Infliximab in paediatric inflammatory bowel disease: External evaluation of population pharmacokinetic models.

AIMS: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations. CONCLUSION: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

Pharmacokinetics of 2 oral paracetamol formulations in hospitalized octogenarians.

AIMS: It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. METHODS: Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6 h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg ) of 10 mg/L. RESULTS: The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n = 26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10 mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin. CONCLUSION: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate.

Pharmacokinetics of the most commonly used antihypertensive drugs throughout pregnancy methyldopa, labetalol, and nifedipine: a systematic review.

PURPOSE: Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and are therefore recommended in international guidelines for treatment of hypertension. In this review, we provide a complete overview of what is known on the pharmacokinetics (PK) of the antihypertensive drugs methyldopa, labetalol, and nifedipine throughout pregnancy. METHODS: A systematic search was performed to retrieve studies on the PK of methyldopa, labetalol, and nifedipine used throughout pregnancy. The search was restricted to English and original studies. The systematic search was conducted on July 27, 2021, in Embase, Medline Ovid, Web of Science, Cochrane Library, and Google Scholar. Keywords were methyldopa, labetalol, nifedipine, pharmacokinetics, pregnancy, and placenta. RESULTS: A total of 1459 unique references were identified of which title and abstract were screened. Based on this screening, 67 full-text papers were assessed, to retain 30 PK studies of which 2 described methyldopa, 12 labetalol, and 16 nifedipine. No fetal accumulation is found for any of the antihypertensive drugs studied. CONCLUSION: We conclude that despite decades of prescribing methyldopa, labetalol, and nifedipine throughout pregnancy, descriptions of their PK during pregnancy are hampered by a large heterogeneity in the low number of available studies. Aiming for evidence-based and personalized dosing of antihypertensive medication in the future, further studies on the relationship of both PK and pharmacodynamics (including the optimal blood pressure targeting) during pregnancy and pregnancy-related pathology are urgently needed to prevent undertreatment, overtreatment, and side effects.

Suboptimal plasma concentrations with posaconazole suspension as prophylaxis in critically ill COVID-19 patients at risk of Covid-associated pulmonary aspergillosis.

WHAT IS KNOWN AND OBJECTIVE: The safety and efficacy of different antifungal agents in the prophylaxis of invasive fungal infection in patients with haematological disorders are known. We comment on the poor bioavailability of posaconazole suspension to suggest that it is not useful in critically ill COVID patients. COMMENT: The increased mortality and high incidence of COVID-associated pulmonary aspergillosis (CAPA) might justify administration of off-label posaconazole for preventing CAPA, being the only drug officially registered for prophylaxis of fungal infections. We decided to initiate off-label posaconazole prophylaxis in COVID-19 patients, who were mechanically ventilated and exposed to high-dose steroids for progressive pulmonary disease or ARDS. We found that posaconazole suspension was inadequate. Very low trough levels were observed after administration, and the dose adjustments necessary for the therapeutic drug monitoring (TDM) of the drug in our critically ill ICU patients were not useful. WHAT IS NEW AND CONCLUSION: Posaconazole suspension should not be used to prevent CAPA in COVID-19 patients on high-dose steroid therapy.

Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

AIMS: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry-based enantiomer-specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S- and R-ketorolac exposure. RESULTS: S- and R-ketorolac PK were best described with a 3- and a 2-compartment model, respectively. The allometry-based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S-ketorolac concentration of 0.057 mg/L, but a mean S-ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S-ketorolac-concentration (0.057 mg/L) in typical infants, the EC50-racemic should be increased to 0.41 mg/L. CONCLUSION: Enantiomer-specific changes in ketorolac PK yield different concentrations and S- and R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.

Elevated methaemoglobin in a critically ill patient as a result of hydrogen peroxide exposure: A case study.

WHAT IS KNOWN AND OBJECTIVE: Formation of methaemoglobinaemia (MetHb) decreases oxygen capacity in the blood, leading to tissue hypoxia. This condition may be acquired following exposure to certain drugs. CASE SUMMARY: A critically ill patient with necrotizing fasciitis unexpectedly developed marked and unexplained MetHb (6.7%). Her digital medication list did not reveal the causative factor. However, deeper exploration showed the use of other compounds (acetone, hydrogen peroxide) not routinely visible on the medication list. WHAT IS NEW AND CONCLUSION: Elevated MetHb likely resulted from high-volume hydrogen peroxide 3% exposure. Clinicians should be cautious rinsing large open wounds with hydrogen peroxide. When MetHb is diagnosed, less familiar compounds, usually not on the medication list, should be considered in the differential diagnosis and extensive hetero-anamnesis is mandatory.

Acute teriflunomide overdose with relatively mild symptoms: A case report.

WHAT IS KNOW AND OBJECTIVE: Teriflunomide is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis. CASE SUMMARY: We present a rare intoxication with a high dose (672 mg) of teriflunomide. According to its product label, the only known treatment is the administration of colestyramine and activated carbon (charcoal). No serious adverse events occurred during the time the patient was admitted (<24 h). No long-term overdose-related symptoms or complaints were reported. WHAT IS NEW AND CONCLUSION: The fact that after the acute overdose both adverse events and laboratory parameters were acceptable, prescribing colestyramine and activated carbon, as well as monitoring of laboratory parameters such as full blood count, liver and kidney values and QTc, seems sufficient during the early stage (<24 h after intake) of teriflunomide overdose.

Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: a case series analysis.

Recent case reports describe an association between maternal paracetamol intake and fetal ductus arteriosus constriction or closure. To put these cases into perspective and explore causality, a structured literature search was conducted. The World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality tool was applied to the cases retrieved. The search resulted in 12 papers with 25 case descriptions, of which one case was classified as unlikely, nine as possible, 11 as probable and four as certain. Consequently, we concluded that a causal relationship between maternal paracetamol intake and fetal ductus arteriosus constriction or closure is likely. These findings suggest that pharmacovigilance studies on paracetamol safety during pregnancy are warranted to quantify the event and put the current findings into clinical perspective. Although analgesia during pregnancy and during the peripartum period is of obvious relevance, alternative analgesics such as opioids or other nonsteroidal anti-inflammatory drugs also have side effects.

Pregnancy affects the pharmacokinetics of sildenafil and its metabolite in the rabbit.

1. There is growing interest in the use of sildenafil during pregnancy for various maternal and fetal conditions. This study aims to investigate the effect of pregnancy on the maternal pharmacokinetics (PK) of sildenafil and its main metabolite desmethylsildenafil in rabbits. Using NONMEM, population PK modeling was performed based on plasma samples from 31 rabbits of whom 15 were pregnant and 16 were not. All received a single subcutaneous sildenafil dose of 10 mg/kg. One sample was obtained per rabbit at either 30, 60, 120, 360, 720 or 1320 min after sildenafil administration. 2. A two- and one-compartment PK-model best described the data for sildenafil and desmethylsildenafil, respectively. Compared to non-pregnant rabbits, the central and peripheral volume of distribution and inter-compartmental clearance of sildenafil were lower in pregnant rabbits [32.1 versus 12.2 L, 110 versus 44.4 L and 25.5 versus 12.1 L/h; all p < 0.05]. The formation clearance from sildenafil to desmethylsildenafil was also reduced during pregnancy [13.3 versus 7.8 L/h; p < 0.05]. 3. In contrast, the elimination clearance of desmethylsildenafil, was higher in pregnancy [73.5 versus 116. 9; p < 0.05]. In rabbits, pregnancy impacts PK parameters of sildenafil and its metabolite, leading to an increased peak concentration and 24 h exposure for sildenafil and a decreased 24 h exposure for desmethylsildenafil.

Morphine treatment for neonatal abstinence syndrome: huge dosing variability underscores the need for a better clinical study design.

INTRODUCTION: At present, morphine is the most commonly used first-line therapy to treat Neonatal Abstinence Syndrome (NAS). Unfortunately, there is still lack of evidence and consensus to guide pharmacologic therapy for NAS. In this review, we provide an overview on dosing regimens of morphine currently reported to treat NAS, with the aim to stimulate discussion on the need for a standardized dosing through better study design. EVIDENCE ACQUISITION: A search strategy was performed in PubMed to identify studies that provide a dosing regimen used, or advised by a review or guideline for morphine to treat NAS. In addition, dosing regimens from labels and formularies were collected. EVIDENCE SYNTHESIS: On 138 articles identified, 33 were retained after reading the full-text. In addition, 10 articles were included based on reference check. Extensive variability was observed for dosing advice, threshold in the initiating phase, dosing advice and maximum dose in the escalating phase. The same applies for dosing advice and detail during weaning, dosing interval and stabilization phase. CONCLUSIONS: This review shows a large variability in dosing regimens of morphine used to treat NAS. This is likely a reflection of the heterogeneous populations included in NAS studies, the lack of standardization in assessment tools and study outcomes. We suggest that the development and validation of a core outcome set, subsequently applied in pragmatic point-of-care clinical trials or specific subgroups (e.g. iatrogenic postnatal NAS) are useful approaches to improve the current setting.

Quantification of Acetaminophen and Its Metabolites in Plasma Using UPLC-MS: Doors Open to Therapeutic Drug Monitoring in Special Patient Populations.

BACKGROUND: Acetaminophen (APAP, paracetamol) is the most commonly used drug for pain and fever in both the United States and Europe and is considered safe when used at registered dosages. Nevertheless, differences between specific populations lead to remarkable changes in exposure to potentially toxic metabolites. Furthermore, extended knowledge is required on metabolite formation after intoxication, to optimize antidote treatment. Therefore, the authors aimed to develop and validate a quick and easy analytical method for simultaneous quantification of APAP, APAP-glucuronide, APAP-sulfate, APAP-cysteine, APAP-glutathione, APAP-mercapturate, and protein-derived APAP-cysteine in human plasma by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry. METHODS: The internal standard was APAP-D4 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity ultraperformance liquid chromatography HSS T3 column with a runtime of only 4.5 minutes per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate, formic acid in Milli-Q ultrapure water or in methanol at flow rate of 0.4 mL/minute. RESULTS: A plasma volume of only 10 µL was required to achieve both adequate accuracy and precision. Calibration curves of all 6 analytes were linear. All analytes were stable for at least 48 hours in the autosampler; the high quality control of APAP-glutathione was stable for 24 hours. The method was validated according to the U.S. Food and Drug Administration guidelines. CONCLUSIONS: This method allows quantification of APAP and 6 metabolites, which serves purposes for research, as well as therapeutic drug monitoring. The advantage of this method is the combination of minimal injection volume, a short runtime, an easy sample preparation method, and the ability to quantify APAP and all 6 metabolites.

Sertraline, citalopram and paroxetine in lactation: passage into breastmilk and infant exposure.

Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.

Pharmacokinetics of Tacrolimus in Pregnant Solid-Organ Transplant Recipients: A Retrospective Study.

Data on the pharmacokinetics of tacrolimus during pregnancy are limited. Therefore, the aim of this retrospective study was to characterize the whole-blood pharmacokinetics of tacrolimus throughout pregnancy. In this single-center retrospective cohort study, whole-blood tacrolimus trough concentrations corrected for the dose (concentration-to-dose [C/D] ratios) were compared before, monthly during, and after pregnancy in kidney, liver, and lung transplant recipients who became pregnant and gave birth between 2000 and 2022. Descriptive statistics and linear mixed models were used to characterize changes in tacrolimus C/D ratios before, during, and after pregnancy. The total study population included 46 pregnancies (31 pregnant women). Nineteen, 21, and 6 pregnancies were following kidney, liver, and lung transplantation, respectively. Immediate-release or extended-release formulations were used in 54.5% and 45.5% of the women, respectively. Tacrolimus C/D ratios significantly (P < .001) decreased (-48%) compared to the prepregnancy state at 7 months of pregnancy. These ratios recovered within 3 months postpartum (P = .002). C/D ratios tended to be lower during treatment with an extended-release formulation than with an immediate-release formulation (P = .071). Transplantation type did not significantly affect C/D ratios during pregnancy (P = .873). In conclusion, we found that tacrolimus whole-blood pharmacokinetics change throughout pregnancy, with the lowest C/D ratios (48% decrease) in the 7th month of pregnancy. In general, the decrease in C/D ratios seems to stabilize from month 4 onward compared to prepregnancy.

Pharmacokinetics of Monoclonal Antibodies Throughout Pregnancy: A Systematic Literature Review.

BACKGROUND AND OBJECTIVE: Although little information is available on the pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy, multiple mAbs are being used during pregnancy for various indications. The aim of this systematic literature review was to characterize the PK of mAbs throughout pregnancy. METHODS: A systematic literature search was carried out in PubMed and Embase on 21 April 2023. Articles were included when information on PK or exposure parameters of mAbs in pregnant women was available. RESULTS: A total of 42 relevant articles were included, of which eight discussed adalimumab, three certolizumab pegol, five eculizumab, one golimumab, 12 infliximab (IFX), two natalizumab, one canakinumab, one omalizumab, five tocilizumab, eight ustekinumab, and five vedolizumab. One of the 42 studies reported information on clearance (CL) and volume of distribution (VD) of IFX; all other studies only reported on serum concentrations in the pre-pregnancy state, different trimesters, and the postpartum period. For all of the assessed mAbs except IFX, serum concentrations were similar to concentrations in the pre-pregnancy state or modestly decreased. In contrast, IFX trough concentrations generally increased in the second and third trimesters in comparison to the non-pregnant state. CONCLUSION: Available information suggests that the anatomical and physiological changes throughout pregnancy may have meaningful effects on the PK of mAbs. For most mAbs (not IFX), modestly higher dosing (per mg) maybe needed during pregnancy to sustain a similar serum exposure compared to pre-pregnancy.

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature. METHODS: Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort. RESULTS: The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas. CONCLUSION: All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known. CLINICAL TRIALS REGISTRATION: NCT03858491.

Evaluation of Target Attainment for Tobramycin in Children and Adults with Cystic Fibrosis.

Introduction: Patients with cystic fibrosis (CF) commonly experience pulmonary exacerbations, and it is recommended by the TOPIC study to treat this with tobramycin at a dose of 10 mg/kg once daily. The aim of this study was to evaluate the target attainment of the current dosing regimen. Methods: A single-center retrospective cohort study of child and adult patients with CF who received tobramycin between 2019 and 2022 was conducted. Descriptive statistics and linear mixed models were used to assess target attainment for tobramycin. Results: In total, 25 patients (53 courses), of which 10 were children (12 courses) and 15 were adults (41 courses), were included. Those 25 patients all received 10 mg/kg/day. The tobramycin peak concentrations were supratherapeutic in 82.9% and therapeutic in 100.0% of adults and children, respectively. The trough concentrations were outside the target range in 0% and 5.1% of children and adults, respectively. We found lower tobramycin concentrations with the same dose in children compared to adults. Conclusions: This study illustrates the need to validate dosing advice in a real-world setting, as supratherapeutic concentrations of tobramycin were prevalent in adults with CF.

Ustekinumab trough levels in children with Crohn's disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use.

Background: Ustekinumab is used off-label in pediatric Crohn's disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited. Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration. Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250 mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure-response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued. Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn's disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels.