, establishing a theoretical basis for further in-vivo studies and clinical applications. This study will help expand the database of CYP2C9 gene-drug pairs and identify appropriate treatment strategies for azilsartan, contributing to the field of precision medicine.

Introduction Glipizide is an oral antidiabetic drug widely used to treat non-insulin-dependent type II diabetes mellitus (NIDDM). This systematic review extensively examines all reported pharmacokinetic (PK) parameters of glipizide in healthy and diseased populations. Areas covered A total of 31 articles were retrieved after screening various databases, i.e. Google Scholar, PubMed, Science Direct, and Cochrane, regarding the PK parameters of glipizide in healthy, diseased, drug–drug, and drug–food interaction studies. The Cmax was 35% higher in healthy Koreans than in Caucasian Americans. In type II diabetes patients, the AUC0-∞ increases ~2-fold after multiple dosage regimen in comparison with a single dose. Furthermore, the Cmax increased in fasting conditions compared to the non-fasting state in diabetic individuals i.e. 1338.28 ± 125.18 ng/mL and 1297.29 ± 47.22 ng/mL, respectively. Expert opinion The presented data has depicted that glipizide exposure varies between single and multiple dosing and its Cmax also changes between different demographic populations. Since it has a shorter half-life, the development of its new extended-release formulations may assist practitioners in improving adherence among diabetic patients.

Introduction: The modern treatment of chorioretinal vascular diseases follows the recent development and rapid adoption of drugs that inhibit vascular endothelial growth factor (VEGF). All anti-VEGF drugs are delivered intravitreally, with clinical behavior, including efficacy, durability, and safety, largely determined by their pharmacokinetic properties. Areas covered: Properties of these new drugs include additional binding targets (placental growth factor (PlGF) and angiopoietin 2 (Ang 2)), binding affinity, potency, intravitreal half-life, and increased molar dose. A PubMed search for 'pharmacokinetics of anti-VEGF drugs' was performed from 2000 to 2023. Relevant studies were reviewed and referred to in the manuscript. Expert opinion: Early developers concentrated on improving efficacy, but since maximum efficacy with VEGF inhibition has been reached, development has pivoted to extending the duration of action. Durability strategies include inhibiting additional pathways (faricimab), increasing molar dose (abicipar, brolucizumab, faricimab, and aflibercept 8 mg), and prolonging the intravitreal half-life (abicipar and KSI-301). Recent phase 3 trials demonstrated modest improvements in durability, but failures that might be attributed to these strategies (conjugation and manufacturing processes) have occurred. Future drug development focuses on extending duration of action with implantable reservoirs (ranibizumab port delivery system), sustained release devices (tyrosine kinase inhibitors), and gene therapy.

Introduction: Antithrombotic therapy is the mainstay of ischemic stroke prevention. Current drugs (antiplatelets and oral anticoagulants) lead to increased bleeding risks, and the rates of stroke recurrence, despite antithrombotic therapy, are still elevated. There is a need for novel antithrombotic therapies with superior effectiveness but without increased bleeding risk. Factor XIa inhibitors might cover this gap. Areas covered: This manuscript examines the pharmacokinetic and pharmacodynamic properties of asundexian and the current clinical evidence regarding its application in preventing ischemic stroke. Expert opinion: Asundexian shows a very favoring pharmacokinetic profile. Despite asundexian being inferior to apixaban for cardioembolic ischemic stroke, it could be useful in patients with non-cardioembolic ischemic stroke. Although antiplatelet therapy is the recommended treatment to prevent non-cardioembolic ischemic stroke, adding an anticoagulant might have beneficial effects through the dual-pathway inhibition strategy. Due to the potential risk of hemorrhagic transformation, there is hesitation to administer anticoagulants early to patients who have recently had an ischemic stroke, especially if they are also on antiplatelet therapy. However, clinical trials on asundexian confirmed its safety for bleeding, even when used with antiplatelets. A phase 3 trial is currently investigating the efficacy of asundexian in preventing non-cardioembolic ischemic stroke.

Introduction: The treatment of advanced cervical cancer is continuously developing. There is a critical need to explore new treatment options to improve cure rates and make treatment more affordable. Despite efforts in prevention, cervical cancer remains the fourth most common cancer worldwide in terms of both incidence and mortality. Areas covered: This article offers an updated and critical analysis of angiogenesis inhibitors used in the treatment of advanced cervical cancer. It should be noted that this is not a systematic review. Expert opinion: Bevacizumab is currently the primary antiangiogenic agent used alongside chemotherapy and has become the standard of care for advanced cervical cancer. However, there are still uncertainties regarding the molecular mechanisms and associations in cervical cancer that could help in optimizing the use of Bevacizumab. Factors such as cost, toxicity, and methodological issues in the GOG-240 trial must be considered.

Introduction: Chemotherapy induced peripheral neurotoxicity (CIPN) is a long-lasting, or even permanent, late toxicity caused by largely used anticancer drugs. CIPN affects a growing population of cancer survivors and diminishes their quality of life since there is no curative/preventive treatment. Among several reasons for this unmet clinical need, there is an incomplete knowledge on mechanisms leading to CIPN. Therefore, bench side research is still greatly needed: in vitro studies are pivotal to both evaluate neurotoxicity mechanisms and potential neuroprotection strategies. Areas covered: Advantages and disadvantages of in vitro approaches are addressed with respect to their applicability to the CIPN field. Different cell cultures and techniques to assess neurotoxicity/neuroprotection are described. PubMed search-string: (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (in vitro) AND (((((model) OR SH-SY5Y) OR PC12) OR iPSC) OR DRG neurons); (chemotherapy-induced) AND (((neuropathy) OR neurotoxicity) OR neuropathic pain) AND (model) AND (((neurite elongation) OR cell viability) OR morphology). No articles published before 1990 were selected. Expert opinion: CIPN is an ideal experimental setting to test axonal damage and, in general, peripheral nervous system mechanisms of disease and neuroprotection. Therefore, starting from robust preclinical data in this field, potentially, relevant biological rationale can be transferred to other human spontaneous diseases of the peripheral nervous system.

Introduction: Statins are the primary therapeutic approach for treating hypercholesterolemia in hyperlipidemic high cardiovascular-risk patients, as stated by the recent European and American guidelines. However, in some patients, statin treatment is not sufficient to achieve the recommended plasma LDL-C levels, and the addition of a second hypolipidemic drug becomes mandatory. Concomitant administration of multiple medications may increase the risk of adverse events, potentially leading to statin-associated muscle or liver symptoms and non-adherence or discontinuation of statin therapy, such as in women. The addition of a second hypolipidemic drug (such as ezetimibe, anti-PCSK9 monoclonal antibodies, bempedoic acid, and inclisiran) may lead to drug-drug interactions (DDIs). The evaluation of the different pharmacokinetic profiles may improve and personalize the treatment. Areas covered: We aimed to give an update on the potential DDIs between statins and other hypolipidemic drugs currently used to treat high-risk hyperlipidemic patients. Expert opinion: It is fundamental to understand the risk associated with DDIs to manage better the addition of a concomitant hyperlipidemic drug to a statin-treated patient. Many health agencies have published specific guidelines for assessing DDIs, but these mainly apply to in vitro studies. New predictive approaches are being proposed and may help evaluate and manage DDIs.

Introduction Nicardipine is a type of calcium channel blocker that is commonly used in the treatment of angina pectoris, hypertension, and related cardiovascular disorders. This systematic review assesses the reported pharmacokinetic (PK) and associated pharmacodynamic (PD) parameters of nicardipine in humans. Areas Covered An exhaustive literature search using four internet databases was conducted up to 5 October 2023, which yielded 871 papers, of which 32 fulfilled the eligibility requirements by including human PK and related PD data. The area under the plasma concentration vs. time curve from zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax) of nicardipine rise proportionately with increasing dosage. One study revealed that AUC0-∞ of nicardipine was increased by 5-fold in hepatic cirrhosis patients compared to the control subjects. Moreover, related PD data in renal-impaired hypertensive patients revealed that a notable reduction in blood pressure was associated with nicardipine administration. Expert opinion This review covers comprehensive data on clinical PK, drug-drug interaction studies, effects of dosage form on ADME, and associated PD parameters of nicardipine using all relevant published studies. The present study will also aid in the development and evaluation of PK models for suggesting model-informed dosing regimens.

Introduction: Alopecia Areata (AA), characterized by non-scarring hair loss due to the dysregulation of the JAK/STAT pathway, has long lacked effective treatment. In 2023, Ritlecitinib, a novel Janus kinase (JAK) 3 and tyrosine kinase family inhibitor, received its first approval from the US FDA to treat AA, followed by approvals in Japan, Europe, China, and the UK. This development aims to address the challenges faced by millions of individuals affected by this condition globally. Areas covered: This review offers an overview of Ritlecitinib's pharmacological properties, biological targets, and development strategies. It examines its mechanism of action, pharmacokinetics, pharmacodynamics, and clinical trial insights. Additionally, it covers the drug's chemical synthesis, contraindications, drug interactions, and potential adverse effects, with special attention to its use in adolescents, pregnant women, and the elderly. Expert opinion: Ritlecitinib represents a significant advancement in treating AA, offering a targeted approach with promising efficacy and a favorable safety profile. While long-term safety data and real-world effectiveness studies are needed, its oral administration and efficacy in both adults and adolescents position it as a potentially transformative therapy. Ongoing research should focus on optimizing treatment strategies, identifying predictive biomarkers, and assessing cost-effectiveness to fully realize Ritlecitinib's potential in improving outcomes.