Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

OBJECTIVE: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants. STUDY DESIGN: Plasma L-citrulline concentrations were measured in six premature infants receiving 60 mg/kg L-citrulline every 6 h for 72 h before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study. RESULTS: Target trough plasma L-citrulline concentrations were achieved in 2/6 subjects. No serious adverse events occurred. CONCLUSIONS: Multi-dose L-citrulline was well tolerated. These results will assist in the design of phase II RCTs evaluating L-citrulline dosage strategies to achieve target plasma L-citrulline concentrations in infants at risk for BPD-PH. CLINICAL TRIALS: gov ID: NCT03542812.

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

Enactment of the US Food and Drug Administration Amendments Act (FDAAA) in 2007 and the Pregnancy and Lactation Labeling Rule (PLLR) in 2015 are important milestones giving the FDA the authority to request studies in pregnant and lactating women. Our objective was to characterize trends of pregnancy and lactation-related postmarketing commitments (PMCs) and postmarketing requirements (PMRs) for new molecular entities approved by the FDA between 2000 and 2022. Approval letters of original New Drug Applications (NDAs, N = 488) for new molecular entities were obtained from the FDA website. NDAs with pregnancy and lactation-based PMCs/PMRs were identified, and data extracted. Data included: PMC/PMR timelines and attributes of requested study(ies) (type, design elements, and outcomes) when available. Fifty-nine NDAs included 92 PMCs/PMRs related to pregnancy and lactation. Forty-one NDAs had pregnancy-related PMRs/PMCs, 4 had lactation-related PMRs, and 14 had both. Most PMRs/PMCs were for nervous system medications (N = 33). Forty-seven NDAs specified safety data collection in infants in at least the first year of life. All pregnancy-related PMRs were issued after 2008, most PMCs (N = 8) were issued before 2008. Only one PMC requested a pharmacokinetic study in pregnant women. All lactation-related PMRs (N = 18) requested measurement of drug concentrations in breast milk with one also requiring measurement of maternal blood concentrations. Eighty-nine percent of lactation-related PMRs were requested after 2015. There was a steady increase in pregnancy and lactation-related PMRs following enactment of FDAAA and PLLR. Additions involved information collection pertaining to safety of the medication in pregnant and lactating women and children exposed to medications during pregnancy and breastfeeding.

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

Objective: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline as a therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Our goal was to evaluate the tolerability and ability to achieve a target steady-state L-citrulline plasma concentration in prematures treated enterally with a multi-dose L-citrulline strategy based on our single-dose pharmacokinetic study. Study Design: Six prematures received 60 mg/kg of L-citrulline every 6 hours for 72 hours. Plasma L-citrulline concentrations were measured before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study. Results: Plasma L-citrulline concentrations agreed with the simulated concentration-time profiles. No serious adverse events occurred. Conclusions: Simulations based on single-doses can be used to predict target multi-dose plasma L-citrulline concentrations. These results assist the design of RCTs evaluating the safety and effectiveness of L-citrulline therapy for BPD-PH. Clinical trials.gov ID: NCT03542812.

Pharmacokinetics and safety of prolonged paracetamol treatment in neonates: An interventional cohort study.

AIMS: To investigate the pharmacokinetics and safety of prolonged paracetamol use (>72 h) for neonatal pain. METHODS: Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. RESULTS: Forty-eight neonates were enrolled (38 received paracetamol for >72 h). Median gestational age was 38 weeks (range 25-42), and bodyweight at inclusion was 2954 g (range 713-4750). Neonates received 16 doses (range 4-55) over 4.1 days (range 1-13.8). The median (range) dose was 10.1 mg/kg (2.9-20.3). The median oxidative metabolite concentration was 14.6 µmol/L (range 0.12-113.5) and measurable >30 h after dose. There was no significant difference (P > .05) between alanine aminotransferase and bilirubin measures at <72 h or >72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44-3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425-0.570), respectively. Median steady-state concentration from the parent model was 50.3 µmol/L (range 30.6-92.5), and the half-life was 3.55 h (range 2.41-5.65). CONCLUSION: Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates.

Pharmacokinetics of L-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

BACKGROUND: Options to treat pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD) are few and largely ineffective. Improving the bioavailability of nitric oxide (NO) might be an efficacious treatment for BPD-PH. When administered orally, the NO-L-arginine precursor, L-citrulline, increases NO production in children and adults, however, pharmacokinetic (PK) studies of oral L-citrulline have not been performed in infants and children. OBJECTIVES: This study characterized the PK of enterally administered L-citrulline in neonates at risk of developing BPD-PH to devise a model-informed dosing strategy. METHODS AND RESULTS: Ten premature neonates (≤ 28 weeks gestation) were administered a single dose of 150 mg/kg (powder form solubilized in sterile water) oral L-citrulline at 32 ± 1 weeks postmenstrual age. Due to the need to limit blood draws, time windows were used to maximize the sampling over the dosing interval by assigning neonates to one of two groups (ii) samples collected pre-dose and at 1- and 2.5-h post-dose, and (ii) pre-dose and 0.25- and 3-h post-dose. The L-arginine concentrations (µmol/L) and the L-citrulline (µmol/L) plasma concentration-time data were evaluated using non-compartmental analysis (Phoenix WinNonlin version 8.1). Optimal dosage strategies were derived using a simulation-based methodology. Simulated doses of 51.5 mg or 37.5 mg/kg given four times a day produced steady-state concentrations close to a target of 50 µmol/L. The volume of distribution (V/F) and clearance (CL/F) were 302.89 ml and 774.96 ml/h, respectively, with the drug exhibiting a half-life of 16 minutes. The AUC from the time of dosing to the time of last concentration was 1473.3 h*µmol/L, with Cmax and Tmax of 799 µmol/L and 1.55 h, respectively. CONCLUSION: This is the first PK study in neonates presenting data that can be used to inform dosing strategies in future randomized controlled trials evaluating enteral L-citrulline as a potential treatment to reduce PH associated with BPD in premature neonates. REGISTRATION: Clinical trials.gov Identifier: NCT03542812.

Exploring the Past to Inform the Future to Optimize the Pharmacokinetics of Vancomycin in Children With Severe Burn Injuries.

Sepsis remains one of the leading causes of death among pediatric patients with burn injuries. Despite limited vancomycin pharmacokinetic (PK) information within this population, it is widely used to treat severe burn injuries. Those with severe burns are at risk of nephrotoxicity, with an incidence of acute kidney injury (AKI) over 50%. Delivering an effective vancomycin dose and avoiding unnecessary toxicity is essential for improved patient outcomes. This was a retrospective analysis of 115 children aged 0.2 months to 18 years with severe burns, >10% total body surface area. Vancomycin was given via intravenous infusion; blood samples were drawn between 6- and 12-hour postinfusion. A population pharmacokinetic model was developed using nonlinear mixed-effect modeling (Monolix, version 2016R1). A one-compartment model described a steady-state volume of distribution (V), dependent on weight. Vancomycin clearance (CL) was influenced by age and estimated creatinine clearance (CrCL). The study population's (median age = 4 years, median weight = 20 kg, median total body surface area (%TBSA) = 40%) median V and CL were calculated to be 1.25 L/kg (95% CI, 1.04-1.46) and 0.15 L/h/kg (95% CI, 0.126-0.165), respectively. The PK model was explicitly developed to characterize the impact of physiological changes in children under 18 years of age and the percentage of the burn surface area using limited data. The analysis determined that weight, age, and estimated CrCL were important covariates in predicting vancomycin PK with high variability in CL and V.

Management of Anti-Seizure Medications during Pregnancy: Advancements in The Past Decade.

Management of seizures often involves continuous medication use throughout a patient's life, including when a patient is pregnant. The physiological changes during pregnancy can lead to altered drug exposure to anti-seizure medications, increasing patient response variability. In addition, subtherapeutic anti-seizure medication concentrations in the mother may increase seizure frequency, raising the risk of miscarriage and preterm labor. On the other hand, drug exposure increases can lead to differences in neurodevelopmental outcomes in the developing fetus. Established pregnancy registries provide insight into the teratogenicity potential of anti-seizure medication use. In addition, some anti-seizure medications are associated with an increased risk of major congenital malformations, and their use has declined over the last decade. Although newer anti-seizure medications are thought to have more favorable pharmacokinetics in general, they are not without risk, as they may undergo significant pharmacokinetic changes when an individual becomes pregnant. With known changes in metabolism and kidney function during pregnancy, therapeutic monitoring of drug concentrations helps to determine if and when doses should be changed to maintain similar seizure control as observed pre-pregnancy. This review concentrates on the results from research in the past decade (2010-2022) regarding risks of major congenital malformations, changes in prescribing patterns, and pharmacokinetics of the anti-seizure medications that are prescribed to pregnant patients with epilepsy.

Preferential Formulation of Second Generation Antipsychotic Asenapine as Inclusion Complex with Sulphobutylether-ßCD (Captisol): In vitro and In vivo Evaluation.

BACKGROUND: Asenapine is an anti-psychotic agent approved by the US-FDA for treatment of acute schizophrenia and manic or bipolar I disorder in adults. It is poorly absorbed when administered orally, hence exhibits poor oral bioavailability, which limits its use in clinical practice. OBJECTIVE: Enhancement in solubility of asenapine through complexation with three different cyclodextrins, viz. ßCD, HPßCD and sulphobutylether-ßCD (Captisol®) was attempted and compared due to its poor bioavailability. METHOD: Kneading method was used for preparation of inclusion complexes which were characterized by FTIR, DSC, and XRD methods. Extent of binding and stability of the 1:1 inclusion complexes were evaluated by molecular modelling and phase solubility studies. Pharmacokinetic studies were also carried out of these inclusion complexes. RESULTS: Captisol® complex was the most stable amongst all complexes showing 4.9 times solubility enhancement of asenapine and 96% drug release at the end of 60 min, whereas asenapine maleate (uncomplexed drug) was released completely at the end of 120min. The Cmax and AUC values of Captisol® asenapine complex (AS-Captisol complex) were 2.8 and 2.3 times higher than the uncomplexed drug. CONCLUSION: This study thus demonstrated that Captisol® inclusion complex is an effective strategy for solubility and bioavailability enhancement of asenapine.