Monitoring levetiracetam concentration in saliva during pregnancy is stable and feasible.

AIMS: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy. METHODS: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy. RESULTS: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 µg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 µg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007. CONCLUSION: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

BACKGROUND: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. ANIMALS: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. METHODS: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. RESULTS: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 µg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. CONCLUSION AND CLINICAL IMPORTANCE: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

Therapeutic Drug Monitoring of Levetiracetam in Different Trimesters of Pregnant Women with Epilepsy in a Tertiary Care Center: A Prospective Study.

BACKGROUND: Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM). MATERIALS AND METHODS: This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC). RESULTS: The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018). CONCLUSION: There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome.

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 µL effluent samples were used to quantify levetiracetam. Plasma samples were purified by protein precipitation, evaporated under nitrogen gas at room temperature and reconstituted in 50 mm potassium dihydrogen phosphate buffer (pH of 4.5). Reverse-phase chromatographic separation was achieved within 20 min using a mobile phase eluting gradient of 50 mm potassium dihydrogen phosphate and acetonitrile. UV detection was set at 195 nm. The calibration curve was found to be linear over the range of 2-80µg/mL. Inter- and intra-day precisions were < 8% for both plasma and effluent samples. The accuracy was determined to be within -12-10% of nominal concentrations. The method was selective and sensitive with a lower limit of quantification of 2 µg/mL. Overall recovery of levetiracetam from plasma was ~100%. The validated assay was successfully applied in a pharmacokinetic study to determine potential dose adjustments in patients undergoing CRRT and receiving levetiracetam.

Determination of plasma Levetiracetam level by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) and its application in pharmacokinetics studies in neonates.

BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug which has good safety and efficacy in neonatal seizure (NS), a common incident in neonates with weight <1500 g. The pharmacokinetics for LEV in neonatal populations is yet to be clearly understood. In this study, we developed and validated a method for determination of LEV in plasma by liquid chromatography tandem mass spectrometry for the purpose of pharmacokinetic study. METHODS: Plasma LEV was spiked with Lamivudine as internal standard before extraction by C18 solid-phase extraction (SPE) cartridge. Chromatography was performed using isocratic elution with mobile phase A: B (10: 90) for 2.0 min with flow rate 0.4 mL/min. The mobile phase was composed of 0.1% formic acid in 10.0 mM ammonium acetate (A) and 100% methanol (B). The injection volume was 1.0 µL and the total run time was 2.0 min. Multiple reaction monitoring (MRM) with electro spray in positive mode was used. The mass transition for LEV was 171.2/126.0 and 230.0/112.0 for IS with retention time of 0.73 and 0.72 min, respectively. RESULTS: A calibration curve range from 0.50-80.0 µg/mL was obtained with a correlation coefficient >0.99 in the quadratic model. Precision and accuracy was within the acceptable range and the intra- and inter-day %CV for three concentrations of QCs were <10%. CONCLUSION: This method was reliable, accurate and applicable for LEV pharmacokinetic study in neonates with seizure.

Serum levetiracetam concentrations and adverse events after multiple dose extended release levetiracetam administration to healthy cats.

BACKGROUND: Multiple dose administration of antiepileptic drugs to cats presents a challenge for owners. Extended release levetiracetam (XRL) has once daily recommended dosing interval, but multiple dose administration of XRL has not been evaluated in cats. OBJECTIVE: Evaluate serum levetiracetam concentrations and adverse clinical effects after 11 days of once daily XRL administration to healthy cats. ANIMALS: Nine healthy privately owned cats, body weight ≥ 5 kg METHODS: Extended release levetiracetam (500 mg/cat) was administered PO q24h for 10 days. On day 11, blood was collected at trough, 4, 6, and 8 hours after tablet administration. Owners maintained records of adverse effects throughout study. Levetiracetam was quantitated in serum using immunoassay validated in cats. RESULTS: Median dose 94.3 mg/kg q24h. Median (range) trough, 4, 6, and 8 hour serum levetiracetam concentrations were 7.0 (2.3-14.1), 82.6 (7.8-125.3), 92.3 (13.3-97.3), and 72 (22.8-96.4) µg/mL, respectively. Peak was not observed in 4 cats because of missed samples (n = 2) and failure to reach maximal concentration (Cmax ) by 8 hours (n = 2). Median time of maximal concentration (Tmax ) for the remaining 5 cats 5.2 (range 4-6) hours. Adverse effects were minimal and included ataxia (n = 1), sedation (n = 1), and vomiting or regurgitation (n = 1). All signs resolved without dose adjustment or additional treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Mean trough serum levetiracetam concentrations were ≥5 µg/mL and adverse effects were minimal throughout dosing period, indicating that the drug was well tolerated. Once daily XRL (500 mg/cat) administration may provide an easier alternative to 3 times daily dosing of intermediate-release levetiracetam for epileptic cats.

Development and full validation of an innovative HPLC-diode array detection technique to simultaneously quantify lacosamide, levetiracetam and zonisamide in human plasma.

AIM: To implement pharmacokinetic drug monitoring and individualize the posology of new antiepileptic drugs, the first HPLC-diode array detection method was developed and validated to simultaneously quantify lacosamide, levetiracetam and zonisamide in human plasma. MATERIALS & METHODS: Preceded by a reproducible liquid-liquid extraction, chromatographic separation was achieved by using a C18 column of 5 cm length and a mobile phase of water/acetonitrile. Full validation was performed according to international guidelines. RESULTS: The method was linear within 0.5-30, 2.5-40.0 and 0.5-50.0 µg ml-1 for lacosamide, levetiracetam and zonisamide, respectively (r2 ≥ 0.998), accurate (-12.411-8.303%), precise (≤8.875%). CONCLUSION: This innovative HPLC-diode array detection method was successfully employed in clinical practice and is expected to empower epileptic patients with a personalized pharmacotherapy service. [Formula: see text].

Population pharmacokinetic model of levetiracetam in Korean neonates with seizures
.

OBJECTIVE: This study was conducted to develop a population pharmacokinetic (PK) model of levetiracetam in Korean neonates with seizures. MATERIALS AND METHODS: Data were obtained from a retrospective study of 18 neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of Severance Children's Hospital for the period of from 2013 to 2015. Sampling and dosing times were recorded by clinical research coordinators on case report forms. Demographic factors and laboratory results were tested as potential covariates for PK parameters. Model development was performed within a mixed-effect modeling framework using NONMEM. RESULTS: With a one-compartment model with first-order elimination chosen as a basic PK model based on theory-based allometric relationships, postmenstrual age and serum creatinine were found to have significant influences on clearance (CL). Typical parameter estimates of the final PK model obtained, evaluated at covariate medians, were 1.08 L/kg for volume of distribution (V) and 0.073 L/h/kg (= 1.23 mL/min/kg) for CL, illustrating that V in Korean neonates is a little larger than in Western population while CL is similar. CONCLUSION: A population PK model of levetiracetam for Korean neonates with seizures was developed in this study. The result of this study can be used as a basis to develop an optimal dosage regimen in Korean neonates with seizures.
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Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model.

OBJECTIVE: We previously demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate subtype 2 (mGlu2 ) receptors have potential synergistic interactions with the antiseizure drug levetiracetam (LEV). The present study utilizes isobolographic analysis to evaluate the combined administration of JNJ-46356479, a selective and potent mGlu2 PAM, with LEV as well as sodium valproate (VPA) and lamotrigine (LTG). METHODS: The anticonvulsant efficacy of JNJ-46356479 was evaluated in the 6-Hz model of psychomotor seizures in mice. JNJ-46356479 was administered in combination with LEV using 3 fixed dose-ratio treatment groups in the mouse 6-Hz (44-mA) seizure test. The combination of JNJ-46356479 with LEV was also evaluated in the mouse corneal kindling model. The potential interactions of JNJ-46356479 with the antiseizure drugs VPA and LTG were also evaluated using fixed dose-ratio combinations. Plasma levels were obtained for analysis of potential pharmacokinetic interactions for each combination studied in the mouse 6-Hz model. RESULTS: JNJ-46356479 was active in the 6-Hz model at both 32-mA and 44-mA stimulus intensities (median effective dose = 2.8 and 10.2 mg/kg, respectively). Using 1:1, 1:3, and 3:1 fixed dose-ratio combinations (LEV:JNJ-46356479), coadministration was significantly more potent than predicted for additive effects, and plasma levels suggest this synergism was not due to pharmacokinetic interactions. Studies in kindled mice further demonstrate the positive pharmacodynamic interaction of LEV with JNJ-46356479. Using 1:1 dose-ratio combinations of JNJ-46356479 with either VPA or LTG, there were no significant differences observed for coadministration. SIGNIFICANCE: These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu2 PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.

Carbamazepine, lamotrigine, levetiracetam and valproic acid in dried blood spots with liquid chromatography tandem mass spectrometry; method development and validation.

Monitoring of antiepileptic drugs in children with epilepsy require multiple visits at a clinic for blood collection. Dried blood spot sampling is an alternative way of collection, performed at home by self-collection and can save time and costs for patients and family members. The aim was to develop and validate an LC-MS/MS dried blood spot method for carbamazepine, lamotrigine, levetiracetam and valproic acid with the requirements of using standard equipment and material in a routine laboratory setting. Whatman-903 filter paper was utilized, and discs were punched into a 96 well plate with an automated puncher and barcode reading. Extraction with methanol/water solution including internal standards on an orbital shaker was followed by a vacuum centrifuge step and reconstitution in mobile phase. Bioanalytical validation was performed according to guidelines from European Medicines Agency and additional dried blood spot specific validation. Calibration curves of the four included drugs had R2 values ≥0.994. Therapeutic relevant concentrations were well within measuring ranges. Within and -between run precision had %CV:s of 2.9-10.5%. Accuracy (%bias) was between -16.5% (lower limit of quantification) to +7.4%. Blood spots in a volume range of 15-50µL with hematocrit in expected ranges for this patient group were within precision and accuracy limits. To test the method, concentrations from dried blood spot venous and capillary patient samples (n=50) were compared with plasma concentrations. Good correlations for all four drugs with R2 of >0.92 was shown. In summary, a fast method for dried blood spots based on a 96 well format was developed for four commonly prescribed antiepileptic drugs. This validated method with traceability in sample preparation by bar code reading makes it suitable for the clinical laboratory.

Influence of Comedication on Levetiracetam Pharmacokinetics.

BACKGROUND: To evaluate the effect of concomitant antiepileptic therapy on levetiracetam (LEV) pharmacokinetics. METHODS: A 6-year retrospective observational study. Patients were grouped according to the antiepileptic drug used as concomitant medication: group A, LEV in monotherapy; group B, LEV + enzyme-inducing antiepileptic drugs (EIAEDs); and group C, LEV + non-enzyme-inducing antiepileptic drugs (NEIAEDs). Apparent oral levetiracetam clearance (LEV CL/F) and basal serum levetiracetam concentrations (LEV C0) were compared among the different groups by analysis of variance. RESULTS: A total of 330 LEV C0 corresponding to 205 patients (56% men) were identified. The mean (±SD) of LEV CL/F in group A (n = 180), B (n = 92), and C (n = 58) was 4.41 ± 2.06 L/h, 7.23 ± 3.72 L/h, and 4.87 ± 1.65 L/h, respectively. EIAEDs increased LEV CL/F (L/h) by 64% compared with the monotherapy group and by 48% compared with the NEIAEDs group. The greatest induction in LEV CL/F, compared with the LEV monotherapy group, was observed with carbamazepine, followed by oxcarbazepine and phenobarbital, and was increased by 81%, 64%, and 44%, respectively. LEV C0 values were significantly lower in the EIAEDs group than in the monotherapy group (17.30 ± 7.77 versus 20.08 ± 9.69 mcg/mL; P = 0.038) or indeed the NEIAEDs group (17.30 ± 7.77 versus 20.49 ± 9.46 mcg/mL; P = 0.027). CONCLUSIONS: Comedication with EIAEDs increased LEV CL/F by more than 40%, whereas carbamazepine had the greatest inducing potency with LEV CL/F being 81% higher than that of the monotherapy group. These data suggest that monitoring LEV serum concentration during polytherapy with EIAEDs is indicated.

Disposition of levetiracetam in healthy adult horses.

Nine horses received 20 mg/kg of intravenous (LEVIV ); 30 mg/kg of intragastric, crushed immediate release (LEVCIR ); and 30 mg/kg of intragastric, crushed extended release (LEVCER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEVCIR and LEVCER were 50.72 ± 10.60 and 53.58 ± 15.94 µg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 µg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEVCIR , LEVCER, and LEVIV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg-1  hr-1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEVCIR and LEVCER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

Pharmacokinetics of the anticonvulsant levetiracetam in neonatal foals.

BACKGROUND: Seizures are a common manifestation of neurological disease in the neonatal foal and are an important cause of morbidity and mortality in this population. Current antiepileptic options are effective, but often have undesirable adverse effects, short duration of action and high cost. Levetiracetam has an ideal safety and pharmacokinetic profile in multiple species, including the adult horse, and may be a safe and cost-effective alternative anticonvulsant in neonatal foals. Due to differences in drug disposition and clearance dosages in neonates, dosing recommendations in other species or adult horses cannot be extrapolated to foals. OBJECTIVE: To establish the pharmacokinetic profile of single-dose i.v. and intragastric administration of levetiracetam in healthy neonatal foals. STUDY DESIGN: Randomised crossover experimental study. METHODS: Levetiracetam was administered as a single dose to six healthy foals (ages 1-10 days) at a dose of 32 mg/kg bwt i.v. or intragastrically. Plasma levetiracetam concentrations were measured using a validated HPLC protocol. RESULTS: After i.v. administration to healthy foals, levetiracetam had a mean (±s.d.) elimination half-life of 7.76 ± 0.51 h, a mean systemic clearance of 61.67 ± 10.96 (mL/h/kg) and a mean apparent volume of distribution at steady state of 0.670 ± 0.124 (L/kg). Following intragastric administration, levetiracetam had a peak concentration of 38.34 ± 7.42 mg/L and time to achieve peak concentration was 0.875 (0.5-1.5) h. Mean bioavailability for IG administration was excellent (103.04 ± 14.51%). No significant differences in pharmacokinetic variables between routes and order of administration were observed. MAIN LIMITATIONS: Small sample size and single-dose administration. CONCLUSIONS: Levetiracetam has excellent intragastric bioavailability in foals and is predicted to maintain plasma concentrations at or above the proposed target concentration with twice daily i.v. or oral administration. Once-daily administration may be possible in some foals based on the therapeutic range recommended in other species.

Pharmacokinetics of Single Oral Dose Extended-Release Levetiracetam in Healthy Cats.

BACKGROUND: Repeated PO dosing of anti-epileptic drugs may contribute to poor compliance in treated cats. Intermediate-release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5-45 µg/mL). Approved extended-release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. HYPOTHESES: In healthy cats, serum levetiracetam concentration will remain above 5 µg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. ANIMALS: 7 healthy cats. METHODS: Extended-release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. RESULTS: The median dosage of 86.2 mg/kg, (range, 80-94.3) achieved a mean maximum concentration (Cmax ) of 89.8 ± 25.8 µg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 µg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 µg/mL at 12 and 24 hours, respectively. The half-life was 4.1 ± 1.0 hours. The drug was well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 µg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats.

Switch From Originator to Equivalent Drug in the Era of Generic Antiepileptic Drugs: Study of Keppra Versus Epitiram Clinical Equivalence.

OBJECTIVES: Generic antiepileptic drugs represent a measure to maximize cost saving. Levetiracetam (LEV) is one of most commonly used and effective antiepileptic drugs. The objective of our work was to demonstrate the effectiveness and safety of overnight switch from monotherapy with Keppra (original drug) to epitiram (generic drug) at the same dose. METHODS: In our observational study, we consecutively enrolled 37 seizure-free patients with epilepsy who expressed the wish to switch to a generic drug for economic reasons. During the 6-month evaluation period, we assessed treatment efficacy, tolerability, compliance, and intersubject variability of LEV serum concentration. At each visit, clinical and neurological examination, scales, video-electroencephalogram, and blood sample analysis to evaluate LEV plasma level were performed. RESULTS: A total of 36 of 37 enrolled patients switched from Keppra to epitiram, which was administered at the same dose in monotherapy. Three of 36 patients dropped out during follow-up for adverse events. The other 33 subjects had neither seizures nor adverse events. No significant differences in electroencephalogram features and scale scores were revealed; the intersubject variability of LEV serum concentration did not differ significantly at follow-up evaluation (P = 0.53). All the patients expressed good clinical personal impression and continued to take epitiram. The switchback rate was 8 %. CONCLUSIONS: The switch from Keppra to epitiram was easy and safe in our population, and epitiram can be considered as effective and tolerable as Keppra. Only a slight, non-statistically significant variability in LEV serum concentration was documented after the switch from Keppra to epitiram. Larger epileptic populations should be studied to confirm these results.

Impact of generic substitution on levetiracetam serum concentration-A prospective study in an outpatient setting.

BACKGROUND: Switching patients from a branded antiepileptic drug (AED) to a generic is often challenging. Several studies have shown that considerable proportions of patients report deteriorated seizure control or increased adverse effects, enforcing a switchback to the original drug. Since tolerability and seizure control usually correlate with AED serum concentrations, we examined the fluctuation of levetiracetam (LEV) serum concentrations in patients with epilepsy before and after generic substitution. METHODS: This was an 18-week, naturalistic, open, prospective, two-center study. After a baseline period of 10 weeks, 33 outpatients on stable treatment with branded LEV (Keppra®) either continued with this product or were switched overnight to a generic LEV preparation (1A Pharma) for an eight-week study period. Throughout the study, patients were monitored with bi-weekly LEV serum concentration measurements and seizure diaries. RESULTS: 16 out of 33 patients were switched to a generic LEV product. No switchbacks were seen. LEV dose, LEV serum concentrations, fluctuation index and concentration/dose-ratio (C/D-ratio) were not significantly different within-group (baseline vs. study period) or between-group. Large within-subject variability in serum concentrations was seen in both groups. None of the patients that were seizure-free before inclusion experienced seizures while on the generic LEV product. CONCLUSIONS: Our results show equal fluctuation of LEV serum concentrations with branded LEV and the generic LEV. Most importantly, within-subject variability was much larger than the small, non-significant differences between brands.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

BACKGROUND: Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. OBJECTIVE: To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. METHODS: Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. RESULTS: We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. CONCLUSIONS: Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures: Case report.

WHAT IS KNOWN AND OBJECTIVE: Levetiracetam is used in the treatment of some forms of epilepsy. In renal impairment and patients on chronic haemodialysis, dose adjustment is required. We report a case. CASE DESCRIPTION: This case report describes a woman on levetiracetam treatment who presented with generalized tonic-clonic seizures during a haemodialysis session. We report on treatment adjustment and on the impact of dialysis on levetiracetam levels. WHAT IS NEW AND CONCLUSION: Haemodialysis reduces serum levetiracetam concentration and can lead to subtherapeutic levels. Close monitoring is necessary when dialysis is used on patients receiving anticonvulsant drugs that are extensively eliminated by the procedure.

Comparison of Plasma, Saliva, and Hair Levetiracetam Concentrations.

BACKGROUND: Previous findings revealed high correlations between serum/plasma and saliva levetiracetam concentrations, indicating saliva as an alternative matrix for monitoring levetiracetam therapy. Levetiracetam concentration in the hair, which could reflect long-term drug exposure and patients' compliance, has not been systematically tested, as yet. The aim of this study was to determine the correlation between plasma, saliva, and hair levetiracetam concentrations in 47 patients with epilepsy. METHODS: Plasma, saliva, and hair levetiracetam concentrations were measured by liquid chromatography-tandem mass spectrometry with positive ionization. RESULTS: Levetiracetam saliva and plasma concentrations were highly correlated (r = 0.93). Plasma concentrations were not influenced by sex, age, and other concomitant antiepileptic drugs. Levetiracetam hair concentrations correlated with plasma concentrations (r = 0.36) but not daily dose (mg/kg). Drug hair concentrations were not influenced by hair color or treatment (dyed). CONCLUSIONS: The results tend to indicate that saliva may be a reliable alternative to plasma for monitoring levetiracetam concentrations. Levetiracetam can also be detected in human hair.

Levetiracetam Pharmacokinetics in a Patient with Intracranial Hemorrhage Undergoing Continuous Veno-Venous Hemofiltration.

BACKGROUND Levetiracetam is an antiepileptic drug frequently used in critically ill patients. Levetiracetam is primarily eliminated as a parent compound via glomerular filtration and requires dose adjustment in renal insufficiency, but the literature on patients receiving continuous veno-venous hemofiltration (CVVH) is scant. CASE REPORT We report the levetiracetam pharmacokinetic profile of a patient being treated with levetiracetam 1000 mg intravenously every 12 h who required continuous veno-venous hemofiltration (CVVH). The patient underwent CVVH utilizing a high-flux polyethersulfone membrane filter. The blood flow rate was 250 ml/min, and the predilution replacement therapy fluid flow rate was 2000 ml/h. After achieving presumed steady-state on levetiracetam 1000 mg q12h, serial plasma samples (pre- and post-filter) and effluent samples were drawn at 2, 4, 6, 8, and 10 h. Levetiracetam concentrations were determined utilizing LC-MS/MS. The levetiracetam maximum concentration (Cmax), minimum concentration (Cmin), half-life, area under the concentration-time curve (AUC0-12), clearance (CL), and volume of distribution (Vd) were 30.7 µg/ml, 16.1 µg/ml, 12.9 h, 272 mg·hr/L, 3.68 L/h, and 0.73 L/kg, respectively. The sieving coefficient was 1.03±0.08. CVVH represented 61.3% of the total levetiracetam clearance. The patient was maintained on CVVH for 24 consecutive days and then transitioned to intermittent hemodialysis and remained seizure-free. CONCLUSIONS CVVH is highly effective in removing levetiracetam from circulating plasma. Due to the effective removal, standard doses of levetiracetam are required to maintain adequate plasma concentrations. Dose reductions utilizing HD or estimated creatinine clearance recommendations will likely lead to subtherapeutic levels, especially if higher CVVH flow rates are used.