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Clinical Utility of a Continuous Intravenous Infusion of Valproic Acid in Pediatric Patients

Lisa M. Taylor, Pharm.D.; Farjam Farzam, M.D.; Aaron M. Cook, Pharm.D.; Daniel A. Lewis, Pharm.D.; Robert J. Baumann, M.D.; Robert J. Kuhn, Pharm.D. Posted: 05/17/2007; Pharmacotherapy. 2007;27(4):519-525. 2007 Pharmacotherapy Publications Abstract and Introduction Abstract Study Objective: To describe the dose-concentration relationship of a continuous intravenous infusion of valproic acid (VPA) in pediatric patients when a dosing protocol is used. Design: Retrospective and concurrent chart review. Setting: Tertiary care, 473-bed, academic medical center with a 120-bed, dedicated children's hospital. Patients: Twenty-six pediatric patients (< 18 yrs old) who received VPA according to the protocol for continuous intravenous infusions between January 1, 2004, and March 31, 2006, identified by using a pharmacy order-entry system. Measurements and Main Results: Patient demographics, VPA treatment regimens, clinical responses, and safety data were recorded and analyzed. Median patient age was 8.5 years (range 1.4 16 yrs). Approximately two thirds received VPA for seizures, and one third for migraines. Patients were given a mean SD VPA loading dose of 28.5 5.2 mg/kg followed by a continuous infusion rate of 1 0.2 mg/kg/hour. Mean SD serum concentration measured 4.5 1.6 hours after the loading dose was 83.3 22.8 g/ml. Steady-state concentration at 23.3 3.0 hours after the start of the continuous infusion was 80.0 26.0 g/ml. Postload and steady-state serum concentrations were within the target concentration of 50-100 g/ml in 77% and 69% of patients, respectively. On further analysis, when the target range was expanded to 50-125 g/ml (125 g/ml was deemed acceptable if no adverse effects were noted), 89% and 92% of patients, respectively, had postload and steady-state VPA serum concentrations within this range. The response rate was excellent, with nearly 85% of patients achieving a complete or partial response to therapy. Adverse effects were generally mild and uncommon. Conclusions: The continuous-infusion protocol permitted rapid intravenous loading of VPA in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

Introduction Valproic acid (VPA) is an anticonvulsant commonly used for the treatment of epilepsy and for other indications, including the management of migraine headache and psychiatric illnesses. [1] It is particularly valuable in the treatment of childhood epilepsy because of its broad spectrum of activity against several seizure types, including partial, generalized, and mixed seizure disorders.[2,3] In 1996, the United States Food and Drug Administration approved intravenous VPA sodium as monotherapy or adjunctive therapy for complex partial seizures, absence seizures, and mixed seizure types. The intravenous formulation is approved for short-term substitution in patients who are unable to take the oral dosage forms. Since its approval, however, many practitioners have explored other roles for intravenous VPA, including its use in patients with status epilepticus, refractory seizures, or status migraine.[410] Variability in the pharmacokinetics of VPA makes consistently achieving therapeutic concentrations difficult, and routine monitoring of serum concentrations is often required. Concentration-dependent, saturable protein binding and wide interpatient variability in systemic clearance, particularly in children, are the principal reasons for this pharmacokinetic variability.[11] Systemic clearance of VPA is substantially increased in children. Likely explanations include an increase in the unbound fraction of VPA available for metabolism and elevated drug metabolizing capacity based on the intrinsic clearance by the liver. [11,12]
As a result of this increased systemic clearance, the elimination half-life is markedly shortened, and increased frequency of dosing or use of a special formulation is required to maintain trough serum concentrations in the accepted therapeutic range of 50100 g/ml in most patients.[1316] In patients who are unable to take the extendedrelease formulation of VPA, frequent, intermittent dosing may elevate peak concentrations to maintain trough concentrations in the desired range. Researchers described the fluctuation of VPA serum concentrations between doses of an oral, immediate-release formulation in pediatric patients with epilepsy (age range 4.5-13 yrs).[17] Mean increases from predose concentration to the peak concentration were 82% with every-12-hour dosing and 62% with every-8-hour dosing. If used, intermittent doses of an intravenous formulation would accentuate this large serum concentration fluctuation because they are immediately absorbed into the systemic circulation. Delivering intravenous valproate by means of continuous infusion can address this clinical problem by providing a consistent serum concentration throughout the dosing interval to avoid fluctuation. The optimal loading dose and the initial infusion rate for VPA in children are unknown. The aim of this observational study was to determine the efficiency of a continuous-infusion protocol in achieving VPA serum concentrations in the accepted target range of 50-100 g/ml in pediatric patients. We expected this protocol to achieve target serum concentrations in 80% of the patients at 24 hours. Secondary objectives of this study were to determine the systemic clearance of VPA and to estimate the relative efficacy and safety of intravenous VPA in the treatment of seizures and migraines when given as a continuous intravenous infusion. Methods Patients We retrospectively and/or concurrently reviewed the medical records of pediatric patients who were prescribed a continuous intravenous infusion of VPA to treat seizures or migraines between January 1, 2004, and March 31, 2006. Patients were included in this analysis if they were less than 18 years of age and if they received VPA according to the protocol for continuous intravenous infusion. Approval was obtained from the local institutional review board, and written informed consent was obtained for concurrent data collection. This study was conducted in accordance with the Helsinki Declaration of 1975. Drug Protocol The drug protocol consisted of a loading dose of VPA 20-40 mg/kg intravenously infused over 1 hour followed by a continuous intravenous infusion at 1-1.5 mg/kg/hour (VPA concentration 4 mg/ml in normal sodium chloride solution or dextrose 5% in water). The dose ranges in the protocol were developed before this study was conducted. They were selected to reflect loading dose regimens published in the literature and the maintenance dose range typically required to achieve concentrations in the therapeutic range. Serum VPA concentrations were obtained 2-4 hours after the loading dose was administered and at 24 hours after the start of the continuous infusion. The infusion rate was adjusted according to the patient's 24-hour serum concentration and clinical response. End Points and Objectives The primary end point was the percentage of patients starting the standard protocol who achieved VPA serum concentrations in the target range of 50-100 g/ml at 24 hours. Secondary end points were systemic clearance, adverse effects, and clinical response rates (classified as complete response, partial response, or no response). Systemic clearance (Cls [L/hr]) was calculated using the following equation: Css = X0/Cls, where Css is the steady-state concentration (mg/L) and X0 is the infusion rate (mg/hr). Clinical Response Classification A pediatric neurologist (Dr. Farzam) classified the patients' clinical responses as complete, partial, or none. Complete response was complete cessation and partial response was a partial or incomplete reduction in the frequency, intensity, and duration of seizures or headaches. No response was defined as no change in the frequency,
intensity, or duration of seizures or headaches. The pediatric neurologist evaluated the response after the completion of therapy by using medical records. Safety and Adverse Effects Adverse effects were documented during each patient's inpatient hospitalization in the medical record. The pediatric neurologist evaluated safety and adverse effects after the completion of therapy. Data Collection Demographic characteristics that were collected were the patient's age, weight, ethnicity, sex, and age at the onset of seizures or migraines, as well as the duration of the condition since diagnosis or first episode. Variables related to VPA treatment were the indication for treatment, previous anticonvulsant therapy, concurrent anticonvulsants, the loading dose of VPA, the initial infusion rate of VPA, the number of adjustments to the infusion rate, and the conversion to oral VPA therapy. Monitoring parameters were VPA serum concentration at 2-4 hours after the loading dose was administered, the 24-hour VPA serum concentration (which was assumed to be at steady state), adverse effects, and response rates. Statistical Analysis All values are expressed as the mean SD, median and range, or number and percentage as appropriate. Descriptive statistics were used to report demographic characteristics, VPA treatment variables, and the percentage of patients achieving the target serum concentrations of VPA. Results Using the pharmacy order-entry system over the 2-year study time period, we retrospectively identified 25 patients and prospectively identified 16 patients who received a continuous intravenous infusion of VPA. Ten patients in the retrospective group were excluded as their care deviated from the hospital's continuous-infusion protocol; in nine patients, a postload and/or steady-state serum concentration were not obtained, and one did not receive a loading dose. Five patients were excluded from the prospective group; parents or guardians refused consent for two patients and were unavailable for consent for two others, and VPA was discontinued in one patient because of an episode of confusion that was suspected to be an adverse reaction to the loading dose. Therefore, 26 patients were included in the analysis (Figure 1).

Figure 1. Flow chart of sample-selection process. VPA = valproic acid.
The median age of the patients was 8.5 years (range 1.4-16 yrs) with slightly more female than male patients ( Table 1 ). About 92% of the patients were Caucasian. Among the 17 patients with seizures (65% of all patients), nine (53%) had new-onset seizures; among the nine patients with migraines (35% overall), seven (78%) had new-onset migraines. The age at seizure or migraine onset ranged from 3 weeks-16 years. Of the few patients who had a history of seizures or migraines before receiving the continuousinfusion VPA, the median duration of the condition was 0 years (i.e., first episode, new onset); however, the range was 4 months-12 years. Table 2. Calculated Systemic Clearance

Eleven (42%) of the 26 patients previously received antiepileptic therapy before the continuous-infusion VPA was started. In all except one of these patients, VPA was started for treatment of seizures. One patient, for whom VPA was begun for treatment of migraine, previously received topiramate for migraine prophylaxis. Of the 11 patients who were previously receiving antiepileptic therapy, five received two antiepileptic agents. Eight patients (31%) received concurrent antiepileptic therapy while receiving VPA. All eight patients were receiving VPA for the treatment of seizures. Patients received a mean loading dose of VPA 28.5 5.2 mg/kg followed by a mean continuous infusion of 1 0.2 mg/kg/hour. Seven (27%) patients required an adjustment to the initial dosage of the continuous infusion. The mean serum concentration at 4.5 1.6 hours after completion of the loading dose was 83.3 22.8 g/ml. The mean steady-state serum concentration at 23.3 3.0 hours after the start of the continuous infusion was 80.0 26.0 g/ml. Systemic clearance was calculated as 14.5 5.3 ml/kg/hour in patients who received monotherapy with VPA ( Table 2 ). As expected, patients concurrently receiving phenobarbital or phenytoin, both potent hepatic enzyme inducers, had increased calculated systemic clearances. On further analysis of patients given VPA monotherapy, those aged 12 years had the highest systemic clearance of all age groups. Postload and steady-state VPA serum concentrations were in the target range of 50-100 g/ml in 77% and 69% of patients, respectively (Figure 2). Our pediatric neurologists considered serum concentrations of 125 g/ml permissible if the patient was not having adverse effects. Therefore, on further analysis of an expanded target serum concentration range of 50-125 g/ml, 88% and 92% of patients had postload and steady-state concentrations in the range, respectively.

Figure 2. Percentage of valproic acid (VPA) serum concentrations within the target ranges of 50100 g/ml and 50125 g/ml. Overall, the response rate was good for the treatment of either seizures or migraines. Of the 17 patients treated for seizures, 65% achieved a complete response to therapy, and 56% of the nine patients treated for migraines achieved a complete response to therapy (Figure 3). Patient responses did not seem to be correlated with serum VPA concentrations because mean concentrations were similar across all response categories irrespective of the indication for treatment (Figure 4).

Figure 3. Clinical response rates.

Figure 4. Valproic acid (VPA) serum concentrations versus patients' clinical responses. Of the patients who started the VPA protocol, 85% were converted to an oral VPA regimen. The mean oral dosage was 21.6 8.2 mg/kg/day; the frequency was determined on the basis of the dosage form selected. All patients who were being treated for seizures were converted to an equivalent dose of oral VPA or the nearest dosage form as tolerated (e.g., delayed-release sprinkle capsules, delayed-release tablets). However, patients treated for an acute onset of migraines were converted to an oral VPA dose of approximately 10 15 mg/kg/day or a dose at the discretion of the attending pediatric neurologist. Most patients were able to convert to an oral dosage regimen after receiving the continuous intravenous infusion for only 24 hours. Overall, the intravenous treatment regimen was well tolerated and caused little toxicity. Adverse effects were generally mild with the exception of hyperammonemia, which developed in one patient approximately 3 months after VPA was started. This patient was later found to have an undiagnosed metabolic disorder that may have contributed to the hyperammonemia. During the VPA infusion, one patient had hallucinations, which did not seem to be related to the concentration because the patient's postload and steadystate serum concentrations were 83 and 59 g/ml, respectively. One patient had an episode of confusion during the initial loading dose infusion, and VPA was subsequently discontinued. No patients had nausea or vomiting during administration of the VPA loading dose or continuous infusion. The only patient who did have nausea developed the symptom after taking the first oral dose of VPA. In addition, no patient had elevated hepatic aminotransferase concentrations or thrombocytopenia (platelet count < 200 103/mm3) during their hospital admission. Discussion Intravenous VPA is an attractive anticonvulsant for managing childhood epilepsy for several reasons, including its broad spectrum of activity and its inability to exacerbate syndromes involving generalized spike-wave discharges. In contrast, intravenous phenytoin has the potential to aggravate generalized epilepsy when used as an initial anticonvulsant in children.[18] Intravenous VPA lacks the incompatibilities and hemodynamic instability associated with intravenous phenytoin and does not cause depression of the central nervous system that is commonly associated with phenobarbital.[18] In addition, the availability of many oral formulations, including sprinkle capsules, with excellent oral bioavailability and controlled-release mechanisms as options for maintenance therapy make the use of VPA appealing in children.[1921] The clinical effect of the drug, in addition to its serum concentration, should be taken into account when one assesses VPA pharmacotherapy. The therapeutic range of VPA for epilepsy treatment has historically been reported as 50100 g/ml.[22] However, the studies conducted to determine the therapeutic range were small, uncontrolled, and primarily in the adult population.[1416] In addition, the time of sampling greatly varied from 2 4 hours after dose administration to true trough concentrations obtained immediately before dosing. All of the studies demonstrated large interpatient variability in the concentration response relationships. Nevertheless, keeping serum concentrations in the therapeutic range may help avoid adverse effects and provide pertinent information regarding the concentration- response relationship for an individual patient. In clinical practice, serum concentrations of VPA are routinely monitored, and the target range is often expanded to include high serum concentrations, depending on the patient's response.[23]
Our results demonstrated that the standard protocol for continuous intravenous infusion of VPA efficiently achieved serum concentrations in the upper end of the therapeutic range. This protocol achieved target serum concentrations in both postload and steady-state samples, especially when the target range was expanded to include serum concentrations of 50125 g/ml. Most patients achieved a complete or partial response to therapy. Similar to previous reports, VPA serum concentrations did not seem to be well correlated with the response. [1416] Only four patients had VPA serum concentrations below 50 g/ml. This small sample limited our ability to determine a concentration-response relationship. The finding that more than 80% of patients were successfully converted to oral maintenance therapy after only 24 hours of the intravenous infusion of VPA is important. Use of a standard protocol that can attain VPA serum concentrations in the upper end of the therapeutic range in a short period without adverse effects, specifically gastrointestinal upset, provides an attractive alternative to oral VPA-loading regimens. Using our protocol, we were able to start an adequate maintenance dose of VPA before the patients were discharged from the hospital without requiring lengthy oral titration schedules. Adverse effects were rare and generally mild, with no patient having gastrointestinal upset during the intravenous loading dose or the continuous infusion. Gastrointestinal upset (nausea, vomiting, diarrhea, abdominal pain, and anorexia) is estimated to occur in 20 40% of patients during treatment with the oral divalproex sodium. [1] The occurrence of gastrointestinal upset considerably hinders the use of oral formulations of VPA as an effective means of loading. Similar to our patients, only 1 3% of patients who received intravenous valproate sodium during the initial clinical trials had gastrointestinal upset.[1] Another study similarly demonstrated that a rapid infusion of high loading doses of intravenous VPA could safely be performed without serious adverse events.[24] Our results expand on these findings and indicate that large doses of intravenous VPA are well tolerated in pediatric patients. Although no patients had thrombocytopenia or elevated hepatic aminotransferase concentrations, these adverse effects are not expected to occur immediately after the start of VPA. In addition, aminotransferase levels, platelet counts, ammonia levels, and amylase and lipase levels were not available for all patients in this analysis, which limited our ability to assess these potential adverse effects of VPA. Laboratory values were obtained when clinically warranted, and, as evidenced by how infrequently these values were obtained, continuous-infusion VPA did not seem to present a problem. Nevertheless, further study of this regimen is needed to ensure that it is not more likely than another regimen to be associated with the adverse drug events of thrombocytopenia, elevated hepatic aminotransferase levels, pancreatitis, or hyperammonemia. Limitations of this study included a relatively small sample size and the retrospective arm, which depended on chart documentation. The lack of detailed seizure diaries or other similar documentation prevented precise calculation of changes in seizure frequency during treatment. The lack of free VPA serum concentrations precluded a determination of the free fraction of VPA. Most patients were treated for new-onset seizures or migraines and, therefore, were receiving VPA as monotherapy. As a consequence, these results may not be applicable to patients receiving several anticonvulsant drugs, including enzyme-inducing agents. Because of the induction of hepatic enzymes, these children may require high doses to maintain VPA serum concentrations in the upper end of the therapeutic range. Overall, only four patients had VPA serum concentrations below 50 g/ml at either the postload or the steady-state time points. Although we were unable to show a relationship between VPA serum concentration and clinical response, this may have been the result of a type II error due to the small number of patients who had low VPA serum concentrations. Conclusion Our findings indicated that a standard continuous-infusion VPA protocol was an efficient method of rapidly achieving VPA serum concentrations in the upper region of the therapeutic range while minimizing adverse effects and yielding consistent serum concentrations. A VPA loading dose of approximately 30 mg/kg followed by a continuous intravenous infusion of 1 mg/kg/hour appeared to yield consistent serum concentrations with minimal toxicity in children with seizures or migraines. Further study is necessary to determine if this is indeed the optimal dosing strategy for intravenous VPA in acute clinical situations.
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Reprint Address Robert J. Kuhn, Pharm.D., Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, UK HealthCare, 800 Rose Street, C-113, Lexington, KY 40536-0293; e-mail: . Pharmacotherapy. 2007;27(4):519-525. 2007 Pharmacotherapy Publications Copyright 1999, Pharmacotherapy Publications, Inc., All rights reserved. Preliminary results presented at the meeting of the Pediatric Pharmacy Advocacy Group, Baltimore, Maryland, March 31 April 2, 2006, and as a poster at the Kentucky Society of Health Systems Pharmacists, Louisville, Kentucky, May 19 20, 2006.