Valproic Clearance Research Articles

Population Pharmacokinetics of Valproate in Children: The Importance of Total Daily Dose, Compliance and Co-Treatment

Abstract Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002DD. When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002DD×1.2CBZ. Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.

Pharmacokinetics of Valproate and Lamotrigine Combined Therapy in Pregnancy and its Effect on the Newborn – A Case Report

In a previous paper we found that birth length and weight were inversely related to maternal and umbilical cord levels of valproate (VPA), but not to dose. In a case report we tried to determine, whether it is possible to use this data for prediction of fetal plasma concentrations during pregnancy. A 30-year-old woman (59 kg prior to pregnancy) was treated by a combined therapy of VPA (Orfiril long®, 800 mg/day) and lamotrigine (Lamictal®, 200mg/day) for pseudoabsences. Plasma levels of both drugs were measured at steady-state before, during and after pregnancy and also during the delivery. Levels of VPA were measured by gas chromatography and levels of lamotrigine (LTG) by high performance liquid chromatography. Apparent oral clearance (Cl) was calculated for both drugs: daily dose (mg/kg)/serum concentration (mg/L). Drug levels before the pregnancy were 67.9 mg/L for VPA and 15.2 mg/L for LTG. By the time of delivery both levels have decreased to 32.2 mg/L for VPA and 6 mg/L for LTG in maternal serum. Values measured in umbilical cord were 41.6 mg/L (129% of maternal value) for VPA and 5.9 mg/L for LTG (100% of maternal value). Apparent oral clearance of VPA was increased by 171% (from 0.2 L/24 h to 0.54 L/24 h) and of LTG by 143% (from 0.22 L/24 h to 0.54 L/24 h) at the end of 3rd trimester. The birth length was 43 cm and weight 2.15 kg. The low total values of LTG clearance can be attributed to interaction with VPA. The difference between maternal levels and the levels in umbilical cord can be used for prediction of VPA fetal levels during the 1st trimester = 81 mg/L, which is possibly teratogenic and could explain the low birth length.

The Impact of Dosage of Sustained-Release Formulation on Valproate Clearance and Plasma Concentration in Psychiatric Patients

Pharmacokinetic parameters were compared between 2 dosages of valproic acid (VPA) sustained-release (SR) formulation in psychiatric patients. A total of 66 psychiatric patients (21 women and 45 men; age range, 18-60 years) receiving 500 mg/d (n = 28) or 1000 mg/d (n = 38) of VPA SR for at least 4 weeks were recruited into the study. A 5-mL blood sample was collected into a plain tube and immediately centrifuged for plasma. Separation of free VPA was further done using Centrifree micropartition devices. Both total and free VPA concentrations (C(total) and C(free)) were analyzed by TDx analyzer with fluorescence polarization immunoassay technique. The patients' characteristics and pharmacokinetic parameters were compared between the 2 dosage groups using independent t test or χ² test where appropriate. The results show that the increment in C(total) (mg/mL) for every milligram-per-kilogram increment in dosage was decreased from 7 ± 3 to 4 ± 1 (mg/L) / (mg/kg) when the total VPA clearance (CL(total)) increased from 6.1 ± 2.6 to 9.0 ± 3.1 mL/kg per hour with the increasing dose in the 500 mg/d and 1000 mg/d groups, respectively (P < 0.05). The increment in C(free) [0.6 ± 0.3 vs 0.5 ± 0.2 (mg/L) / (mg/kg)] and CL(free) (80.4 ± 41.5 vs 92.2 ± 47.6 ml/kg per hour) were not significantly different. Owing to the saturation of protein binding, percent free VPA was significantly increased from 8 ± 3 to 11 ± 3 when the dose was increased from 500 to 1000 mg/d (P < 0.05). In conclusion, an increase in the VPA dose resulted in a disproportional increase between dosage and C(total), whereas a proportional increase between dosage and C(free) still existed. Therefore, our study suggests that the therapeutic range of C(free) is 4 to 12 mg/L based on the therapeutic range of C(total) (45-100 mg/L) for general psychiatric conditions.

Factors influencing valproate pharmacokinetics in children and adults

The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh-1 and +0.539 lh-1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.

Pharmacokinetic modelling of valproate in epileptic patients

The aim of our study was to develop and use a population pharmacokinetic model for assessment of individual valproate clearance in children and young adults suffering from epilepsy. The analysis was performed using 52 steady-state concentrations of valproate collected from 26 epileptic patients during the routine clinical practice in our hospital. The mean values of age and total body weight were 19.92 years and 57.12 kg, respectively. NONMEM software with ADVAN 1 subroutine was used for model building and assessing the influence of different covariates. A validation set of 20 epileptic patients (one blood sample per a patient) was used to estimate predicted performances of the pharmacokinetic model. The typical mean value of the clearance of valproate estimated by the base model in our population was 0.3 77 I/h. Out of five considered covariates (total body weight, age, total daily dose, gender and polytherapy) only the age of the patients was a significant determinant of the clearance of valproate. The final regression model for the clearance of valproate was as following: CL (l/h) = 0.223 + 0.00819 * AGE CONCLUSION: The derived pharmacokinetical model describes the clearance of valproate in relation to patient's age in the observed population. it will help to improve the seizure control in young patients with epilepsy in Serbian population.

Population pharmacokinetics of valproate in Mexican children with epilepsy

The aim of this study was to determine the factors that influence valproate clearance (CL) in Mexican epileptic pediatric patients using a mixed-effect model and sparse data of serum concentrations of valproic acid (VPA) collected during routine clinical care of patients. The number of patients included in the study was 110. The population CL was calculated by using the NONMEM program. The following covariates were tested by their influence on CL: total body weight (TBW), height, age, body surface area, daily dose (DD), sex of the patient and comedication with phenobarbital (PB) or carbamazepine. The final regression model for valproic CL found best to describe the data was: CL/F=(0.0466+0.00363 TBW+0.000282 DD)*(1+0.236 PB). This model allows a reduction of 50% of the interindividual variability and of 31% of the residual variability described by the basic model that does not include covariables. Total body weight, daily dose of valproate and concomitant therapy with PB are factors that significantly influence VPA kinetic disposition and they should be considered in programming dosage regimens for this antiepileptic drug in the pediatric population. The validation of the model supports its acceptability for clinical purposes.

Pharmacokinetic modelling of valproate from clinical data in Serbian epileptic patients

The aim of this study was to define a population pharmacokinetic model that could estimate the clearance of valproate (VPA) in a Serbian epileptic population. For the analysis, 97 steady-state concentrations of VPA were used, collected from 93 patients with epilepsy during routine clinical care in our hospital. To build a final model, we selected the ADVAN1 program subroutine from the NONMEM library for estimating the drug clearance (CL) and determining the influence of different covariates. This is a one-compartment model with first-order elimination and without absorption. Estimation of the predictive performances of the final model was performed on a validation set consisting of 20 epileptic patients. Typical mean value of CL of VPA estimated by the base model in our population was 0.368 l h(-1). The results of the final model show that the CL of VPA increased linearly with total body weight (TBW) and patients' age, while carbamazepine (CBZ) comedication did not affect it significantly. Interindividual variability (coefficient of variation) for CL was 27.2%. Residual error, including intraindividual variability, was 29.68%. The results of the validation process and the analysis of prediction errors suggest a good predictive performance of the final population model. The defined model describes CL of VPA in terms of specific Serbian patient characteristics, using serum concentration data obtained from routine therapeutic drug monitoring.

Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly.

Valproate exhibits a complex pharmacokinetic profile due to concentration-dependent protein binding and clearance. It has been shown that the protein binding of valproate decreases as the serum concentration increases in a young adult population. Furthermore, the percentage of protein binding is lower in the elderly compared with young adults at comparable low therapeutic serum concentrations. The extent of valproate protein binding at higher concentrations in the elderly has not been described. Studies conducted in the elderly have found unbound valproate clearance to be decreased compared with younger adults, although these changes in clearance have not been evaluated at higher therapeutic serum concentrations. We evaluated the pharmacokinetics of valproate (protein binding and clearance) across a wide dosage range in the elderly and measured the impact of this on drug-related side effects using a single-blind within-subject study design in 6 healthy elderly volunteers (aged 65-76 years). Steady-state total and unbound serum valproate concentrations were assessed at 3 doses: 500, 1000, and 1500 mg/d. As doses and valproate serum concentrations increased, the unbound fraction (10.0%, 13.0%, 17.4%) and total clearance (4.8, 6.0, 6.7 mL/h/kg) increased, respectively. Unbound clearance decreased (49.4, 45.8, 39.4 mL/h/kg) with increasing valproate serum concentrations. Drug-induced CNS effects and nausea severity scores correlated with total and unbound serum valproate concentrations. Significant dose-dependent changes in valproate pharmacokinetics were observed in the elderly.

Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits.

We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits. Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM. The plamsa total clearance of VPA was significantly increased to about 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P < 0.05). The values of the area under the plasma concentration-time curve (AUC) of 2-en-VPA, a product of beta-oxidation, and VPA-glucuronide (VPA-G) were significantly decreased to about 55% and 78% of the control, respectively (P < 0.05). The cumulative urinary excretions of VPA in the control and MEPM-treated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P < 0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchanged by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control. The increase of the total clearance of VPA caused by MEPM appears to be a consequence of increased renal clearance of VPA-G, as well as suppression of VPA-G hydrolysis in the liver.

Potential Pharmacokinetic Interaction between Felbamate and Phenobarbital

To report a case of a potential pharmacokinetic interaction between felbamate and phenobarbital in a patient with epilepsy. A patient with a history of a mixed seizure disorder and static encephalopathy who was receiving sodium valproate 750 mg/d and phenobarbital 230 mg/d was initiated on felbamate (as part of a compassionate use program). Upon instituting felbamate, valproate dosage was reduced to 500 mg/d and phenobarbital to 200 mg/d. Felbamate dosage was titrated to approximately 50 mg/kg/d over three weeks. In this patient, plasma phenobarbital concentrations increased from 48 micrograms/mL to 68 micrograms/mL, at which point the patient was hospitalized because of clinically significant neurotoxicity. Phenobarbital dosage was subsequently reduced to 150 mg/d; this resulted in phenobarbital trough concentrations of 60 micrograms/mL. Felbamate has been shown previously to interact with multiple other anticonvulsant medications, including valproate, phenytoin, and carbamazepine. Felbamate appears to decrease the clearance of valproate, phenytoin, and carbamazepine epoxide to a significant extent, an effect that may be the result of inhibition of the metabolism of these compounds. Carbamazepine plasma concentrations have been demonstrated to decrease following administration of felbamate, suggesting metabolic induction. It is reasonable to suggest that based on these findings and the observations in our patient, felbamate comedication may result in clinically significant increases in plasma phenobarbital concentrations. It would seem prudent, therefore, when initiating or adjusting felbamate therapy in patients receiving this drug combination, to monitor phenobarbital plasma concentrations.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple stepwise linear regression. Children who were receiving enzyme-inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme-inducing antiepileptic drugs.

Influence of co-medication on the metabolism of valproate.

Valproate is extensively metabolized in the liver and at least six main pathways which produce about 50 metabolites have been identified in man. The enzyme-inducing antiepileptic drugs phenobarbital, primidone, phenytoin and carbamazepine increase total valproate clearance by 30-85%, whereas cimetidine and the new anticonvulsant compound striripentol display a small inhibitory effect (10-20%). Both carbamazepine and phenytoin induce a two-fold increase in the formation of delta 4-valproate and stimulate omega-oxidation and omega-1-oxidation. Acetylsalicylic acid causes a fall of 60-70% in the content in the urine of the metabolites of the beta-oxidative pathway, i.e. delta 2-valproate, 3-OH-valproate and 3-oxo-valproate, and an increase of glucuronidation (approximately 30%) and delta-dehydrogenation (approximately 20%). Stiripentol inhibits the formation clearance of delta 4-valproate by 30%. In the light of the possible therapeutic and toxic effects of some valproate metabolites, drug interactions with valproate at metabolic level may have important clinical implications.

β‐Oxidation of Valproate

The effects of glucose infusion, fasting, and clofibrate pretreatment on valproate (VPA) disposition were investigated in rats to determine the role of endogenous fatty acid beta-oxidation in the metabolic formation of 2-en-VPA. Rats undergoing each treatment received a continuous steady-state infusion of VPA and a single intravenous (i.v.) bolus of 2-en-VPA. Elimination clearance of VPA was significantly higher (median 31%, p = 0.002) with glucose infusion as compared with fasting but was unchanged by clofibrate pretreatment as compared with control. Formation clearance of 2-en-VPA was significantly higher with glucose infusion as compared with fasting (median 147%, p = 0.001) and with clofibrate pretreatment as compared with control (median 73%, p = 0.041). Fractional metabolism of VPA by this route averaged 6% in fasted and control rats and 10% in glucose-infused and clofibrate-pretreated rats. Thus, VPA elimination clearance was not greatly influenced by effects on this route in rats. Elimination clearance of 2-en-VPA was also higher with glucose infusion as compared with fasting (median 149%, p = 0.002), and with clofibrate pretreatment as compared with control (median 167%, p less than 0.001). These observations are consistent with glucose-sparing release of endogenous fatty acids (FAs) to compete with VPA for beta-oxidation, and increased beta-oxidative activity after clofibrate treatment. The results of this study provide strong in vivo evidence for involvement of beta-oxidation in metabolism of VPA.

Variability in Level‐Dose Ratio of Valproate: Monotherapy Versus Polytherapy

One of the most useful pharmacokinetic parameters of a drug is the level‐dose ratio. This ratio originates from a relationship between the dosing rate (i.e., the daily dose) and the corresponding steady‐state plasma level. For most drugs that relationship is linear, indicating that changes in doses are associated with proportional changes in plasma levels. This proportionality between plasma level and dose is an expression of the fact that the clearance of the drug is constant. Valproic acid has been available in a number of countries for over a decade, and in spite of the large number of pharmacokinetic studies available in the literature, it is not possible, at the present time, to define a characteristic level‐dose ratio. This situation is a result of the fact that the clearance of valproate exhibits large interpatient variability. This article presents an analysis of the causes for the variability in valproate clearance. It is shown that when the determinants of valproate clearance are understood and taken into consideration, only a few factors are found to have a profound influence on it. Most important among these are age and polytherapy.

Effect of increased bile flow and bile acid secretion on the hepatic elimination of sodium valproate in the cat.

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.15 mol/l NaCl. Less than 1% of the drug administered to controls appeared as unchanged valproate in the bile over 6 h. Although SC-2644, T12K, and secretin significantly increased biliary excretion of valproate, it did not exceed 2% of the intravenous dose. Biliary clearance was directly related to the rate of bile flow, but not to the bile acid flux. By contrast, 18-19% of the dose appeared in bile as metabolite in controls, and none of the choleretic agents significantly increased this percentage. As a result, systemic clearance of valproate was unaltered. We conclude that the movement of unchanged valproate into bile is consistent with a process of simple diffusion. The fact that choleretic agents do not increase metabolite excretion into bile suggests that metabolite formation may be the rate-limiting step in the hepatic elimination of valproate, rather than transport and excretion of metabolites into bile.

The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children

The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children

Plasma Protein Binding Interaction Between Valproic and Salicylic Acids in Rhesus Monkeys

The effects of three levels of salicylic acid on the steady-state plasma concentrations of free and total valproic acid were examined in catheterized rhesus monkeys. Valproate was infused intravenously for a total of 41 hr, and salicylate was added after the first 8 hr. The three salicylate infusions were randomly assigned to each monkey. Valproate free fraction was determined by equilibrium dialysis. Statistically significant increases in valproate free fraction and total body clearance were observed after addition of salicylic acid. The increase in valproate clearance was positively correlated with the molar ratio of salicylate to valproate steady-state plasma concentrations. There was no significant change in valproate free concentration after salicylate treatment. The proposed mechanism of this in vivo interaction includes plasma protein binding displacement with no change in valproate intrinsic clearance.

Linear Relationship between Plasma Concentration and Dosage of Sodium Valproate

Plasma valproate concentration was studied in 7 hospitalized nonepileptic patients who received sodium valproate at daily doses of up to 60 mg/kg. A linear relationship between dose and plasma concentration of valproate (r = 0.81--0.99) was found in each patient, although the slopes of the regression lines (reflecting clearance rates) varied twofold. This suggests that if the valproate plasma concentrations at two different doses are known and the clearance of valproate is not altered by concomitant administration of other drugs, it should be possible to predict the plasma valproate concentration that will result from further dose increments.

Pharmacokinetics and bioavailability of sodium valproate

The pharmacokinetics of the antiepileptic drug, sodium valproate (VPA), was investigated in 6 healthy volunteers after a single intravenous dose of 400 mg, as well as a solution and enteric‐coated tablets. The bioavailability of the enteric‐coated tablets was compared with that of normal tablets in 3 of these subjects. The bioavailability studies demonstrated that the solution was rapidly and almost completely (86% to 100%) absorbed. Peak plasma levels (66 to 196 µg/ml) were reached within 0.5 to 2 hr. Tablets had comparable bioavailabilities which varied in the different persons (68% to 100%). In some subjects VPA was found in plasma only after a lag time of 1 to 4 hr and the peak plasma concentrations of 46 to 88 µg/ml developed after 3 to 7 hr. After the intravenous dose, plasma levels declined biexponentially. The pharmacokinetic parameters were computed according to the two‐compartment open model. The half‐life of the initial phase, t½(α), could be calculated to 1.0 ± 0.86 hr (mean ± SD) and the terminal half‐life, t½(β), varied independently of the route of administration between 8.7 and 21.5 hr (12.2 ± 3.7 hr). The distribution space of the central compartment (V1) was 0.065 ± 0.010 Llkg, and both the apparent volume of distribution at steady‐state (VdSS) and Vdβ had similar values of 0.13 ± 0.04 L/kg and 0.14 ± 0.05 L/kg, respectively. These small volumes indicate that VPA distributes mainly into the extracellular space. The total plasma or blood clearance (Cl) ranged from 4.3 to 10.5 ml/min (7.8 ± 2.4 ml!min) and from 11.9 to 44.3 ml/min (30.1 ± 11.9), respectively. Therapeutic concentrations of VPA (80 µg/ml) revealed relatively strong plasma protein binding between 80% and 94%. The bloodlplasma concentration ratio ranged about 0.28 ± 0.06. Since the calculated hepatic extraction ratio of 0.02 is smaller than the free fraction, it is concluded that clearance of VPA is independent of liver blood flow and of the restrictive type. No measurable amounts of unchanged VPA were excreted during the 2 days of observation. Approximately 10% to 30% of a single dose was eliminated as VPA conjugates which could be hydrolyzed by 2 N HCl and β‐glucuronidase/aryl‐sulfatase.