Persistent low concentrations of antiepileptics in a critically ill paediatric patient: an example of multiple potential drug interactions ========================================================================================================================================== * Lone Bak Posada * Anne Estrup Olesen * Tine Høg Sørensen * Samuel Azuz ## Abstract A middle childhood boy with epilepsy exhibited persistent low concentrations of valproic acid, lamotrigine and topiramate for over 1 month, primarily due to pharmacokinetic interactions involving fosphenytoin, meropenem and phenobarbital. Awareness of these clinically significant interactions is crucial for ensuring effective seizure control. However, further research is needed to establish optimal evidence-based treatment strategies in complex paediatric cases. * Drug interactions * Epilepsy and seizures * Paediatrics (drugs and medicines) * Pharmacokinetics ## Background Ensuring optimal antiepileptic treatment can be challenging due to potential drug interactions, especially in critically ill children undergoing polypharmacy. To highlight possible implications of pharmacokinetic interactions between antiepileptic treatments and medications commonly used in an acute setting, we present a paediatric patient exhibiting persistent low concentrations of valproic acid, lamotrigine and topiramate. ## Case presentation A middle childhood boy diagnosed with neuronal ceroid lipofuscinosis type 2 (CLN2) and epilepsy was hospitalised for approximately 3 months due to a complex clinical course characterised by a severe intra-abdominal infection and related complications. ### Clinical course According to the CLN2 Clinical Rating Scale, the patient could be scored to a motor score of 1 and a language score of 1 indicating an advanced stage of disease.1 He had been treated with a disease-modifying therapy (recombinant human cerliponase alfa) until 4 months before admission. The patient was initially hospitalised for the insertion of a gastrostomy tube but subsequently developed a severe infection, complicated by intra-abdominal abscesses and fungal peritonitis. Continuous assessment and adjustments of the antibiotic and antifungal regimen targeting the intra-abdominal infection were made based on clinical and biochemical indicators. This ultimately led to an intensified antimicrobial treatment with meropenem (20 mg/kg three times a day) and anidulafungin (1.5 mg/kg once daily), consistent with regional paediatric guidelines for severe infections. Throughout hospitalisation, the patient experienced mixed-type seizures, myoclonic jerks and dystonic muscle contractions. Several electroencephalogram (EEG) evaluations were conducted, revealing a minor epileptic focus characterised by intermittent 3–4 Hz spike-waves in the right post-temporo-occipital region. However, this finding did not correlate with the clinical presentation. The seizures, myoclonic jerks and dystonic muscle contractions were suspected to be caused by several contributing factors, including worsening of the underlying neurological condition, fever, pain and withdrawal symptoms. Neuroimaging was not performed as there were no symptoms indicating cerebral catastrophe, and seizures are to be expected during critical illness in children with CLN2. ### Antiepileptic treatment and concentrations Under the guidance of a specialised national epilepsy unit, the antiepileptic medication regimen was systematically monitored and adjusted in accordance with the patient’s symptoms, concentrations of antiepileptic medications and clinical protocols. At admission (day 0), the daily antiepileptic medication regimen included valproic acid (750 mg), lamotrigine (65 mg), topiramate (100 mg) and clobazam (12.5 mg). This daily regimen persisted throughout hospitalisation, with the exception of periodic adjustments to the valproic acid dosage. The antileptic medications were primarily administered orally through a gastrostomy or nasogastric tube. Only valproic acid was intermittently administered intravenously, as intravenous formulations of lamotrigine, topiramate, and clobazam were unavailable. Starting on the 11th day of hospitalisation, the plasma concentration of valproic acid and serum concentrations of lamotrigine and topiramate rapidly decreased and remained below therapeutic levels for over 1 month, despite continuous treatment (figure 1). Clobazam levels were not consistently monitored during this period. Significant rises in the concentrations of valproic acid and lamotrigine were observed at day 30 and from day 59. Notably, both rises were preceded by a doubling of the valproic acid dose to 1600 mg on days 28–30 and 54–74, with each period followed by a gradual taper until days 32 and 81, respectively. It should further be noted that valproic acid was switched from oral to intravenous administration on days 7–8 and 25–32. Thus, the latter switch coincided with the rise in the valproic acid plasma concentration observed on day 30. ![Figure 1](http://casereports.bmj.com/https://casereports.bmj.com/content/bmjcr/18/1/e261648/F1.medium.gif) [Figure 1](http://casereports.bmj.com/content/18/1/e261648/F1) Figure 1 Concentrations of lamotrigine (green, dashed line), topiramate (red line) and valproic acid (blue line) and their temporal correlation with the administration of fosphenytoin (F), meropenem (M) and phenobarbital (P). A red cross indicates the occurrence of suspected seizures. The daily doses of lamotrigine, topiramate and valproic acid within a given time period are marked above. All antiepileptic medications were given orally with the exception of valproic acid on days 7–8 and 25–32 (intravenous treatment). *The daily doses of valproic acid varied, occasionally exceeding the stated dose. Supplementary antiepileptic treatment, including fosphenytoin, levetiracetam, midazolam and phenobarbital, was intermittently administered with erratic effects (table 1). Elevated phenobarbital plasma concentrations were detected and remained above the recommended therapeutic range from day 35 to 52, prompting gradual dosage reductions until withdrawal was initiated on day 47. View this table: [Table 1](http://casereports.bmj.com/content/18/1/e261648/T1) Table 1 Medications administered throughout hospitalisation, including medication class, administration form, dosage, treatment duration (days), and notes on therapeutic purpose or effect All blood samples were correctly obtained as trough levels. ### Potential pharmacokinetic interactions During hospitalisation, the patient received a total of 34 medications (table 1). A thorough assessment for potential drug interactions was conducted by the local Department of Clinical Pharmacology, identifying fosphenytoin (day 11–18), meropenem (day 13–23) and phenobarbital (day 31–58) as agents likely to cause clinically significant interactions with valproic acid, lamotrigine and topiramate, potentially explaining the observed subtherapeutic levels (figure 2). ![Figure 2](http://casereports.bmj.com/https://casereports.bmj.com/content/bmjcr/18/1/e261648/F2.medium.gif) [Figure 2](http://casereports.bmj.com/content/18/1/e261648/F2) Figure 2 Potential pharmacokinetic interactions between the patient’s daily antiepileptic medication regimen (valproic acid, lamotrigine, topiramate and clobazam) and additional medications that the patient received during hospitalisation. The number of small, vertical arrows indicates the degree to which the concentration of a given medication is expected to be altered (↑/↓ = minor, ↑↑/↓↓= moderate, ↑↑↑/↓↓↓ = major). ↔ A thick, solid arrow indicates that the interaction is presumed to partially explain the alterations in concentration levels illustrated in figure 1. ⇠⇢A thin, dashed arrow represents potential interactions in a general context. (): Prevailing data is inconsistent. * : Concurrent treatment did not occur. NB: Potential pharmacodynamic interactions are not included in this figure. ## Outcome and follow-up The patient stabilised around day 66 and was discharged on day 94 with his initial daily antiepileptic medication regimen, with modifications including an increased valproic acid dose (1200 mg) and the addition of levetiracetam (880 mg). ## Discussion In this case, the true impact of pharmacokinetic interactions is particularly difficult to estimate due to concurrent critical illness, potential pharmacokinetic alterations and frequent treatment adjustments within a short time frame. While the identified pharmacokinetic interactions likely accounted for several of the observed fluctuations in the antiepileptic concentrations, they do not fully explain the complex clinical presentation and the persistent low concentrations of antiepileptics. ### Variations attributable to pharmacokinetic interactions Fosphenytoin, a prodrug of phenytoin, and phenobarbital are recognised as potent inducers of various cytochrome P450 (CYP) isoenzymes and uridine glucuronyl transferases (UGTs), capable of significantly reducing the concentrations of valproic acid, lamotrigine and topiramate.2 3 Additionally, meropenem is documented to substantially reduce the plasma concentration of valproic acid by 67–82% through an undetermined mechanism.4–7 Conversely, valproic acid increases the serum concentration of lamotrigine and the plasma concentration of phenobarbital, possibly through the inhibition of UGT1A4 and CYP isoenzymes, respectively.2 3 These interactions likely influenced the subtherapeutic levels of valproic acid, lamotrigine and topiramate detected between days 20 and 26 and around days 33–52, as well as the increased phenobarbital plasma concentrations between days 35 and 52. ### Fluctuations potentially attributable to either pharmacokinetic interactions or changes in dosage and/or administration form The impact of enzyme induction is generally dose-dependent, gradual and contingent on the rate of enzyme synthesis and degradation.2 In contrast, the adverse impact of meropenem on valproic acid plasma levels may occur rapidly (<24 hours) and dose independently. Normalisation of valproic acid plasma levels varies, with durations up to 3 weeks demonstrated in paediatric patients.4 7 However, due to multiple treatment adjustments occurring within a short time frame, it is challenging to determine whether the increased valproic acid plasma concentrations noted on days 30 and 59 stem from the declining impact of fosphenytoin (days 11–18), meropenem (days 13–23) and the subsequent withdrawal of phenobarbital (days 47–58), or the escalated valproic acid dosage (days 28–30 and 54–74) combined with a switch from oral to intravenous administration (days 25–32). Although data have indicated that increased valproic acid dosage cannot counteract the interaction with meropenem,5 the collective evidence regarding paediatric patients remains limited.4 ### Observations beyond the influence of pharmacokinetic interactions Several observations cannot exclusively be explained by the identified pharmacokinetic interactions. First, given the gradual enzyme induction, the initial halving of the valproic acid plasma concentration detected on day 11 cannot solely be attributed to the concurrent initiation of fosphenytoin. Second, while the temporal increase in the topiramate level observed on day 24 could suggest a diminishing impact of fosphenytoin induction, this hypothesis is contradicted by the abrupt and inexplicable reduction in the topiramate serum concentration detected on day 26, despite ongoing treatment and stable renal and hepatic function. The significant reduction is particularly noteworthy considering topiramate has a relatively long half-life (30–40 hours) and is predominantly excreted unchanged renally.3 Third, the patient’s need for intensified antiepileptic treatment on discharge is unlikely to be a result of prior interactions with either fosphenytoin, meropenem or phenobarbital, given the lapse of a minimum of 1 month after their discontinuation. ### Potential contributing factors Given that the subtherapeutic levels of valproic acid, lamotrigine and topiramate cannot solely be attributed to pharmacokinetics interactions, it is imperative to investigate additional contributing factors. These potentially include (1) worsening of the underlying neurological condition; (2) uncertainty of measurements; (3) altered gastrointestinal absorption, metabolism and distribution of antiepileptics; (4) the presence of concurrent critical illness; and (5) iatrogenic toxicity. Especially, the latter three factors merit a more detailed exploration. During critical illness, the gastrointestinal bioavailability of medications has been described to be significantly compromised due to reduced gastrointestinal motility, interaction with enteral nutrition and diminished intestinal blood perfusion.8 Moreover, reduced intestinal motility has been demonstrated in animal models of CLN2 in mice and reported in patients with CLN2.9 10 These factors suggest that the patient may have experienced impaired gastrointestinal absorption of the antiepileptic treatment, which potentially could explain the observed rise in the plasma concentration of valproic acid on day 30, following the switch from oral to intravenous administration 5 days earlier. Nonetheless, data on the oral bioavailability of antiepileptic medications in critically ill patients are limited, making it difficult to determine the precise impact of potentially reduced gastrointestinal absorption in this case.11 Furthermore, the rate at which this paediatric patient metabolised the antiepileptics is uncertain. While it has been demonstrated that the capacity for metabolising antiepileptic medications is enhanced in children compared with adults,12 the presence of concurrent infection and/or inflammation may cause downregulation of various CYP enzymes.13 In addition, critical illness may alter the tissue distribution of a given medication due to changes in protein concentration, blood pH, fluid shifts and abnormal capillary permeability,14 further impacting the antiepileptic concentrations to an unknown extent. Finally, it is important to consider the potential iatrogenic nature of the abnormal neuromotor manifestations (mixed-type seizures, myoclonic jerks and dystonic muscle contractions) observed throughout hospitalisation. At high doses, beta-lactams are known to be central nervous system (CNS) irritants and may trigger movement disorders, such as myoclonus, convulsions and status epilepticus.15 In this case, the patient received a high dose of meropenem in accordance with guidelines. Although therapeutic drug monitoring for beta-lactams was not available, we consider it less likely that the abnormal neuromotor movements were a result of beta-lactam neurotoxicity for two main reasons: (1) beta-lactam is cleared renally, and the patient had no renal impairment and (2) the neuromotor dysfunction persisted several weeks after the antibiotic treatment was concluded. ### Learning points The presented case highlights: * The necessity of recognising the potentially severe impact of pharmacokinetic interactions. Treatment with fosphenytoin, meropenem and phenobarbital may lead to prolonged subtherapeutic levels of valproic acid, lamotrigine and/or topiramate, heightening the susceptibility to seizures. * The importance of exploring alternative antiepileptic and antibiotic regimens when significant pharmacokinetic interactions are identified. If coadministration is deemed necessary, it is advisable to closely monitor antiepileptic drug concentrations and to exercise caution when implementing multiple therapeutic modifications simultaneously. * The need for further research to gain a better understanding of the complex interplay between these pharmacokinetic interactions in critically ill paediatric patients undergoing antiepileptic therapy. ## Ethics statements ### Patient consent for publication Consent obtained from parent(s)/guardian(s). ## Footnotes * Contributors The clinician in charge of the clinical care of the patient, who supervised the preparation of the manuscript, was responsible for obtaining informed consent from the patient/guardian/family members and is responsible for the overall integrity of the content of the manuscript and guarantor is: THS The following authors were responsible for drafting of the text, investigation results, drawing original diagrams and critical revision for important intellectual content: LBP and SA. The following authors gave final approval of the manuscript: THS and AEO. ChatGPT/CoPilot was used to assist with correct spelling and grammatics. * Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. * Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy. * Competing interests None declared. * Provenance and peer review Not commissioned; externally peer reviewed. * Accepted December 7, 2024. * © BMJ Publishing Group Limited 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/) This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/). ## References 1. Wyrwich KW, Schulz A, Nickel M, et al. An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease. J Inborn Errors Metab Screen 2018;6:232640981878838. [doi:10.1177/2326409818788382](http://dx.doi.org/10.1177/2326409818788382) 2. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2:347–56. [doi:10.1016/s1474-4422(03)00409-5](http://dx.doi.org/10.1016/s1474-4422(03)00409-5) [CrossRef](http://casereports.bmj.com/lookup/external-ref?access_num=10.1016/S1474-4422(03)00409-5&link_type=DOI) [PubMed](http://casereports.bmj.com/lookup/external-ref?access_num=12849151&link_type=MED&atom=%2Fbmjcr%2F18%2F1%2Fe261648.atom) [Web of Science](http://casereports.bmj.com/lookup/external-ref?access_num=000183115000017&link_type=ISI) 3. Iapadre G, Balagura G, Zagaroli L, et al. Pharmacokinetics and Drug Interaction of Antiepileptic Drugs in Children and Adolescents. Pediatr Drugs 2018;20:429–53. [doi:10.1007/s40272-018-0302-4](http://dx.doi.org/10.1007/s40272-018-0302-4) 4. Miranda Herrero MC, Alcaraz Romero AJ, Escudero Vilaplana V, et al. Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics? Eur J Paediatr Neurol 2015;19:155–61. [doi:10.1016/j.ejpn.2014.12.010](http://dx.doi.org/10.1016/j.ejpn.2014.12.010) 5. Wu C-C, Pai T-Y, Hsiao F-Y, et al. The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations. Ther Drug Monit 2016;38:587–92. [doi:10.1097/FTD.0000000000000316](http://dx.doi.org/10.1097/FTD.0000000000000316) 6. Haroutiunian S, Ratz Y, Rabinovich B, et al. Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study. J Clin Pharmacol 2009;49:1363–9. [doi:10.1177/0091270009334377](http://dx.doi.org/10.1177/0091270009334377) [CrossRef](http://casereports.bmj.com/lookup/external-ref?access_num=10.1177/0091270009334377&link_type=DOI) [PubMed](http://casereports.bmj.com/lookup/external-ref?access_num=19773524&link_type=MED&atom=%2Fbmjcr%2F18%2F1%2Fe261648.atom) [Web of Science](http://casereports.bmj.com/lookup/external-ref?access_num=000270956500009&link_type=ISI) 7. Taha FA, Hammond DN, Sheth RD. Seizures from valproate-carbapenem interaction. Pediatr Neurol 2013;49:279–81. [doi:10.1016/j.pediatrneurol.2013.03.022](http://dx.doi.org/10.1016/j.pediatrneurol.2013.03.022) 8. Van der Merwe F, Wallis S, Udy A. Understanding the impact of critical illness on drug pharmacokinetics - scientifically robust study design. Clin Toxicol 2011. 9. Jansen MJ, Williams LL, Wang SH, et al. Bowel dysmotility and enteric neuron degeneration in lysosomal storage disease mice is prevented by gene therapy. Neuroscience [Preprint]. [doi:10.1101/2023.05.26.542524](http://dx.doi.org/10.1101/2023.05.26.542524) 10. Simonati A, Williams RE. Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview. Front Neurol 2022;13:811686. [doi:10.3389/fneur.2022.811686](http://dx.doi.org/10.3389/fneur.2022.811686) 11. Forsberg J, Bedard E, Mahmoud SH. Bioavailability of Orally Administered Drugs in Critically Ill Patients. J Pharm Pract 2023;36:967–79. [doi:10.1177/08971900221100205](http://dx.doi.org/10.1177/08971900221100205) 12. Verrotti A, Iapadre G, Di Donato G, et al. Pharmacokinetic considerations for anti-epileptic drugs in children. Expert Opin Drug Metab Toxicol 2019;15:199–211. [doi:10.1080/17425255.2019.1575361](http://dx.doi.org/10.1080/17425255.2019.1575361) 13. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103–41. [doi:10.1016/j.pharmthera.2012.12.007](http://dx.doi.org/10.1016/j.pharmthera.2012.12.007) [CrossRef](http://casereports.bmj.com/lookup/external-ref?access_num=10.1016/j.pharmthera.2012.12.007&link_type=DOI) [PubMed](http://casereports.bmj.com/lookup/external-ref?access_num=23333322&link_type=MED&atom=%2Fbmjcr%2F18%2F1%2Fe261648.atom) 14. Thakkar N, Salerno S, Hornik CP, et al. Clinical Pharmacology Studies in Critically Ill Children. Pharm Res 2017;34:7–24. [doi:10.1007/s11095-016-2033-y](http://dx.doi.org/10.1007/s11095-016-2033-y) 15. Roger C, Louart B. Beta-Lactams Toxicity in the Intensive Care Unit: An Underestimated Collateral Damage? Microorganisms 2021;9:1505. [doi:10.3390/microorganisms9071505](http://dx.doi.org/10.3390/microorganisms9071505)