Plasma Valproic Acid Concentrations Research Articles

Effect of Time, Injury, Age and Ethanol on Interpatient Variability in Valproic Acid Pharmacokinetics after Traumatic Brain Injury

Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL(u)) is equal to intrinsic or metabolic clearance. The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL(u). In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL(u). Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL(u) was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures. CL and CL(u) were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CL(u) was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CL(u) was significantly longer in patients with head injury plus other injuries compared with those with head injury alone. As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CL(u) (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of anti-inflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.

Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients

Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are common. Case reports suggest an interaction between valproic acid and drug substrates of CYP2C9. The aim of this study was to evaluate the inhibitory effect of valproic acid on CYP2C9 activity by using losartan oxidation as a marker in epilepsy patients. A single oral dose of 25 mg losartan was given to patients (n=11) at the baseline. Losartan and its CYP2C9 derived metabolite E3174 were assayed in 8-hour urine samples by using HPLC. The same procedure was repeated after the first dose and at the completion of the first and fourth weeks of valproic acid treatment. Urinary losartan/E3174 ratio (median, range) did not change significantly at the first day or the first week, while a significant increase was observed at the fourth week of valproic acid treatment (1.09, 0.28–5.71) as compared with the baseline (0.60, 0.10–2.07) (P=0.039). The degree of inhibition was correlated with the steady state plasma concentrations of valproic acid (r2=0.82, P=0.018). These results provide an in vivo evidence that valproic acid is an inhibitor of CYP2C9 at concentrations reached during steady state in human. The risk of pharmacokinetic drug-drug interactions should be considered during concomitant use of valproic acid and CYP2C9 substrates. (Supported by TUBITAK-SBAG COST B25-105S027 and UY/TUBA-GEBIP/2005-17)

Therapeutic Monitoring of Antiepileptic Drugs: A Comparison Between a Czech and a Swedish University Hospital

Plasma concentrations obtained during routine therapeutic monitoring of antiepileptic drugs (AED) (N03A ATC group) were compared in patients treated with one or several AED in the University Hospitals in Ostrava, Czech Republic and Huddinge, Sweden. Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of mean plasma concentrations (PC). The study included 2,824 adult out- and inpatients in Huddinge treated from 1995 to 1999 and 1,268 outpatients treated in Ostrava from 1993 to 2004. PC of valproic acid in Huddinge and all AED except clonazepam in Ostrava were analyzed with gas-liquid chromatography. Plasma concentrations of clonazepam in Ostrava and all AED except valproic acid in Huddinge were analyzed by HPLC. The differences in PC were tested by Student's t-test. Chi(2) method was used for the differences in the distribution of PC relative to the therapeutic window. The mean plasma concentrations generally reached the apparent therapeutic ranges but were below the range in the cases of phenytoin monotherapy in both hospitals, and clonazepam, phenobarbital and phenytoin in polytherapy in Ostrava. In monotherapy 33% of the analyses showed sub-therapeutic concentrations in Huddinge, compared to 38% in Ostrava. Eight percent of the analyses showed potentially toxic concentrations in Huddinge, but only 3% in Ostrava. The highest number of sub-therapeutic concentrations was detected for phenytoin in both hospitals: 59% in Huddinge, 78% in Ostrava. In polytherapy only slight differences between the hospitals were found. PC/dose ratios were significantly lower in polytherapy than in monotherapy for carbamazepine and valproic acid in both hospitals. In contrast a higher PC/dose ratio was found in polytherapy for phenytoin in both cohorts and for lamotrigine in Ostrava. Drug treatment of epilepsy in our two hospitals is surprisingly similar in terms of achieved plasma concentrations, in spite of socioeconomic and cultural differences between our two countries. This may be explained by the long experience with TDM in both hospitals, which has the inherent capacity to promote evidence based drug therapy.

Phase I trial of a sequence-specific combination of the HDAC inhibitor, valproic acid (VPA), and the topoisomerase II inhibitor, epirubicin, in advanced solid tumors: Clinical results and correlative studies

3068 Background: Multiple lines of evidence indicate that histone deacetylase inhibitors (HDACi) potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explored a sequence-specific combination of VPA and epirubicin in solid tumors. A VPA loading dose and 6 oral doses (q12h) were given prior to epirubicin in 3-week cycles. Histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: To date, 42 patients [median age 53 (39–78)] have been treated in 12 cohorts: IV VPA loading (mg/kg)/epirubicin (mg/m2): 15/75, 30/75, 45/75, 60/75, 75/75 and 75/100, oral loading: 75/100, 90/100, 100/100, 120/100, 140/100 and 160/100. Tumor types included: breast (10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (6). Dose-limiting toxicities included somnolence (1) and neutropenia (1). No exacerbation of epirubicin-related toxicities was observed. Objective responses were seen across different tumor types in anthracycline-resistant and -refractory tumors, despite a median number of 3 (0–6) prior regimens: Partial response; 7/37 (19%), stable disease/minor response: 16/37 (43%). Patients received a median number of 4 (1–10) treatment cycles. Study treatment was stopped despite a clinical benefit or response in 4/33 patients after reaching maximal epirubicin doses (≤750 mg/m2). VPA peak and trough plasma concentrations increased linearly up to 120 mg/m2. MTD is being defined at 160/100 mg/kg/d VPA. H3 and H4 histone acetylation and topo II expression have been correlated with VPA dose, plasma concentration and response. Conclusion: A sequence-specific combination of VPA and epirubicin is active without exacerbation of epirubicin toxicity. VPA plasma peak and trough levels exceeding concentrations needed for biological effects and in vitro synergy are easily achievable with minimal toxicity. The noteworthy anti-tumor activity seen in this heavily pretreated Phase I population warrants further exploration. [Table: see text]

Does It Really Matter When a Blood Sample for Valproic Acid Concentration is Taken Following Once-Daily Administration of Divalproex-ER?

Divalproex sodium extended-release (divalproex-ER) is a novel formulation intended for once-daily oral administration, either morning or evening. Questions have risen concerning the optimal time for obtaining a blood sample for valproic acid (VPA) concentration in relation to the dose. Trough sampling is easily achieved just before a morning daily dose, but the best time to sample after an evening daily dose is unclear, because collecting a blood sample 21 to 24 hours later may be limited by the operational hours of the laboratory. This investigation provides practical guidance regarding blood sample timing. Steady-state plasma VPA concentration-time profiles from 5 published divalproex-ER studies (healthy subjects and epilepsy patients) were analyzed. The concentration-time profile for each subject/patient was expressed as a percentage of his/her trough concentration and summary statistics computed. Typically, when taking divalproex-ER once daily in the morning, a blood sample collected 21 to 24 hours later is expected to have a concentration within 3% of the trough value. Conversely, for divalproex-ER dosed once-daily in the evening, for example 8 PM, a blood draw 12 to 15 hours later (ie, 8 to 11 AM) will give a plasma VPA concentration value that is 18% to 25% higher, on average, than the trough value. However, waiting longer, (for example 18 to 21 hours, ie 2 to 5 PM) will result in concentration values that are merely 3% to 13% higher than trough values, which may provide acceptable information for monitoring purposes. The greatest deviation from trough VPA concentration occurs around the peak, that is 3 to 15 hours after a once-daily divalproex-ER dose; sampling during this time period is recommended only if a clinical need exists to test for a higher VPA concentration. Despite the apparent smoothness of the VPA concentration-time profile after a once-daily divalproex-ER dose, the timing of the blood sample does matter and impacts the proper interpretation of the VPA concentration.

Predicted plasma valproic acid concentrations in patients missing and replacing a full daily dose of extended-release divalproex sodium

We have previously reported the predicted plasma valproic acid concentrations in patients missing and replacing a dose of extended-release (ER) divalproex sodium (Depakote ER, Abbott Laboratories), concluding that one missed dose could be replaced up to 12 hours later, and regular daily therapy

Effect of intracerebroventricular continuous infusion of valproic acid versus single i.p. and i.c.v. injections in the amygdala kindling epilepsy model

Two protocols were tested to assess anticonvulsant efficacy and drug concentrations after intracerebroventricular (i.c.v.) continuous valproic acid (VPA) infusion, as compared with acute injections in the kindling epilepsy model. Protocol 1: amygdala-kindled rats were injected via intraperitoneal (i.p.) and i.c.v. routes with varying doses of VPA and tested for seizure intensity, afterdischarge and seizure duration, ataxia and sedation. Concentrations of VPA were determined by immunofluorescence in the brain, plasma, cerebrospinal fluid (CSF) and liver in matching rats. Protocol 2: amygdala-kindled rats were implanted with osmotic minipumps containing a VPA solution in saline and connected to intraventricular catheters for 7 days. Seizure threshold, latency and duration, afterdischarge duration, ataxia and sedation were recorded daily before, during, and until 5 days after VPA infusion. In matching animals, CSF, brain, plasma and liver VPA concentration was determined. Acute i.c.v. VPA injection suppressed seizures with a remarkable ataxia and sedation. However, continuous i.c.v. infusion controlled generalised and even focal seizures without producing important side effects, high plasma levels or hepatic drug concentrations. In conclusion, continuous i.c.v. VPA infusion may protect against kindled seizures by minimising ataxia and sedation, and achieving suitable intracerebral, yet low plasma or hepatic drug concentrations, thus avoiding potential systemic toxicity.

Every-12-hour administration of extended-release divalproex in patients with epilepsy: Impact on plasma valproic acid concentrations

Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma valproic acid (VPA) minimum concentration ( C min) for divalproex-ER q12h was higher than the once-daily divalproex-ER C min ( P = 0.043). Once-daily divalproex-ER C min values were not different from those for divalproex q6h, suggesting that adequate trough steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak–trough fluctuation (DFL, calculated as ( C max − C min)/ C avg) in VPA concentration was less with both q12h (35.2% less) and once-daily (16.9% less) divalproex-ER regimens compared with q6h divalproex ( P ⩽ 0.024). The DFL for divalproex-ER dosed as a q12h regimen was 22% less than that for once-daily divalproex-ER ( P = 0.02). The DFL in VPA concentration with divalproex-ER can be minimized with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.

Interacción farmacocinética entre ácido valproico y meropenem

Several reports have described a decrease in valproic acid (VPA) serum concentrations when carbapenem therapy is administered. The exact mechanism of this pharmacokinetic interaction is unknown, although several experimental studies have been carried out in animals. Because of these interactions, plasma concentrations of VPA in these patients should be monitored and, whenever possible, VPA or carbapenem therapy should be substituted by other drugs. We describe the cases of two epileptic children who simultaneously received meropenem and VPA. Concentrations of VPA decreased to subtherapeutic levels. We review the various mechanisms for this interaction proposed to date, as well as all reported cases.

Valproate‐induced Proximal Renal Tubular Dysfunction: Clinically Relevant in the Severely Disabled Epileptic Population

To the Editor: We read with interest the article by Knorr et al., Fanconi Syndrome Caused by Antiepileptic Therapy with Valproic Acid, Epilepsia 2004;45:868–71, and their observation that this severe proximal renal tubular dysfunction on literature review has occurred almost exclusively in mentally retarded, severely disabled, often wheelchair-bound children. As consultants to several developmental centers, we follow valproic acid (VPA)-treated epilepsy patients with profound mental retardation and other accompanying severe central nervous system disabilities. After observing a septicemic death associated with a reduction in serum albumin to 2.1 g/dl (3.4–5.0 g/dl, normal range) during VPA monotherapy, we systematically monitored these VPA-treated epilepsy patients and not uncommonly observed declining serum albumin levels to well below normal range. Of the first 12 patients (10 women, two men; ages, 16–50 years) so categorized, those supported with enteral nutrition (five of 12) who had weight increase, edema, and reduced serum albumin levels had no change in intake of calories and protein. Pearson correlations did not reveal a relation between the serum albumin levels and the protein intake. Plasma VPA concentrations were found to be within therapeutic range in the entire group, and none had a history of renal or hepatic disease. Serum glutamic oxaloacetic transaminase (SGOT) levels were within normal limits in 10 of 12, but ammonia levels were slightly elevated in seven of 12. The 24-h urine protein levels were found to be elevated, with a range of 115 to 2,850 mg, with a mean serum albumin level of 3.1 g/dl. The blood urea nitrogen (BUN) levels were all within normal limits. On discontinuance of VPA, the serum albumin levels increased to normal range (mean, 3.8 g/dl) within 2 to 3 weeks. We now routinely monitor VPA-treated patients at our developmental centers, discontinuing VPA when serum albumin levels decrease persistently to >2.8–3.0 g/dl, or even slightly higher levels if liver function appears to be problematic as well. Although the full-blown Fanconi syndrome appears rare, in our experience, a significant degree of proximal tubular dysfunction as a result of VPA toxicity with significant reductions in serum albumin is relatively common in this severely disabled epilepsy patient group, both children and adults, and requires systematic attention. Korinthenberg et al. (Renal tubular dysfunction following treatment with anti-epileptic drugs. Eur J Pediatr 1994;153:855–8) documented subclinical VPA (monotherapy)-induced proximal tubular dysfunction in otherwise healthy children with epilepsy. Therefore the superimposed loss of weight-bearing with its multiple endocrine/renal effects in our severely disabled epilepsy patient group could be the predisposing factor producing clinically significant VPA proximal renal tubular toxicity (Regnard et al. Validity of microgravity simulation models on earth. Am J Kidney Dis 2001;38:668–74).

Acute Seizures Due to a Probable Interaction between Valproic Acid and Meropenem

To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

Ｃｈｕｒｇ‐Ｓｔｒａｕｓｓ症候群の末梢神経痛に対してバルプロ酸ナトリウムが著効した症例

There have been few reports on valproic acid (VPA) -mediated pain control in multiple mono-neuropathies accompanied by vasculitis. We present a case of the successful treatment of Churg-Strauss Syndrome (CSS) -induced neuropathic pain with VPA. The patient was a 74 year-old man who was diagnosed with CSS based on the history of bronchial asthma, multiple peripheral neuropathy, eosinophilia, and vasculitis. The degree of neuropathic pain was assessed using the pain score. He had been given prednisolone, diazepam, carbamazepine, naproxen and amitriptyline before treatment with VPA but their analgesic effects were not sufficient. The administration of VPA was started at a dose of 400 mg/day and when the dose was increased to 800 mg/day, there was a marked decrease in Pmax and it stayed at a low level thereafter. The mean area under the daily pain score vs. time curve (AUC) during the treatment with VPA at 800 mg/day was significantly less than that for 600 mg/day. The steady-state plasma concentrations of total and free VPA at a dose of 800 mg/day were 62.1μg/mL and 8.8μg/mL, respectively. Our results indicate that when administered in the therapeutic range for patients with epilepsy, VPA is also effective in the treatment of neuropathic pain induced by CSS.

Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium

Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.

Pharmacokinetics and safety of extended-release divalproex sodium tablets: morning versus evening administration

The pharmacokinetics and safety of 1000-mg extended-release divalproex sodium given once daily either in the morning or evening were compared. Healthy volunteers 19-55 years of age were enrolled in this open-label, parallel-design study. Subjects were randomized to receive extended-release divalproex either in the morning or in the evening. Blood samples were taken immediately before and at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5, and 144 hours after the first dose of each six-day regimen. Plasma samples were assayed for total valproic acid concentrations using gas chromatography. Valproic acid pharmacokinetic values were measured, and the safety of each regimen was evaluated. Mean steady-state valproic acid exposure, maximum concentration, and minimum concentration were 1771 mg x hr/L, 86.9 mg/L, and 55.5 mg/L for the morning dosing and 1728 mg x hr/L, 84.8 mg/L, and 57.4 mg/L for the evening dosing regimens, respectively. Adverse events reported by two or more subjects were abdominal pain and somnolence for the morning dosing regimen and asthenia, headache, and pain for the evening dosing regimen. All adverse events were mild or moderate; none caused subject withdrawal from the study. There were no significant differences in the pharmacokinetic parameters (p > 0.51) and safety between groups. Diurnal variation in plasma valproic acid concentrations was minimal with once-daily administration of extended-release divalproex. Evening once-daily administration of extended-release divalproex was not associated with substantial differences in pharmacokinetics or safety compared with morning once-daily administration.

Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats.

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM, and doripenem [S-4661; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5'-diphosphate D-glucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.

Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid

Valproic acid (2-propylpentanoic acid, VPA), an effective inhibitor of histone deacetylases (HDAC) is used for the treatment of epilepsia. In this study, structure–activity relationships for the action of structurally modified VPA derivatives on human cytomegalovirus (HCMV) replication and HDAC inhibition were defined. Pretreatment of human foreskin fibroblasts with VPA (0.125–1 mM) caused a concentration-dependent increase of HCMV immediate early and antigen late antigen expression. Structure–activity relationships of VPA derivatives for HCMV stimulation were compared to those for teratogenic action and those for HDAC inhibition. Side chain elongation and introduction of a triple bond in 4-position of the other chain caused teratogenicity, stimulated HCMV replication, and increased HDAC inhibition, as demonstrated by enhanced levels of acetylated histones. Teratogenic VPA derivatives with a branched chain in 3-position as well as a non-teratogenic anticonvulsive active VPA derivative did not stimulate HCMV or accumulation of acetylated histones. This demonstrates a strict correlation between inhibition of HDAC and increased HCMV replication.

Divalproex-ER pharmacokinetics in older children and adolescents

Valproic acid pharmacokinetic profile and tolerability after administration of divalproex sodium extended-release tablets was characterized in older children and adolescents. In this multiple-dose, open-label, pharmacokinetic study, the patients were divided into two age groups, 8-11 years (older children; n = 15) and 12-17 years (adolescents; n = 14). Once-daily administration of divalproex sodium extended-release tablets (doses ranged from 250 to 1750 mg) in older children and adolescents produced relatively flat plasma valproic acid concentration-time profiles over the entire 24-hour dosing interval, similar to the pharmacokinetic performance of this formulation in adults. The mean (standard deviation) oral clearance values for unbound valproic acid were 94.3 (51.8) and 82.3 (28.2) mL/h/kg and for total valproic acid were 11.2 (3.77) and 9.06 (2.03) mL/h/kg in older children and adolescents, respectively. Two patients discontinued for administrative reasons, whereas one discontinued for an adverse event (flulike syndrome). Adverse events reported by three or more patients were flu syndrome (5 patients, 17.2%) and headache (3 patients, 10.3%). Reported adverse events were generally mild to moderate in severity and similar to those reported in previous divalproex studies. This study demonstrates that in older children and adolescents, once-daily administration of divalproex sodium extended-release tablets may potentially be used to sustain plasma valproic acid concentrations within the usually accepted therapeutic ranges for various indications.

Divalproex-ER pharmacokinetics in older children and adolescents

Valproic acid pharmacokinetic profile and tolerability after administration of divalproex sodium extended-release tablets was characterized in older children and adolescents. In this multiple-dose, open-label, pharmacokinetic study, the patients were divided into two age groups, 8-11 years (older children; n = 15) and 12-17 years (adolescents; n = 14). Once-daily administration of divalproex sodium extended-release tablets (doses ranged from 250 to 1750 mg) in older children and adolescents produced relatively flat plasma valproic acid concentration-time profiles over the entire 24-hour dosing interval, similar to the pharmacokinetic performance of this formulation in adults. The mean (standard deviation) oral clearance values for unbound valproic acid were 94.3 (51.8) and 82.3 (28.2) mL/h/kg and for total valproic acid were 11.2 (3.77) and 9.06 (2.03) mL/h/kg in older children and adolescents, respectively. Two patients discontinued for administrative reasons, whereas one discontinued for an adverse event (flulike syndrome). Adverse events reported by three or more patients were flu syndrome (5 patients, 17.2%) and headache (3 patients, 10.3%). Reported adverse events were generally mild to moderate in severity and similar to those reported in previous divalproex studies. This study demonstrates that in older children and adolescents, once-daily administration of divalproex sodium extended-release tablets may potentially be used to sustain plasma valproic acid concentrations within the usually accepted therapeutic ranges for various indications.

Population pharmacokinetics (P?PK) of valproic acid (VPA) following rapid infusion in epilepsy patients

Purpose Characterize VPA PopPK following rapid infusion. Methods: Epilepsy patients (N=112), with or without enzyme inducing comedications, were randomized to either 3.0 or 1.5 mg/kg/min 5-min VPA infusions. VPA plasma albumin binding was examined using 1 & 2 binding-site models. PopPK analysis of total & free plasma VPA concentrations (up to 6 h post-infusion) was performed using NONMEM. Effect of enzyme-induction on clearance (CL) and cholesterol, creatinine, age & inductions status on primary protein binding (PB) constant (K1) was examined using the chi-square test. Results: One & 2-comparment models optimally characterized total & free VPA concentrations, respectively. Estimated parameters±SE for uninduced subjects were: totalCL=1.21±0.0854 L/h, totalV=12.3±0.373 L, freeCL=18.4±8.17 L/h, freeV1=2.09±2.43 L, freeQ=63.7±61.7 L/h, & freeV2=65.8±25.7 L. Enzyme-induction was a significant covariate; totalCL & freeCL increased by 61 & 24%. VPA PB was nonlinear; 2-site PB model parameters±SE, viz., N1, K1, N2, & K2, were 1.54±0.108, 11.9±1.99 (1/mM), 0.194±0.0783, and 164±141 (1/mM). No significant covariates were identified for VPA PB. Inter-subject variabilities in totalCL, freeCL, & K1 were 45, 75 & 30%. Conclusions: These PopPK models accounting for induction status and albumin levels may be used to predict VPA concentrations. Accounting for other factors such as health status and genetics may reduce some of the unexplained variability and improve model predictability. Clinical Pharmacology & Therapeutics (2004) 75, P31–P31; doi: 10.1016/j.clpt.2003.11.116

What Is the Best Strategy for Converting from Twice-Daily Divalproex to a Once-Daily Divalproex ER Regimen?

To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L). Four distinct 12-hourly (q12h) divalproex to once-daily divalproex ER conversion strategies were explored: immediate, delayed, stepwise and mixed conversion. These strategies were each used in simulations for hypothetical adult patients being treated under different conditions: monotherapy (uninduced, at 1500 mg/day divalproex ER) and polytherapy on enzyme-inducing co-medications (induced, at 3000 and 4500 mg/day divalproex ER). The proportion of uninduced patients expected to have minimum VPA concentrations (C(min)) >50 mg/L was 90% for immediate, 83% for stepwise and 82% for mixed-conversion strategies; only 52% undergoing a delayed-conversion strategy had C(min) >50 mg/L. More importantly, 33% of induced patients under-going delayed conversion to 3000 mg/day divalproex ER maintained an adequate VPA C(min). Maximum VPA concentrations (C(max)) attained after conversion to divalproex ER are unlikely to rise beyond the steady-state C(max) observed with divalproex q12h regimens with any conversion strategy tested in uninduced or induced patients. Marked perturbation in VPA concentration is not likely when converting to once-daily divalproex ER 'all-at-once' 12 hours after the last divalproex q12h dose. Stepwise and mixed-conversion strategies do not offer any advantage; delayed conversion may produce a large drop in VPA concentration. An ideal conversion strategy for q12h divalproex to once-daily divalproex ER appears to be an immediate conversion 12 hours after the last divalproex q12h dose; it causes the least perturbation in plasma VPA, even for patients required to take high divalproex ER doses.