During recent years there has been a surge in developing and applying physiologically based pharmacokinetic (PBPK) models in pregnant women to better understand and predict changes in drug pharmacokinetics throughout pregnancy. As a consequence, the number of publications focusing on pregnancy PBPK models has increased substantially. However, to date these models, especially across various platforms, have not been systematically evaluated. Hence, this review aims to assess published PBPK models in pregnancy used for therapeutic purposes.
Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of singleascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (t max ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and t max delayed by 1.5 h. Pharmacokinetic modelling predicted that twicedaily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
Background Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin. Methods We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness. Results Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days vs. 40.7/1000 infant days, P<0.001). There was no difference in seizures with meropenem vs. imipenem/cilastatin (adjusted odds ratio [OR] 0.96; 95% confidence interval 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use—OR 0.68 (0.50, 0.88) and OR 0.77 (0.62, 0.95), respectively. Conclusion In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
Tremendous efforts have been directed to investigate the ontogeny of drug transporters in fetuses, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (ie, in the fetus and newborn infant), there is special interest in transporters expressed in the placenta that modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth, stressing the relevance of elucidating expression in the placenta and potential gestational age‐dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. In addition, various in vitro, ex vivo, and in silico models that can be used to investigate placental drug transfer, namely, placental cancer cell lines, ex vivo cotyledon perfusion experiments, and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information, and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetuses.
The broad-spectrum activity of fosfomycin, including against multidrug-resistant (MDR) strains, has led to renewed interest in its use in recent years. Neonatal sepsis remains a substantial cause of morbidity and mortality at a global level, with evidence that MDR bacteria play an increasing role. The evidence for use of fosfomycin in neonatal subjects is limited. We summarise current knowledge of the pharmacokinetics and clinical outcomes for the use of fosfomycin in neonatal sepsis and issues specific to neonatal physiology. While fosfomycin has a broad range of coverage, we evaluate the extent to which it may be effective against MDR bacteria in a neonatal setting, in light of recent evidence suggesting it to be most effective when administered in combination with other antibiotics. Given the urgency of clinical demand for treatment of MDR bacterial sepsis, we outline directions for further work, including the need for future clinical trials in this at-risk population.
Aims Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT‐1014‐6470 was well tolerated in a single‐ascending dose study in healthy subjects. This double‐blind, randomized, placebo‐controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple‐ascending doses of ACT‐1014‐6470. Methods Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT‐1014‐6470 administered twice daily for 4.5 days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120 h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60‐mg dose level, PK samples were collected until 8 weeks post last dose. Results The total adverse event number was 57 and no treatment‐related safety pattern was apparent. At steady state, ACT‐1014‐6470 reached maximum plasma concentrations after 2–3 h and the half‐life estimated up to Day 10 was 115–146 h across dose levels. Exposure parameters increased dose‐proportionally, steady state was attained between Day 3–5, and ACT‐1014‐6470 accumulated 2‐fold. At the 60‐mg dose level, ACT‐1014‐6470 was quantifiable until 8 weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT‐1014‐6470. Conclusion The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.
ObjectiveThe main aim of this analysis was to characterize the pharmacokinetics (PK) of the strong analgesic tapentadol in 2-year-old to <18-year-old patients with acute pain and to inform the optimal dosing strategy for a confirmatory efficacy trial in this patient population.MethodsThe analysis dataset included tapentadol concentrations obtained from 92 pediatric patients receiving a single tapentadol oral solution (OS) dose of 1.0 mg/kg bodyweight in two single-dose PK clinical trials. Population PK analysis was performed using nonlinear mixed effects modeling. Simulations were performed to identify tapentadol OS doses in pediatric subjects (2 to <18 years) that would produce exposures similar to those in adults receiving safe and efficacious doses of tapentadol IR (50–100 mg every 4 hrs).ResultsTapentadol PK in children aged from 2 to <18 years was best described by a one-compartment model. Mean population apparent clearance and apparent volume of distribution for a typical subject weighing 45 kg were 170 L/h and 685 L, respectively. Clearance, expressed in bodyweight units as L/h/kg, decreased with increasing age whereas total clearance (L/h) increased with increasing age. Model-based simulations suggested that a tapentadol OS dose of 1.25 mg/kg to children and adolescents aged 2 to <18 years would result in efficacious tapentadol exposures similar to those in adults receiving tapentadol immediate release 50–100 mg every 4 hrs. The proposed tapentadol OS dose was subsequently applied in a confirmatory efficacy trial in 2 to <18-year-old patients suffering from acute postsurgical pain.ConclusionThis analysis provides an example of a model-based approach for a dose recommendation to be used in an efficacy trial in the pediatric population. Uniform dosing based on bodyweight was proposed for the treatment of acute pain in children aged from 2 to <18 years.
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