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There is paucity of evidence to support clinical decision making and counselling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple comorbidities that require pharmacological intervention; these interventions primarily target the pregnant woman but also sometimes have secondary effects for the foetus. The US Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in paediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives. [ABSTRACT FROM AUTHOR]

Pregnant individuals are at high risk for severe illness from COVID‐19, and there is an urgent need to identify safe and effective therapeutics for this population. Remdesivir (RDV) is a SARS‐CoV‐2 nucleotide analog RNA polymerase inhibitor. Limited RDV pharmacokinetic (PK) and safety data are available for pregnant women receiving RDV. The aims of this study were to translate a previously published nonpregnant adult physiologically based PK (PBPK) model for RDV to pregnancy and evaluate model performance with emerging clinical PK data in pregnant women with COVID‐19. The pregnancy model was built in the Open Systems Pharmacology software suite (Version 10) including PK‐Sim® and MoBi® with pregnancy‐related changes of relevant enzymes applied. PK were predicted in a virtual population of 1000 pregnant subjects, and prediction results were compared with in vivo PK data from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network 2032 study. The developed PBPK model successfully captured RDV and its metabolites' plasma concentrations during pregnancy. The ratios of prediction versus observation for RDV area under the curve from time 0 to infinity (AUC0–∞) and maximum concentration (Cmax) were 1.61 and 1.17, respectively. For GS‐704277, the ratios of predicted versus observed were 0.94 for AUC0–∞ and 1.20 for Cmax. For GS‐441524, the ratios of predicted versus observed were 1.03 for AUC0–24, 1.05 for Cmax, and 1.07 for concentrations at 24 h. All predictions of AUC and Cmax for RDV and its metabolites were within a twofold error range, and about 60% of predictions were within a 10% error range. These findings demonstrate the feasibility of translating PBPK models to pregnant women to potentially guide trial design, clinical decision making, and drug development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease‐ and/or target organ‐specific examples. Identifying and testing PD targets and effects in special populations, and application of age‐ and/or population‐specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD‐related as well as drug safety‐related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development. [ABSTRACT FROM AUTHOR]

Objective: The perspective of real-world study is especially relevant to newborns, enabling dosage regimen optimization and regulatory approval of medications for use in newborns. The aim of the present study was to conduct a pharmacokinetic analysis of cefotaxime and evaluate the dosage used in newborns with early-onset sepsis (EOS) using real-world data in order to support the rational use in the clinical practice. Methods: This prospective, open-label study was performed in newborns with EOS. A developmental pharmacokinetic-pharmacodynamic model of cefotaxime in EOS patients was established based on an opportunistic sampling method. Then, clinical evaluation of cefotaxime was conducted in newborns with EOS using real-world data. Results: A one-compartment model with first-order elimination was developed, using 101 cefotaxime concentrations derived from 51 neonates (30.1-41.3°C weeks postmenstrual age), combining current weight and postnatal age. The pharmacokinetic-pharmacodynamic target was defined as the free cefotaxime concentration above MIC during 70% of the dosing interval (70% fT > MIC), and 100% of neonates receiving the dose of 50 mg/kg, BID attained the target evaluated using the model. Additionally, only two newborns had adverse reactions possibly related to cefotaxime treatment, including diarrhea and feeding intolerance. Conclusion: This prospective real-world study demonstrated that cefotaxime (50 mg/kg, BID) had a favorable efficacy and an accepted safety profile for neonates with EOS. [ABSTRACT FROM AUTHOR]