Pharmacokinetics and Optimal Dosing of Levetiracetam in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy (LEVCRRT)
Levetiracetam may be removed during continuous renal replacement therapy (CRRT), potentially affecting drug concentrations and seizure control. The optimal dosing regimen for critically ill patients receiving CRRT remains unclear. This observational study will investigate the pharmacokinetics of levetiracetam in critically ill adult patients receiving CRRT. Blood, CRRT effluent, and urine samples will be collected throughout one dosing interval to measure levetiracetam concentrations. The data will be used to develop a population pharmacokinetic model and perform pharmacokinetic/pharmacodynamic modeling and Monte Carlo simulations to evaluate dosing regimens and estimate the probability of achieving predefined drug concentration or exposure targets. The findings may help identify an appropriate levetiracetam dosing regimen for critically ill patients receiving CRRT.
Study Overview
Status
Intervention / Treatment
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Supanat Khueankaew, PharmD
- Phone Number: +6622188403
- Email: supanat.khnat@gmail.com
Study Locations
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Bangkok
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Pathum Wan, Bangkok, Thailand, 10330
- King Chulalongkorn Memorial Hospital
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Contact:
- Supanat Khueankaew, PharmD
- Phone Number: +6622188403
- Email: supanat.khnat@gmail.com
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Contact:
- Weerachai Chaijamorn, BSc(Pharm), BCP, FACP, BCPS
- Phone Number: +6622188403
- Email: weerachai.c@chula.ac.th
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Critically ill adult patients aged 18 years or older admitted to ICUs who receive levetiracetam during CRRT. Eligible patients must have received CRRT for at least 24 hours and meet the study's inclusion and exclusion criteria.
Description
Inclusion Criteria:
- Adults aged 18 years or older.
- Patients admitted to any ICUs.
- Patients receiving CRRT for at least 24 hours.
- Hemodynamically stable patients, defined as having a SBP of at least 90 mmHg or a MAP of at least 60 mmHg, with the norepinephrine dose remaining stable or increasing by no more than 0.1 mcg/kg/min during the preceding 6 hours.
- Patients receiving intravenous or oral levetiracetam while receiving CRRT.
- Patients admitted to any ICUs.
- Patients receiving CRRT for at least 24 hours.
Exclusion Criteria:
- Pregnant patients
- Patients who are breastfeeding.
- Patients with a known hypersensitivity to levetiracetam or who develop a hypersensitivity reaction requiring discontinuation of levetiracetam during the study.
- Patients with cirrhosis classified as Child-Pugh-Turcotte class C.
- Patients receiving extracorporeal membrane oxygenation (ECMO).
- Patients who, or whose legally authorized representatives, do not provide informed consent for study participation.
- Patients with an expected survival of less than 24 hours, as assessed by the attending physician.
Study Plan
How is the study designed?
Design Details
- Observational Models: CASE_ONLY
- Time Perspectives: PROSPECTIVE
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
|---|---|
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Critically Ill Adult Patients Receiving Levetiracetam During CRRT
Critically ill adult patients aged 18 years or older admitted to ICUs who receive levetiracetam during CRRT. Eligible participants must have received CRRT for at least 24 hours and meet the study's inclusion and exclusion criteria. |
Levetiracetam administered as part of routine clinical care to critically ill adult patients receiving CRRT. The dose, dosing interval, and route of administration are determined by the treating physician. CRRT is prescribed and managed by the treating clinical team (nephrologist) as part of routine clinical care. The investigators do not assign or modify levetiracetam treatment or CRRT prescriptions for research purposes. Levetiracetam concentrations are measured in blood, CRRT effluent, and urine samples collected at protocol-specified time points to characterize its pharmacokinetic profile during CRRT. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Probability of target attainment for simulated levetiracetam dosing regimens
Time Frame: At completion of population pharmacokinetic model development and Monte Carlo simulations (approximately 23 months after study start).
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Monte Carlo simulations based on the developed population pharmacokinetic model will be used to estimate the probability of target attainment (PTA) for each simulated levetiracetam dosing regimen. Target attainment will be evaluated according to the prespecified therapeutic concentration and AUC target criteria in the study protocol. Results will be reported as the probability or percentage of simulated patients achieving the target for each dosing regimen. |
At completion of population pharmacokinetic model development and Monte Carlo simulations (approximately 23 months after study start).
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Levetiracetam plasma exposure based on the area under the concentration-time curve (AUC)
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Levetiracetam AUC will be estimated using noncompartmental analysis of concentration-time data collected over a single dosing interval. Simultaneous samples will be collected from the pre-filter, post-filter, and effluent ports before dosing and at 7 prespecified time points after intravenous or oral administration. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Volume of distribution of levetiracetam
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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The volume of distribution of levetiracetam will be estimated using noncompartmental pharmacokinetic analysis based on the administered dose, elimination rate constant, and AUC. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Total clearance of levetiracetam
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Total clearance of levetiracetam will be estimated using noncompartmental pharmacokinetic analysis based on the administered dose and AUC. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Levetiracetam sieving and saturation coefficients during continuous renal replacement therapy (CRRT)
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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The sieving coefficient (SC) and saturation coefficient (SA) of levetiracetam will be determined using pre-filter, post-filter, and effluent concentrations to evaluate drug transfer across the CRRT filter under different CRRT modalities, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF). |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Levetiracetam clearance by CRRT
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Levetiracetam clearance by CRRT will be calculated based on pre-filter, post-filter, and effluent concentrations, together with replacement or dialysate flow rates according to the CRRT modality and dilution method, including CVVH, CVVHD, and CVVHDF. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Renal clearance of levetiracetam
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Renal clearance of levetiracetam will be calculated based on urinary levetiracetam concentrations, urine volume, and plasma levetiracetam concentrations. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Non-renal clearance of levetiracetam
Time Frame: From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Non-renal clearance of levetiracetam will be estimated from total systemic drug clearance after accounting for renal and CRRT clearance. |
From predose (0 hours) to pre-next dose (e.g., 12 hours) after initiation of levetiracetam administration.
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Population typical value of levetiracetam clearance
Time Frame: Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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The typical population value of levetiracetam clearance will be estimated using nonlinear mixed-effects modeling based on pre-filter and post-filter plasma concentration data collected from critically ill patients receiving CRRT. |
Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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Population typical value of levetiracetam volume of distribution
Time Frame: Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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The typical population value of levetiracetam volume of distribution will be estimated using nonlinear mixed-effects modeling based on pre-filter and post-filter plasma concentration data collected from critically ill patients receiving CRRT. |
Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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Population typical value of CRRT-mediated levetiracetam clearance
Time Frame: Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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The typical population value of CRRT-mediated levetiracetam clearance will be estimated using levetiracetam concentrations in plasma and effluent fluid, together with effluent flow rate, in critically ill patients receiving CRRT. |
Following completion of pharmacokinetic data collection and population pharmacokinetic analysis (approximately 23 months after study start).
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Weerachai Chaijamorn, BSc (Pharm), BCP, FACP, BCPS, Associate Professor, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
Publications and helpful links
General Publications
- Brockmoller J, Thomsen T, Wittstock M, Coupez R, Lochs H, Roots I. Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests. Clin Pharmacol Ther. 2005 Jun;77(6):529-41. doi: 10.1016/j.clpt.2005.02.003.
- Chaijamorn W, Charoensareerat T, Rungkitwattanakul D, Phunpon S, Sathienluckana T, Srisawat N, Pattharachayakul S. Levetiracetam dosing in patients receiving continuous renal replacement therapy. Epilepsia. 2021 Sep;62(9):2151-2158. doi: 10.1111/epi.16971. Epub 2021 Jul 11.
- Chappell K, Kimmons LA, Haller JT, Canada RB, He H, Hudson JQ. Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy. J Crit Care. 2021 Feb;61:216-220. doi: 10.1016/j.jcrc.2020.10.032. Epub 2020 Nov 2.
- Kalaria SN, Armahizer M, McCarthy P, Badjatia N, Gobburu JV, Gopalakrishnan M. A Practice-Based, Clinical Pharmacokinetic Study to Inform Levetiracetam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-01). Clin Transl Sci. 2020 Sep;13(5):950-959. doi: 10.1111/cts.12782. Epub 2020 Apr 3.
- Louie JM, Raphael KL, Barker B. Levetiracetam Use With Continuous Renal Replacement Therapy. Ann Pharmacother. 2015 Sep;49(9):1079-80. doi: 10.1177/1060028015591845. Epub 2015 Jun 23. No abstract available.
- Van Matre ET, Mueller SW, Fish DN, MacLaren R, Cava LF, Neumann RT, Kiser TH. Levetiracetam Pharmacokinetics in a Patient with Intracranial Hemorrhage Undergoing Continuous Veno-Venous Hemofiltration. Am J Case Rep. 2017 Apr 27;18:458-462. doi: 10.12659/ajcr.902709.
- Nei SD, Wittwer ED, Kashani KB, Frazee EN. Levetiracetam Pharmacokinetics in a Patient Receiving Continuous Venovenous Hemofiltration and Venoarterial Extracorporeal Membrane Oxygenation. Pharmacotherapy. 2015 Aug;35(8):e127-30. doi: 10.1002/phar.1615. Epub 2015 Aug 3.
- New AM, Nei SD, Kashani KB, Rabinstein AA, Frazee EN. Levetiracetam Pharmacokinetics During Continuous Venovenous Hemofiltration and Acute Liver Dysfunction. Neurocrit Care. 2016 Aug;25(1):141-4. doi: 10.1007/s12028-016-0242-1.
- le Noble JL, Foudraine NA, Kornips FH, van Dam DG, Neef C, Janssen PK. Extracorporeal Clearance of Levetiracetam During Continuous Venovenous Hemofiltration in a Critically Ill Patient and New Dosing Recommendation. J Clin Pharmacol. 2017 Apr;57(4):536-537. doi: 10.1002/jcph.844. Epub 2016 Nov 21. No abstract available.
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 0551/2026
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
The study team does not currently plan to share IPD with other researchers due to concerns regarding patient confidentiality, participant privacy, and the potential risk of re-identification. Access to study data will be restricted to researchers in the Pharmacometrics for Health Sciences Research Group, Faculty of Pharmaceutical Sciences, Chulalongkorn University, and individuals authorized in writing by the researchers. Any future proposal to share IPD will be reviewed for consistency with the informed consent, ethics committee requirements, institutional policies, and applicable laws.
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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