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.

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.

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.

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.

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.

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.

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.

Validation of an LC-MS/MS assay for rapid and simultaneous quantification of 21 kinase inhibitors in human plasma and serum for therapeutic drug monitoring.

Kinase inhibitors have revolutionized cancer treatment in the past 25 years and currently form the cornerstone of many treatments. Due to the increasing evidence for therapeutic drug monitoring (TDM) of kinase inhibitors, the need is growing for new assays to rapidly evaluate kinase inhibitor plasma concentrations. In this study, we developed an LC-MS/MS assay for the rapid and simultaneous quantification of 21 kinase inhibitors. First, a literature search was conducted to ensure that the linear ranges of the analytes were in line with the reported therapeutic windows and/or TDM reference values. Subsequently, the assay was validated according to FDA and EMA guidelines for linearity, selectivity, carry-over, accuracy, precision, dilution integrity, matrix effect, recovery, and stability. The assay was fast, with a short run-time of 2 min per sample. Sample pre-treatment consisted of protein precipitation with methanol enriched with stable isotope-labeled internal standards (SIL-IS), and the mixture was vortexed and centrifuged before sample injection. Separation was achieved using a C18 column (3 µm,50 × 2.1 mm) with a gradient of two mobile phases (ammonium formate buffer pH 3.5 and acetonitrile). Analyte detection was conducted in positive ionization mode using selected reaction monitoring. The assay was accurate and precise in plasma as well as in serum. Extraction recovery ranged between 95.0% and 106.0%, and the matrix effect was 95.7%-105.2%. The stability of the analytes varied at room temperature and in refrigerated conditions. However, all drugs were found to be stable for 7 days in the autosampler. The clinical applicability of the analytical method (486 analyzed samples between 1 July 2022-1 July 2023) as well as external quality control testing results were evaluated. Taken together, the results demonstrate that the analytical method was validated and applicable for routine analyses in clinical practice.

Placenta-on-a-Chip as an In Vitro Approach to Evaluate the Physiological and Structural Characteristics of the Human Placental Barrier upon Drug Exposure: A Systematic Review.

Quantification of fetal drug exposure remains challenging since sampling from the placenta or fetus during pregnancy is too invasive. Currently existing in vivo (e.g., cord blood sampling) and ex vivo (e.g., placenta perfusion) models have inherent limitations. A placenta-on-a-chip model is a promising alternative. A systematic search was performed in PubMed on 2 February 2023, and Embase on 14 March 2023. Studies were included where placenta-on-a-chip was used to investigate placental physiology, placenta in different obstetric conditions, and/or fetal exposure to maternally administered drugs. Seventeen articles were included that used comparable approaches but different microfluidic devices and/or different cultured maternal and fetal cell lines. Of these studies, four quantified glucose transfer, four studies evaluated drug transport, three studies investigated nanoparticles, one study analyzed bacterial infection and five studies investigated preeclampsia. It was demonstrated that placenta-on-a-chip has the capacity to recapitulate the key characteristics of the human placental barrier. We aimed to identify knowledge gaps and provide the first steps towards an overview of current protocols for developing a placenta-on-a-chip, that facilitates comparison of results from different studies. Although models differ, they offer a promising approach for in vitro human placental and fetal drug studies under healthy and pathological conditions.

Evaluation of Dosing Guidelines for Gentamicin in Neonates and Children.

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children's Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8-12 mg/L for neonates and 15-20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment.

Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy: Part I-Penicillins.

BACKGROUND AND OBJECTIVE: Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins. METHODS: A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available. RESULTS: Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin. CONCLUSION: The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.

Adsorption of insulin onto neonatal infusion sets: should intravenous administration of insulin to treat hyperglycemia in preterm babies on the NICU be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get to a stable insulin dose?

Insulin is used to treat neonatal hyperglycaemia when blood glucose concentrations are consistently high, and to treat neonatal diabetes. Within this brief report, a review of the existing literature is conducted to determine if intravenous administration of insulin should be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get a stable insulin dose. Within this literature search, we focused on experimental insulin adsorption data (in vitro studies).

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.

The Effect of Pregnancy and Inflammatory Bowel Disease on the Pharmacokinetics of Drugs Related to Inflammatory Bowel Disease-A Systematic Literature Review.

Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed.

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.

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.

Impact of malnourishment on the pharmacokinetics of acetaminophen and susceptibility to acetaminophen hepatotoxicity.

BACKGROUND: Acetaminophen hepatotoxicity is thought to be primarily caused by formation of the specific reactive metabolite N-acetyl-para-benzo-quinone imine (NAPQI). Malnourished individuals are at increased risk of acetaminophen-related hepatotoxicity. We report a case of low acetaminophen clearance in a severely underweight young woman, and elaborate on the possible effects of malnutrition on the total clearance of acetaminophen as well as on the separate contributions of the different metabolic pathways. CASE REPORT: An 18-year-old Caucasian woman weighing 43 kg with a history of eating disorder-related hospital admissions presented at the emergency department after having ingested 33 tablets of acetaminophen 500 mg two hours earlier. She then received intravenous N-acetylcysteine for 33 h. Nine hours after ingestion, the acetaminophen elimination half-life (t½) was estimated to be >100 h. DISCUSSION: While decreased total acetaminophen clearance (twofold) due to malnutrition has been reported in literature, the extremely low clearance in this specific patient cannot be explained. Malnourished individuals generally have reduced antioxidant reserves, coinciding with a shift in metabolic routes toward oxidative metabolism. This may result in increased formation of NAPQI and reduced neutralizing capacity, thereby increasing the risk of acetaminophen-induced hepatotoxicity. Evidence for this observation can be found in animal and to a lesser extent in human studies.

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery.

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

Modelling Tools to Characterize Acetaminophen Pharmacokinetics in the Pregnant Population.

This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5-60.7%) and an increase in the clearance (36.8-84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis.