Expert Opinion on Drug Metabolism & Toxicology

Tomlinson, Brian; Li, Yan-Hong

doi: 10.1080/17425255.2023.2288246pmid: 37997258

Battipaglia, Christian; Feliciello, Lia; Genazzani, Alessandro D.; Facchinetti, Fabio; Grandi, Giovanni

doi: 10.1080/17425255.2023.2279752pmid: 37942662

Introduction Drospirenone/estetrol (DRSP/E4) is a combined oral contraceptive (COC) recently approved in several countries. It is composed of 15 mg of E4, a natural estrogen produced by human fetal liver throughout pregnancy, and 3 mg of DRSP, the first synthetic progestin used in oral contraception derived from 17-α-spirolactone. E4 and DRSP synergistically prevent pregnancy by inhibiting ovulation. E4 differs from 17-β-estradiol or ethinylestradiol because it represents a native estrogen with selective action in tissues (NEST), therefore it displays both agonist and antagonist estrogenic effects in different tissues. Areas Covered In this paper, we reviewed the scientific literature published in English prior to April 2023 and gathered information on the pharmacodynamics and pharmacokinetics of DRSP, E4 and their combination for contraception. We also proposed possible clinical applications based on the characteristics of the components of this COC. Expert Opinion E4/DRSP-based COC has shown high tolerability, safety and satisfaction and may represent a viable choice in young girls in need of oral contraception and pill users who suffer from high cholesterol, breast tenderness or water retention. Moreover, this new COC shows higher scheduled bleeding rate compared to other pills containing natural estrogens. All the data are reassuring, permitting long-term use.

Tuan, Jessica; Okoli, Adaora; Ogbuagu, Onyema

doi: 10.1080/17425255.2023.2292736pmid: 38058292

Introduction The World Health Organization proposed targets to eliminate hepatitis C virus (HCV) by 2030, aiming to treat ≥80% of people with HCV, decreasing new chronic infections by 90% and liver-related mortality by 65%. While children/adolescents represent a minority of cases, the true burden is underestimated. Advances in drug development have resulted in simplified treatments that are well-tolerated, effective, and pangenotypic in activity. Sofosbuvir/velpatasvir, a combined nucleotide analog NS5B polymerase inhibitor and NS5A inhibitor, respectively, is approved for HCV treatment for individuals ≥3 years, supported by safety data using lower-dose, novel formulations. Areas covered This review discusses chemistry, pharmacokinetics/pharmacodynamics, dosing, efficacy, and safety of sofosbuvir/velpatasvir highlighting pediatric data. Literature review included publications/conference abstracts from PubMed, Google, and Google Scholar. Information from key clinical trials/regulatory approvals is reviewed. Expert opinion Sofosbuvir/velpatasvir is a safe and effective therapy for the treatment of pangenotypic chronic HCV infection with limited cases of virologic relapse and adverse events among pediatric populations aged 3 years and older. However, the tolerability among children less than 6 years could be improved by alternative formulations, if not, shorter treatment durations. An aspirational role of direct-acting antivirals (DAAs) that should be explored is for the prevention of infection in exposed and at-risk pediatric populations.

Currò, Diego; Ianiro, Gianluca; Gasbarrini, Antonio

doi: 10.1080/17425255.2023.2294937pmid: 38108081

Introduction Tenapanor is the latest addition to the second-line pharmacotherapeutic options for the treatment of irritable bowel syndrome with constipation. It is a first-in-class inhibitor of type 3 sodium/hydrogen exchanger (NHE3), characterized by very low oral absorption. Its pharmacological properties are discussed here based on the latest literature. Areas covered A general description of tenapanor is provided, highlighting those pharmacokinetic and pharmacodynamic characteristics of the drug which may be of major importance for tolerability and safety. This description is associated with a summary and analysis of currently available toxicological data. Expert opinion Plasma concentrations of free tenapanor after oral administration are well below the half maximal inhibitory concentration for NHE3, so that systemic effects of the drug are minimal. Therefore, the action of tenapanor is limited to NHE3 located on the apical membrane of enterocytes. The consequent reduction in intestinal sodium absorption increases the intraluminal content by osmosis, which in turn enhances the propulsive activity of the colon. Diarrhea is the most frequent adverse effect of tenapanor. Increased fecal sodium and water excretion do not appear to expose patients to short- and long-term hydro-electrolyte imbalances.

Hou, Zihan; Ma, Aijinxiu; Mao, Jiale; Song, Danni; Zhao, Xu

doi: 10.1080/17425255.2023.2287477pmid: 37994776

Introduction Hyperuricemia is a common metabolic disease, which is a risk factor for gouty arthritis and ureteral stones and may also lead to cardiovascular and chronic kidney disease (CDK). Therefore, hyperuricemia should be treated early. Xanthine oxidase inhibitors (XOIs) and uricosuric agents (UAs), which target uric acid, are two types of medications that are used to treat gout and hyperuricemia. XOIs stop the body from producing excessive uric acid, while UAs eliminate it rapidly via the kidneys. Urate transporter 1 (URAT1) belongs to the organic anion transporter family (OAT) and is specifically localized to the apical membrane of the epithelial cells of proximal tubules. Unlike other organic anion transporter family members, URAT1 identifies and transports organic anions that are primarily responsible for urate transport. Areas covered This article reviews the pharmacokinetics and pharmacodynamics of the existing URAT1 inhibitors to serve as a reference for subsequent drug studies. Expert opinion The URAT1 inhibitors that are currently used as clinical drugs mainly include dotinurad, benzbromarone, and probenecid. Results indicate that RDEA3170 may be the most promising inhibitor, in addition to SHR4640, URC-102, and MBX-102, which are in the early stages of development.

Hindley, B.; Lip, G.Y.H.; McCloskey, A.P.; Penson, P.E.

doi: 10.1080/17425255.2023.2287472pmid: 37991392

Introduction Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists to become the most widely used method of anticoagulation for most indications. Their stable and predictable pharmacokinetics combined with relatively simple dosing, and the absence of routine monitoring has made them an attractive proposition for healthcare providers. Despite the benefits of DOACs as a class, important differences exist between individual DOAC drugs in respect of their pharmacokinetic and pharmacodynamic profiles with implications for dosing and reversal in cases of major bleeding. Areas Covered This review summarizes the state of knowledge relating to the pharmacokinetics of dabigatran (factor IIa/thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (factor Xa) inhibitors. We focus on pharmacokinetic differences between the drugs which may have clinically significant implications. Expert Opinion Patient-centered care necessitates a careful consideration of the pharmacokinetic and pharmacodynamic differences between DOACs, and how these relate to individual patient circumstances. Prescribers should be aware of the potential for pharmacokinetic drug interactions with DOACs which may influence prescribing decisions in patients with multiple comorbidities. In order to give an appropriate dose of DOAC drugs, accurate estimation of renal function using the Cockcroft-Gault formula using actual body weight is necessary. An increasing body of evidence supports the use of DOACs in patients who are obese, and this is becoming more routine in clinical practice.

Cuomo, Alessandro; Barillà, Giovanni; Serafini, Gianluca; Aguglia, Andrea; Amerio, Andrea; Cattolico, Matteo; Carmellini, Pietro; Spiti, Alessandro; Fagiolini, Andrea

doi: 10.1080/17425255.2023.2288681pmid: 38032183

Davoutis, Efstathia; Panou, Chrysa; Stachika, Nikolina; Dalla, Christina; Kokras, Nikolaos

doi: 10.1080/17425255.2023.2280750pmid: 37934891

Introduction Antidepressants are widely used for the pharmacological treatment of anxiety and mood disorders. Since the eruption of the SARS-COV-2 pandemic and the later development of targeted treatments against COVID-19, inevitably many patients receive antidepressants as well as targeted treatments against COVID-19 against COVID-19. Co-administration of antidepressants with COVID-19 therapeutics has the potential of drug-drug interactions, of varying severity and clinical significance. Areas Covered This is a curated narrative review of the current state of the art regarding drug-drug interactions between COVID-19 therapeutics and medications licensed for the pharmacotherapy of depression. A systematic search of electronic databases, using as keywords the international nonproprietaty names of currently approved COVID-19 therapeutics and antidepressants was performed, and additionally online interaction checker tools were consulted. Derived data were synthesized for each COVID-19 therapeutic and presented with up-to-date guidance. Expert Opinion Several COVID-19 therapeutics have potential for drug-drug interactions with antidepressants. Remdesivir and Nirmatrelvir-Ritonavir have the higher risk, whereas several monoclonal antibodies appear safer. The most serious drug-drug interactions (serotonin syndrome and QTc prolongation) require close monitoring; however, DDI toward reducing the efficacy of antidepressants may be difficult to recognize. As COVID-19 treatment protocols take precedence, psychiatrists should exert flexibility in antidepressant use and proactively monitor treatment progress.

Takizawa, Tsubasa; Ihara, Keiko; Uno, Shunsuke; Ohtani, Seiya; Watanabe, Narumi; Imai, Noboru; Nakahara, Jin; Hori, Satoko; Garcia-Azorin, David; Martelletti, Paolo

doi: 10.1080/17425255.2023.2280221pmid:

Björnsson, Helgi Kristinn; Björnsson, Einar Stefan

doi: 10.1080/17425255.2023.2288260pmid: 37997265

Introduction Idiosyncratic drug-induced liver injury (DILI) is a common cause of acute liver injury and can lead to death from acute liver failure or require liver transplantation. Although the total burden of liver injury is high, the frequency of DILI caused by specific agents is often low. As the liver injury is by per definition idiosyncratic, the prediction of which patients will develop liver injury from specific drugs is currently a very difficult challenge. Areas covered The current paper highlights the most important studies on prediction of DILI published in 2019–2023, including studies on genetic, metabolomic, and demographic risk factors, concomitant medication, and the role of comorbid liver diseases. Risk stratification using demographic, metabolomic, and multigenetic risk factors is discussed. Expert opinion Great advances have been made in identifying genetic risk factors for DILI. Combining these risk factors with demographic information and other biomarkers into multigenetic risk models might become highly useful in risk stratifying patients exposed to DILI. However, a more detailed mapping of genetic risk factors is needed. Results of these studies need to be validated in the selected ethnic groups before applicability and cost-effectiveness can be determined.