Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.

INTRODUCTION: Maintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy. OBJECTIVE: Our objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity. METHODS: Lamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population-level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively. RESULTS: Individual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%-100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%-100% of women). SIGNIFICANCE: A substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary "one-size-fits-all" philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.

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.

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.

Maternal Exposure and Neonatal Effects of Drugs of Abuse.

The public health crisis of pregnant women being exposed to drugs of abuse and of its impact on their unborn children continues to grow at an alarming rate globally. The state of pregnancy is unique, with physiological changes that can lead to changes in the way drugs are handled by the body in both pharmacokinetics and response. These changes place the pregnant woman, fetus, and newborn infant at risk, as many of these drugs can cross the placenta and into breast milk. The substances most commonly linked to harmful effects include alcohol, tobacco, cannabis, stimulants, and opioids. The pharmacological and toxicological changes caused by in utero exposure or breastfeeding exposure are difficult to study, and the full extent of the mechanisms involved are not fully understood. However, these changes can significantly affect the risks of substance abuse and influence optimal treatment of pregnant women with a substance use disorder. In addition, newborns who were exposed to drugs of abuse in utero can experience withdrawal syndromes. Pharmacological management in infants is used to guide and treat withdrawal symptoms, with the goal being to improve the infant's sleep, eating, and comfort. Several barriers may prevent pregnant women from seeking help for substance use, including stigma and interactions with the legal system. Understanding changes in pharmacology, including pharmacokinetic changes that happen during pregnancy, is essential for anticipating the extent of maternal exposure and neonatal adverse effects.