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(1) Background: To identify a particular setting of biopsy-naïve patients in which it would be reasonable to offer only cognitive targeted prostate biopsy (PBx) with a transrectal approach. (2) Methods: We designed an observational retrospective pilot study. Patients with a prostatic specific antigen (PSA) level > 10 ng/mL, either a normal or suspicious digital rectal examination (DRE), and a lesion with a PI-RADS score ≥ 4 in the postero-medial or postero-lateral peripheral zone were included. All patients underwent a transrectal PBx, including both systematic and targeted samples. The detection rate of clinically significant prostate cancer (csPCa) (Gleason Score ≥ 7) was chosen as the primary outcome. We described the detection rate of csPCa in systematic PBx, targeted PBx, and overall PBx. (3) A total of 92 patients were included. Prostate cancer was detected in 84 patients (91.30%) with combined biopsies. A csPCa was diagnosed in all positive cases (100%) with combined biopsies. Systematic PBxs were positive in 80 patients (86.96%), while targeted PBxs were positive in 84 men (91.30%). Targeted PBx alone would have allowed the diagnosis of csPCa in all positive cases; systematic PBx alone would have missed the diagnosis of 8/84 (9.52%) csPCa cases (4 negative patients and 4 not csPCa) (p = 0.011). (4) Conclusions: Cognitive targeted PBx with a transrectal approach could be offered alone to diagnose csPCa in biopsy-naïve patients with PSA ≥ 10 ng/mL, either normal or suspicious DRE, and a lesion with PI-RADS score ≥ 4 in the postero-medial or postero-lateral peripheral zone.
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Despite the benefits of breastfeeding, lactating mothers who take prescribed medications may discontinue breastfeeding due to concerns associated with infant drug exposure in breastmilk. Consolidating the current knowledge of drug transport to breastmilk may inform understanding of the safety of medication use during lactation. This literature review summarizes the mechanisms of drug transport to breastmilk, details the physicochemical drug properties that may alter the extent of passive transport, and describes the expressional changes in mammary drug transporters that may affect active transport. During the period of 20 July 2023 to 11 August 2023, PubMed® was searched to identify journal articles pertinent to the mechanisms of drug transport from maternal plasma to breastmilk and the expression of mammary drug transporters during lactation. From the 28 studies included in this review, four mechanisms were identified for transporting drugs from maternal plasma to breastmilk: passive transport, active transport, lipid co-transport, and transcytosis. The lactational expression of 20 drug transporters was further summarized, with 9 transporters demonstrating downregulated expression during lactation and 11 transporters demonstrating upregulated expression during lactation. Understanding the mechanisms of drug transport to breastmilk may aid in estimating infant drug exposure, developing physiologically based pharmacokinetic (PBPK) models that describe drug transfer, and initiating clinical drug development programs in the lactating population.
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Background and objective: Published works have discussed the pharmacokinetic interactions of drugs with pregnancy, but none comprehensively identify all the approved United States Food and Drug Administration (FDA) and European Medicines Administration (EMA) drugs that have a pregnancy-related intervention. The objective of this systematic review is to comprehensively identify medications that have clinically meaningful interventions due to pharmacokinetic reasons. Methods: An in-depth search of clinical data using the PDR3D: Reed Tech Navigator™ for Drug Labels was conducted from 1 June to 12 August 2022. The PDR3D was analyzed using the search terms "pregnant" and "pregnancy" within the proper label section. Regarding the US labels, the terms were searched under the "dosage and administration" section, whereas with the EU labels, the terms were searched within the "posology and method of administration" section. If a finding was discovered within the search, the rest of the label was analyzed for further information. Clinical relevance was based on whether an intervention was needed. Results: Using the search strategy, 139 US and 20 EU medications were found to have clinically meaningful interventions in pregnancy. The most common explanations for clinical relevance included hepatic metabolism, protein binding, renal elimination, and P-gp influence. Of the US labels: 40 were found to undergo hepatic metabolism, 11 were found to be influenced by renal elimination, 12 were found to be influenced by protein binding, 7 were found to be influenced by P-gp, and the remaining drugs required further research. Of the EU labels: 11 were found to undergo hepatic metabolism, 3 were found to be influenced by renal elimination, 3 were found to be influenced by protein binding, 1 was found to be influenced by P-gp, and the remaining drugs required further research. Conclusion: This comprehensive review of clinically relevant interventions in pregnancy will potentially aid in the treatment of pregnant females when they are undergoing therapy, provide intervention and dosing guidance for physicians, and save time for prescribers and pharmacists. Advances in non-clinical predictions for pregnancy dosing may guide the need for a future clinical evaluation.
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The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant to drug metabolism and transport in pregnancy. PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population.
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Physiologically based pharmacokinetic (PBPK) modelling in pregnancy is a relatively new approach that is increasingly being used to assess drug systemic exposure in pregnant women to potentially inform dosing adjustments. Physiological changes throughout pregnancy are incorporated into mathematical models to simulate drug disposition in the maternal and fetal compartments as well as the transfer of drugs across the placenta. This mini-review gathers currently available pregnancy PBPK models for drugs commonly used during pregnancy. In addition, information about the main PBPK modelling platforms used, metabolism pathways, drug transporters, data availability and drug labels were collected. The aim of this mini-review is to provide a concise overview, demonstrate trends in the field, highlight understudied areas and identify current gaps of PBPK modelling in pregnancy. Possible future applications of this PBPK approach are discussed from a clinical, regulatory and industry perspective.
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SARS-CoV-2 vaccination is strongly recommended, particularly for fragile patients such as those undergoing active oncological treatments. It is crucial to conduct post-marketing surveillance in this patient population. In our study, we conducted a retrospective analysis of real-world data, including 136 patients who received SARS-CoV-2 vaccines and were undergoing anticancer treatments between March 1st and June 30th, 2021. All patients received mRNA vaccines, namely Pfizer-BioNTech's COMIRNATY (BNT162b2 mRNA) and Moderna's mRNA-1273 COVID-19 vaccines. We collected blood samples from the patients one week to 10 days before and after vaccine administration to assess full blood count with white cell differentials. Additionally, we monitored serology titers to detect any previous SARS-CoV-2 infection before hospital admission and tracked changes over time. Our findings revealed a significant occurrence of leukopenia following both the first and second vaccine doses among patients receiving chemotherapy and chemo-immunotherapy. Importantly, this effect was independent of demographic factors such as sex, age, and Body Mass Index. In the chemo-immunotherapy treated group, we observed that concomitant immune-mediated diseases were significantly associated with leukopenia following the second vaccine dose. Notably, in healthy subjects, transient neutropenia was recognized as an adverse event following vaccination. The observed lymphocytopenia during SARS-CoV-2 infection, combined with the impact on leukocyte counts observed in our study, underscores the need for larger post-marketing surveillance studies. Despite a treatment delay occurring in 6.6% of patients, the administration of mRNA vaccines did not have a significant impact on the treatment schedule in our series. These findings from a real-world setting provide valuable insights and suggest avenues for further prospective studies to explore potential complex interactions specific to this patient population.
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Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.
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Physiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5'-diphospho-glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy-related changes in uridine 5'-diphospho-glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs.
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Acetaminofen , Benzodiazepinas , Gravidez , Humanos , Feminino , Cafeína , Clindamicina , GlucuronosiltransferaseRESUMO
Pregnancy-related physiological changes can alter the absorption, distribution, metabolism and excretion of medicines which may affect the safety and efficacy of the medicines administered in pregnancy. Pharmacokinetic data can thus be instrumental in supporting dose adjustments required in this population. This review considers the availability of published pharmacokinetic data for over 200 medicines of interest for use in pregnancy in the UK, to identify whether sufficient data currently exists, in principle, for any medicine or group of medicines to support dose adjustments to maintain maternal health through pregnancy. Very limited data was found for many of the medicines of interest. Nevertheless, well documented, large changes of exposure for some drugs, where data is available, highlights the urgent need to collect more data of good quality to inform appropriate doses, when needed, in this population. In addition, clinical study methodology can have an impact on the usefulness of the data and key clinical design aspects are highlighted for consideration in future clinical study design.
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Physiologically based pharmacokinetic modeling (PBPK) could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations where there are currently no available clinical data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by the kidney. Models were evaluated for ceftazidime, cefuroxime, metformin, oseltamivir, and amoxicillin. Because the passive renal process contributes significantly to the renal elimination of these drugs and changes of the process during pregnancy have been implemented in existing pregnancy physiology models, simulations using these models can reasonably describe the pharmacokinetics of ceftazidime changes during pregnancy and appears to generally capture the changes in the other medicines; however, there are insufficient data on drugs solely passively cleared to fully qualify the models. In addition, in many cases, active transport processes are involved in a drug's renal clearance. Knowledge of changes in renal transport functions during pregnancy is emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is a work in progress. Filling this gap is expected to further enhance predictive performance of the models and increase the confidence in predicting pharmacokinetic changes in pregnant women for other renally cleared drugs.
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Ceftazidima , Modelos Biológicos , Feminino , Humanos , Rim/metabolismo , Testes de Função Renal , Gravidez , Eliminação RenalRESUMO
Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit-risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions.
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The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC.
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On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310-301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin-cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60-75 years with untreated high-risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin-cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52-0.90; one-sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. IMPLICATIONS FOR PRACTICE: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML.
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Leucemia Mieloide Aguda , Lipossomos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/uso terapêutico , Daunorrubicina , Humanos , Irlanda , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
The human mass balance study is a key study in the Clinical Pharmacology package of new drug applications. This study, along with the mass balance studies in toxicology species, provides essential information on the exposure of the parent compound and metabolites. Despite current regulatory guidance and previous publications, a lack of this study, or deficiencies in the study, are still seen in regulatory submissions today. This restricts the assessment of the benefit/risk in all populations and on the potential for drug-drug interactions leading to unnecessary precautions in the label. A review of new drug applications identifies a number of examples of inadequate characterization of circulating drug-related components or of elimination pathways, with questions raised during the regulatory review. In light of this, new insight is given on what is required from the mass balance study and on how to ensure sufficient information is captured.
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Preparações Farmacêuticas/análise , Projetos de Pesquisa/normas , Interações Medicamentosas , Humanos , Legislação de Medicamentos , Farmacocinética , Farmacologia Clínica , Projetos de Pesquisa/legislação & jurisprudência , Medição de RiscoRESUMO
BACKGROUND: The antibacterial agent prulifloxacin, a prodrug of ulifloxacin, is indicated in the treatment of acute lower urinary tract infections, acute exacerbation of chronic bronchitis and acute bacterial rhinosinusitis. OBJECTIVE: We aimed to provide new insights on the pharmacokinetics (PK) of ulifloxacin in patients with different degrees of renal impairment. METHODS: A two-site, international, open-label, parallel-group, single- and repeated-dose study was performed. The drug was administered as a single dose of 600 mg to subjects with normal renal function and patients with mild, moderate and severe renal impairment. Subsequently, the same dose was administered daily for 7 days to subjects with normal renal function and patients with mild and moderate renal impairment, while a dose of 300 mg was administered daily for 7 days to patients with severe renal impairment. Plasma and urine ulifloxacin levels were measured. Complete safety evaluation was performed. RESULTS: Exposure to ulifloxacin increased as renal function decreased due to a lower ulifloxacin clearance. Ulifloxacin PK were significantly changed only in patients with severe renal impairment. The amount of ulifloxacin excreted in urine over a 24-h dosing period was similar in subjects with normal renal function and patients with mild impaired renal function, but lower in those with moderate and severe renal impairment. CONCLUSION: Our data show that prulifloxacin is a safe quinolone and is well tolerated in both subjects with normal renal function and patients with impaired renal function, requiring a minimal dosage adjustment only in patients with severe renal impairment.
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Antibacterianos/farmacocinética , Dioxolanos/farmacocinética , Fluoroquinolonas/farmacocinética , Piperazinas/farmacocinética , Insuficiência Renal/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Dioxolanos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/análise , Adulto JovemRESUMO
The initial evaluation of patients with transient loss of consciousness (LOC) comprises a detailed medical history, physical examination, and 12-lead electrocardiogram. Because there are many causes of syncopal and nonsyncopal LOC, an adequate method of taking the clinical history, which is the cornerstone of diagnosing patients with transient LOC, should be used.
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Síncope/complicações , Inconsciência/etiologia , Diagnóstico Diferencial , Eletrocardiografia , Humanos , Síncope/diagnóstico , Inconsciência/diagnósticoRESUMO
PURPOSE: To study the effect of isoenergetic administration to adult rats of high-fat or high-fat--high-fructose diet for 2 weeks on skeletal muscle mitochondrial energetic. METHODS: Body and skeletal muscle composition, energy balance, plasma lipid profile and glucose tolerance were measured, together with mitochondrial functionality, oxidative stress and antioxidant defense. RESULTS: Rats fed high-fat--high-fructose diet exhibited significantly higher plasma triglycerides and non-esterified fatty acids, together with significantly higher plasma glucose and insulin response to glucose load. Skeletal muscle triglycerides and ceramide were significantly higher in rats fed high-fat--high-fructose diet. Skeletal muscle mitochondrial energetic efficiency and uncoupling protein 3 content were significantly higher, while adenine nucleotide translocase content was significantly lower, in rats fed high-fat or high-fat--high-fructose diet. CONCLUSIONS: The results suggest that a high-fat--high-fructose diet even without hyperphagia is able to increase lipid flow to skeletal muscle and mitochondrial energetic efficiency, with two detrimental effects: (a) energy sparing that contributes to the early onset of obesity and (b) reduced oxidation of fatty acids and lipid accumulation in skeletal muscle, which could generate insulin resistance.
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Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Metabolismo Energético , Frutose/efeitos adversos , Resistência à Insulina , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animais , Ceramidas/metabolismo , Ingestão de Energia , Ácidos Graxos não Esterificados/sangue , Membro Posterior , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Canais Iônicos/metabolismo , Masculino , Mitocôndrias Musculares/enzimologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/enzimologia , Fosforilação Oxidativa , Estresse Oxidativo , Ratos Sprague-Dawley , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Proteína Desacopladora 3 , Aumento de PesoRESUMO
Falls may be accidental (because of slipping, tripping or environmental hazards) or 'unexplained', when there is no apparent cause. Syncope is a transient loss of consciousness (LOC) and, if it occurs when the person is in the upright position, may lead to a fall. The differential diagnosis between 'unexplained' fall and syncopal fall can be difficult, if not impossible, because many patients have retrograde amnesia after syncope, that is they do not remember their prodromal symptoms. Based on the results of many randomized studies, the international guidelines on falls suggest multifactorial assessment and multifactorial treatment. Unfortunately, however, the vast majority of studies have been carried out on a mixed population of patients who have suffered accidental and 'unexplained' falls. As 'unexplained' falls account for a minority of cases, we really do not know the efficacy of multifactorial treatment in patients with this type of fall. Very recent data seem to prove that many older patients with 'unexplained' falls are actually affected by reflex syncope with retrograde amnesia, as they experience LOC during tilt testing or carotid sinus massage. Although these data make an important contribution to our knowledge of the mechanism of 'unexplained' falls, the therapeutic problems remain largely unsolved.