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15 pages, 1490 KiB

Open AccessArticle

Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases

by Natalia Riva, Lucas Brstilo, Aymara Sancho-Araiz, Manuel Molina, Andrea Savransky, Georgina Roffé, Marianela Sanz, Silvia Tenembaum, Maria M. Katsicas, Iñaki F. Trocóniz and Paula Schaiquevich

Pharmaceutics 2023, 15(11), 2534; https://doi.org/10.3390/pharmaceutics15112534 - 26 Oct 2023

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Abstract

Background: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and [...] Read more.

Background: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. Methods: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. Results: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. Conclusions: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results. Full article

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13 pages, 1068 KiB

Open AccessArticle

Pharmacokinetics of Venetoclax Co-Administered with Posaconazole in Patients with Acute Myeloid Leukemia

by Simona De Gregori, Eleonora Gelli, Mara Capone, Giulia Gambini, Elisa Roncoroni, Marianna Rossi, Claudia Patricia Tobar Cabrera, Gianluca Martini, Ludovica Calabretta, Luca Arcaini, Riccardo Albertini and Patrizia Zappasodi

Pharmaceutics 2023, 15(6), 1680; https://doi.org/10.3390/pharmaceutics15061680 - 08 Jun 2023

Cited by 1 | Viewed by 1543

Abstract

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in [...] Read more.

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug–drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography–tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration–time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone—the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring. Full article

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16 pages, 1826 KiB

Open AccessArticle

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling

by Tom G. Jacobs, Marika A. de Hoop-Sommen, Thomas Nieuwenstein, Joyce E. M. van der Heijden, Saskia N. de Wildt, David M. Burger, Angela Colbers and Jolien J. M. Freriksen

Pharmaceutics 2023, 15(5), 1424; https://doi.org/10.3390/pharmaceutics15051424 - 06 May 2023

Cited by 1 | Viewed by 1511

Abstract

Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine [...] Read more.

Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp^® (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations. We developed paediatric CKD population models reflecting subjects with a reduced glomerular filtration and tubular secretion, based on extrapolation from adult CKD population models. These models were verified using ganciclovir as a surrogate compound. Then, lamivudine and emtricitabine dosing strategies were simulated in virtual paediatric CKD populations. The compound and paediatric CKD population models were verified successfully (prediction error within 0.5- to 2-fold). The mean AUC ratios in children (GFR-adjusted dose in CKD population/standard dose in population with normal kidney function) were 1.15 and 1.23 for lamivudine, and 1.20 and 1.30 for emtricitabine, with grade-3- and -4-stage CKD, respectively. With the developed paediatric CKD population PBPK models, GFR-adjusted lamivudine and emtricitabine dosages in children with CKD resulted in adequate drug exposure, supporting paediatric GFR-adjusted dosing. Clinical studies are needed to confirm these findings. Full article

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13 pages, 1130 KiB

Open AccessArticle

Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study

by Chun Liu, Pier Giorgio Cojutti, Maddalena Giannella, Marcello Roberto, Beatrice Casadei, Gianluca Cristiano, Cristina Papayannidis, Nicola Vianelli, Pier Luigi Zinzani, Pierluigi Viale, Francesca Bonifazi and Federico Pea

Pharmaceutics 2023, 15(3), 1022; https://doi.org/10.3390/pharmaceutics15031022 - 22 Mar 2023

Viewed by 1690

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS. Full article

(This article belongs to the Special Issue Dosing Strategies for Protecting the Vulnerable)

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13 pages, 590 KiB

Open AccessCommunication

Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial

by Juan Espinosa-Pereiro, Samiksha Ghimire, Marieke G. G. Sturkenboom, Jan-Willem C. Alffenaar, Margarida Tavares, Sarita Aguirre, Arturo Battaglia, Gladys Molinas, Teresa Tórtola, Onno W. Akkerman, Adrian Sanchez-Montalva and Cecile Magis-Escurra

Pharmaceutics 2023, 15(1), 9; https://doi.org/10.3390/pharmaceutics15010009 - 20 Dec 2022

Cited by 3 | Viewed by 1313

Abstract

Previous clinical trials for drug-susceptible tuberculosis (DS-TB) have shown that first-line treatment with doses of rifampicin up to 40 mg/kg are safe and increase the early treatment response for young adults with pulmonary tuberculosis. This may lead to a shorter treatment duration for [...] Read more.

Previous clinical trials for drug-susceptible tuberculosis (DS-TB) have shown that first-line treatment with doses of rifampicin up to 40 mg/kg are safe and increase the early treatment response for young adults with pulmonary tuberculosis. This may lead to a shorter treatment duration for those persons with TB and a good baseline prognosis, or increased treatment success for vulnerable subgroups (age > 60, diabetes, malnutrition, HIV, hepatitis B or hepatitis C coinfection, TB meningitis, stable chronic liver diseases). Here, we describe the design of a phase 2b/c clinical study under the hypothesis that rifampicin at 35 mg/kg is as safe for these vulnerable groups as for the participants included in previous clinical trials. RIAlta is an interventional, open-label, multicenter, prospective clinical study with matched historical controls comparing the standard DS-TB treatment (isoniazid, pyrazinamide, and ethambutol) with rifampicin at 35 mg/kg (HR³⁵ZE group) vs. rifampicin at 10 mg/kg (historical HR¹⁰ZE group). The primary outcome is the incidence of grade ≥ 3 Adverse Events or Severe Adverse Events. A total of 134 participants will be prospectively included, and compared with historical matched controls with at least a 1:1 proportion. This will provide a power of 80% to detect non-inferiority with a margin of 8%. This study will provide important information for subgroups of patients that are more vulnerable to TB bad outcomes and/or treatment toxicity. Despite limitations such as non-randomized design and the use of historical controls, the results of this trial may inform the design of future more inclusive clinical trials, and improve the management of tuberculosis in subgroups of patients for whom scientific evidence is still scarce. Trial registration: EudraCT 2020-003146-36, NCT04768231. Full article

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21 pages, 844 KiB

Open AccessArticle

Pharmacogenetic Dose Modeling Based on CYP2C19 Allelic Phenotypes

by Julia Carolin Stingl, Jason Radermacher, Justyna Wozniak and Roberto Viviani

Pharmaceutics 2022, 14(12), 2833; https://doi.org/10.3390/pharmaceutics14122833 - 16 Dec 2022

Cited by 1 | Viewed by 1275

Abstract

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, [...] Read more.

Pharmacogenetic variability in drug metabolism leads to patient vulnerability to side effects and to therapeutic failure. Our purpose was to introduce a systematic statistical methodology to estimate quantitative dose adjustments based on pharmacokinetic differences in pharmacogenetic subgroups, addressing the concerns of sparse data, incomplete information on phenotypic groups, and heterogeneity of study design. Data on psychotropic drugs metabolized by the cytochrome P450 enzyme CYP2C19 were used as a case study. CYP2C19 activity scores were estimated, while statistically assessing the influence of methodological differences between studies, and used to estimate dose adjustments in genotypic groups. Modeling effects of activity scores in each substance as a population led to prudential predictions of adjustments when few data were available (‘shrinkage’). The best results were obtained with the regularized horseshoe, an innovative Bayesian approach to estimate coefficients viewed as a sample from two populations. This approach was compared to modeling the population of substance as normally distributed, to a more traditional “fixed effects” approach, and to dose adjustments based on weighted means, as in current practice. Modeling strategies were able to assess the influence of study parameters and deliver adjustment levels when necessary, extrapolated to all phenotype groups, as well as their level of uncertainty. In addition, the horseshoe reacted sensitively to small study sizes, and provided conservative estimates of required adjustments. Full article

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10 pages, 1903 KiB

Open AccessArticle

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation

by Jordan T. Brooks, Belen P. Solans, Ying Lu, Sandhya Kharbanda, Christopher C. Dvorak, Nahal Lalefar, Susie Long, Ashish O. Gupta, Biljana Horn, Jatinder K. Lamba, Liusheng Huang, Beth Apsel-Winger, Ron J. Keizer, Rada Savic and Janel Long-Boyle

Pharmaceutics 2022, 14(11), 2462; https://doi.org/10.3390/pharmaceutics14112462 - 15 Nov 2022

Viewed by 1867

Abstract

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models [...] Read more.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment. Full article

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19 pages, 3242 KiB

Open AccessArticle

Application of Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetics and Fetal Exposure to Oxcarbazepine

by Lixia He, Meng Ke, Wanhong Wu, Jiarui Chen, Guimu Guo, Rongfang Lin, Pinfang Huang and Cuihong Lin

Pharmaceutics 2022, 14(11), 2367; https://doi.org/10.3390/pharmaceutics14112367 - 03 Nov 2022

Cited by 3 | Viewed by 1487

Abstract

Pregnancy is associated with physiological changes that may affect drug pharmacokinetics (PKs). The aim of this study was to establish a maternal–fetal physiologically based pharmacokinetic (PBPK) model of oxcarbazepine (OXC) and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (MHD), to (1) assess differences in pregnancy, (2) [...] Read more.

Pregnancy is associated with physiological changes that may affect drug pharmacokinetics (PKs). The aim of this study was to establish a maternal–fetal physiologically based pharmacokinetic (PBPK) model of oxcarbazepine (OXC) and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (MHD), to (1) assess differences in pregnancy, (2) predict changes in PK target parameters of these molecules following the current dosing regimen, (3) assess predicted concentrations of these molecules in the umbilical vein at delivery, and (4) compare different methods for estimating drug placental penetration. Predictions using the pregnancy PBPK model of OXC resulted in maternal concentrations within a 2-fold error, and extrapolation of the model to early-stage pregnancies indicated that changes in median PK parameters remained above target thresholds, requiring increased frequency of monitoring. The dosing simulation results suggested dose adjustment in the last two trimesters. We generally recommend that women administer ≥ 1.5× their baseline dose of OXC during their second and third trimesters. Test methods for predicting placental transfer showed varying performance, with the in vitro method showing the highest predictive accuracy. Exposure to MHD in maternal and fetal venous blood was similar. Overall, the above-mentioned models can enhance understanding of the maternal–fetal PK behavior of drugs, ultimately informing drug-treatment decisions for pregnant women and their fetuses. Full article

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10 pages, 429 KiB

Open AccessArticle

Clinical Efficacy of Temocillin Standard Dosing in Patients Treated with Outpatient Antimicrobial Therapy

by Evelyne Van den Broucke, Lore Thijs, Stefanie Desmet, Lotte Vander Elst, Matthias Gijsen, Marnix Mylemans, Otto Van de Gaer, Willy E. Peetermans, Charlotte Quintens and Isabel Spriet

Pharmaceutics 2022, 14(11), 2289; https://doi.org/10.3390/pharmaceutics14112289 - 25 Oct 2022

Cited by 2 | Viewed by 1409

Abstract

In 2020, EUCAST introduced breakpoints for temocillin. Based on these guidelines, reporting of temocillin susceptibility of Enterobacterales in the context of complicated urinary tract infections (cUTI) implicates the use of a high dose of temocillin (2 g q8h) constantly. We aimed to evaluate [...] Read more.

In 2020, EUCAST introduced breakpoints for temocillin. Based on these guidelines, reporting of temocillin susceptibility of Enterobacterales in the context of complicated urinary tract infections (cUTI) implicates the use of a high dose of temocillin (2 g q8h) constantly. We aimed to evaluate the clinical outcome of patients treated with the standard dose (4 g/day) of temocillin in outpatient parenteral antimicrobial therapy (tOPAT). Demographics, clinical and treatment parameters, and late clinical cure (at day 30 after tOPAT completion) were recorded. Univariate generalised estimating equation analyses, with clinical cure as outcome variable, were performed to evaluate covariate associations. Fifty-seven tOPAT episodes in 50 patients were included with a median antimicrobial treatment duration of 21 (range 10–228) days, and cUTI was the main indication (87.7%). Late clinical cure was achieved in 85.7% of the tOPAT episodes. Non-disseminated infections and minimal inhibitory concentrations (MIC) values ≤ 8 mg/L were associated with good late clinical outcome. In conclusion, a standard temocillin dose (4 g/day) results in good clinical outcomes in the treatment of cUTIs in tOPAT patients. Therefore, our centre concluded that the use of standard temocillin dosing should be continued instead of the high dose for cUTI in non-critically ill patients infected with Enterobacterales with an MIC ≤ 4 mg/L. Full article

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14 pages, 3935 KiB

Open AccessArticle

Evaluating and Improving Neonatal Gentamicin Pharmacokinetic Models Using Aggregated Routine Clinical Care Data

by Dominic M. H. Tong, Jasmine H. Hughes and Ron J. Keizer

Pharmaceutics 2022, 14(10), 2089; https://doi.org/10.3390/pharmaceutics14102089 - 30 Sep 2022

Cited by 2 | Viewed by 1756

Abstract

Model-informed precision dosing (MIPD) can aid dose decision-making for drugs such as gentamicin that have high inter-individual variability, a narrow therapeutic window, and a high risk of exposure-related adverse events. However, MIPD in neonates is challenging due to their dynamic development and maturation [...] Read more.

Model-informed precision dosing (MIPD) can aid dose decision-making for drugs such as gentamicin that have high inter-individual variability, a narrow therapeutic window, and a high risk of exposure-related adverse events. However, MIPD in neonates is challenging due to their dynamic development and maturation and by the need to minimize blood sampling due to low blood volume. Here, we investigate the ability of six published neonatal gentamicin population pharmacokinetic models to predict gentamicin concentrations in routine therapeutic drug monitoring from nine sites in the United State (n = 475 patients). We find that four out of six models predicted with acceptable levels of error and bias for clinical use. These models included known important covariates for gentamicin PK, showed little bias in prediction residuals over covariate ranges, and were developed on patient populations with similar covariate distributions as the one assessed here. These four models were refit using the published parameters as informative Bayesian priors or without priors in a continuous learning process. We find that refit models generally reduce error and bias on a held-out validation data set, but that informative prior use is not uniformly advantageous. Our work informs clinicians implementing MIPD of gentamicin in neonates, as well as pharmacometricians developing or improving PK models for use in MIPD. Full article

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12 pages, 1105 KiB

Open AccessArticle

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling

by Karel Allegaert, Mohammad Yaseen Abbasi, Robin Michelet and Olusola Olafuyi

Pharmaceutics 2022, 14(9), 1957; https://doi.org/10.3390/pharmaceutics14091957 - 16 Sep 2022

Cited by 1 | Viewed by 1848

Abstract

Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO [...] Read more.

Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp^® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, manual infusion dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80–125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80–125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40–50%, a dose reduction of 15% is warranted in neonates, infants and children, and 25% in adolescents and adults. Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions. Full article

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Review

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16 pages, 742 KiB

Open AccessReview

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

by Charul Avachat, Jessica M. Barry, Xintian Lyu, Catherine M. Sherwin and Angela K. Birnbaum

Pharmaceutics 2022, 14(12), 2733; https://doi.org/10.3390/pharmaceutics14122733 - 06 Dec 2022

Cited by 4 | Viewed by 2886

Abstract

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 [...] Read more.

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. Full article

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