Unbound Valproic Acid Research Articles

Physiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.

Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia. A PBPK model was first developed and evaluated in adults using PK-Sim® and MoBi® (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels. The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (fu) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure. The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.

Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy

To characterize protein binding in patients with epilepsy who achieve transient high (>150 mg/L) total plasma concentrations following rapid valproate infusion at very high doses. Patients with epilepsy (n = 40) were administered 20 or 30 mg/kg loading doses (6 or 10 mg/kg/min) of undiluted valproate sodium injection. Total and unbound valproic acid (VPA) concentrations were used to assess VPA binding to plasma albumin. One- and two-binding site models were explored in a nonlinear mixed effects population analysis framework. The relative importance of weight, age, sex, race and enzyme-inducing comedications on the binding site association constant (K) was examined using the likelihood ratio test. Intersubject and intrasubject variabilities were characterized using exponential or proportional error models. Optimal characterization of the data was achieved using the one-binding site model. Population binding parameter estimates (standard error) for number of binding sites (N) and K were 1.98 (0.0865) and 15.5 [2.28 (1/mM)], respectively. No significant covariates were identified for VPA protein binding. The intersubject and intrasubject coefficients of variation were 32% and 14%, respectively. A one-binding site model without any significant covariates for binding constants optimally described VPA protein binding. As the estimated dissociation constant (1/K, 64.5 microm or 9.3 mg/L) was within the therapeutic range (5-15 mg/L) for unbound VPA concentrations, protein binding was nonlinear. Although the range of unbound fraction and VPA concentrations were much higher than previous studies, the dissociation constant was consistent with historical data in normal healthy adults and epilepsy patients receiving lower doses.

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.

Pharmacokinetic Parameters of Total and Unbound Valproic Acid and Their Relationships to Seizure Control in Epileptic Children

The aims of this study were to define the relationship between total and unbound valproic acid (VPA) concentrations, to compare pharmacokinetic parameters of total and unbound VPA, and to determine the difference in pharmacokinetic parameters between the seizure-controlled and -uncontrolled groups. Total and unbound steady-state serum concentration of VPA were determined at trough and at 5 hours after the morning dose from 29 pediatric patients with epilepsy who were receiving valproic acid as monotherapy every 8 or 12 hours. Pharmacokinetic parameters were calculated and compared by t test (alpha=0.05). A strong relationship between total and unbound concentrations was found. The equation for predicting unbound concentration from total concentration was unbound concentration=-6.01+0.18 * total concentration (r=0.78, P<0.001). A higher percentage of free fraction was found at higher concentrations. There were significant differences between total and unbound VPA pharmacokinetic parameters. Both the elimination rate constant (Ke) and volume of distribution (Vd) of the unbound VPA were much higher than those of the total VPA; clearance (CI) was approximately 10-fold higher. The seizure-uncontrolled group could eliminate VPA much faster than the seizure-controlled group, as indicated by a much higher Ke and a much shorter t1/2 (P<0.05). Vd of the unbound VPA was also much smaller in the seizure-uncontrolled group (P<0.05). There were significant differences in pharmacokinetic parameters between seizure- controlled and -uncontrolled pediatric epileptic patients. Further study with a larger sample size is strongly recommended.

Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein binding.

Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6-7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature.

Pharmacokinetics of total and free valproic acid during monotherapy in infants

The pharmacokinetics of free and total valproic acid (VPA) in plasma and whole blood after oral administration during steady state was investigated in seven infants (mean age 10.7 months) receiving monotherapy. The VPA concentrations in whole blood closely followed those in plasma but at a reduced level. A positive correlation was found between dose and mean plasma concentration (r = 0.71). Mean terminal half-lives were similar in plasma and whole blood (12.5 and 15.5 h, respectively), but were considerably longer than for free VPA (6.4 and 6.5 h, respectively; P less than 0.01). There was a significant decrease in half-lives with increasing age (P less than 0.05). Plasma and whole blood clearance for total VPA was higher than reported in older infants and adults (17.8 and 28.9 ml/kg per hour) and was considerably higher for free VPA (127.6 and 188.8 ml/kg per hour, respectively). The increase in clearance compared with that in older subjects is well in concordance with a lower protein binding of VPA (mean 85.3%). Of special importance is that the percentage of unbound VPA increased with increasing concentrations of total VPA. The fraction of unbound VPA in plasma increased even more in subjects with low albumin concentrations (P less than 0.01).

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.

健常成人におけるバルプロ酸反復投与時の体内動態

200mg of valproic acid (VPA) was orally administered to 7 healthy adults at 9 a.m. and 9 p.m. for 5 days. On the 6th day, blood samples were collected at 0, 10, 20, 30, 45, 60, 90, 180 and 360 min and the obtained 63 sera were prepared for analysis. There was a significant relationship between VPA dose and total VPA concentration in the serum, the regression curve was y=0.330x2+22.051 (r=0.469, p<0.001). After the last dose, maximum change of total VPA concentration reached at 60 min and the value was 84.0±29.9%(mean±S.D. n=7). Maximum change of unbound VPA fraction reached at 90 min and the value was 26.6±33.2%(mean±S.D. n=7).At 360 min, the coefficient of variation of total VPA concentration change was 30.7% and that of unbound VPA fraction change was 191.5%. Protein binding of VPA showed a tendency to depend on its total concentration in the serum.

Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease.

1 Based on the Scatchard plot of the binding data of valproic acid (VPA) it is concluded that the drug is bound by two groups of binding sites with the association constants K1=40.0 X 10(-3) and K2=0.39 X 10(3), and the number of binding sites n1=1.5 and n2=6.8. 2 The binding is dependent on dialysis time, on temperature, on the drug concentration, and on the protein concentration in plasma. 3 At therapeutic plasma concentrations unbound VPA is 8.4 +/- 2.5%, but is increased to 20.3 +/- 4.7% in patients with significant impairment of renal function (P less than 0.001). 4 In patients with renal disease a good correlation is found between unbound VPA and serum creatinine, creatinine clearance, blood nitrogen and uric acid, respectively. A poor correlation is seen between unbound VPA and total protein or albumin concentration in plasma.