Valproate/valproic acid dosing

However, there is one report of a possible decrease in valproate levels in a 30-year-old man after starting lopinavir/ritonavir. This patient, who had been taking valproic acid 375 mg daily as divalproex sodium for 7 months after an episode of mania, had a subtherapeutic valproic acid level of 197 micromol/L, and the dose was increased to 250 mg three times daily. After 25 days his trough valproic acid level was 495 micromol/L, and an antiretroviral regimen of lamivudine, zidovudine, lopinavir/ritonavir was started, and paroxetine for depression. Four days later he was hy-pomanic and the paroxetine was replaced with sertraline, which the patient discontinued. Twenty-one days later he had become increasingly manic, and the valproic acid level was found to be 238 micromol/L, about 50% lower than the previous level. An increase in valproic acid dose to 1.5 g daily was eventually required to achieve a therapeutic level of 392 micromol/L. 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Sodium valproate is converted to valproic acid in the intestine and the acid is absorbed. Absorption may be delayed by food or by enteric-coated tablets. Valproic acid has a low volume of distribution and high plasma protein binding. In the elderly there is a risk for increased free valproic acid concentrations requiring lower doses and plasma concentrations at the lower therapeutic range. However it should be realized that these plasma concentrations do not correlate very well with the therapeutic or toxic effects and careful observation for symptoms is mandatory. 

Increase dose by 10%-20% when converting from valproate, divalproex, or valproic acid to tiie extended-release (ER) formulation of divalproex sodium. 

Catatonia occurred in a 42-year-old woman taking valproic acid, sertraline, and risperidone (79). The catatonic features evolved for the first time after a single dose of valproate and were alleviated by lorazepam the same catatonic signs recurred after a second dose of valproate and again remitted after lorazepam. 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

Each simulation included 100 hypothetical subjects. The model parameters used were derived from an adult population and there were no covariate distribution models for the virtual trial population. Subjects were assumed to be healthy and on valproate monotherapy (31). The simulations assumed that the extended release (ER) formulation was administered once daily and the delayed release (DR) preparation was administered twice daily. Unbound and total valproic acid concentrations were simulated from the time of dose administration to 280 h and the simulations were based on the administration of 1000 mg ER once daily, 500 mg DR twice daily, 2500 mg ER once daily, and 1000 mg DR twice daily. For once-daily regimens, simulation scenarios included doses taken 6, 12, 18, and 24h late from schedule and then two doses taken 24h late (replacement dose for the missed dose). For the twice-daily regimens, doses were simulated 3,6,9, and 12 h later than the scheduled times and then two doses were simulated 12 h later than scheduled to mimic replacement dosing for a missed dose. More extreme cases where two doses are delayed at various times or missed were also simulated. 

Recommended baseline and routine laboratory tests for valproate are listed in Table 68-12. Data from clinical trials in acutely manic patients indicated that there was an earlier response when trough serum levels were greater than 45 mcg/mL during the Hrst week of treatment. Although therapeutic serum concentrations of valproic acid have not been established in bipolar disorder, most clinicians use the anticonvulsant therapeutic range of 50 to 125 mcg/mL taken 12 hours after the last dose. Patients with cyclothymia or mild bipolar II disorder may have a therapeutic response to lower doses and blood levels, whereas some patients with a more severe form of bipolar disorder may require up to 150 mcg/mL. Serum valproic acid levels are usually determined every 1 to 2 weeks during the first 2 months, and then every 3 to 6 months during maintenance therapy. ... 

An isolated case describes a patient who had an increase in her INR the day after starting valproic acid, but was eventually restabilised on the original dose of warfarin while still taking the valproic acid. Valproic acid did not alter the anticoagulant effects of phenprocoumon in one patient. Valproate alone can cause altered bleeding time, bruising, haematoma, epistaxis and haemorrhage. 

A single 250-mg dose of valproic acid was given to 6 healthy subjects either alone, at the same time as colestyramine 4 g twice daily, or with the colestyramine taken 3 hours after the valproic acid. The bioavailability of valproate taken alone and when separated from the colestyramine by 3 hours remained the same. When the valproate was taken at the same time as the colestyramine the valproate AUC fell by 15% and the maximum serum levels fell by 21%. ... 

A report describes two patients whose valproate levels fell when meropenem and amikacin were given. The first patient had heen maintained on intravenous valproate 1.2 to 1.6 g daily with valproate levels of between 50 and 100 mg/L. Two days after the addition of the antihacterials the levels had halved, and after 3 days of subtherapeutic levels, phenytoin was substituted for valproate. The other patient experienced a drop in valproate levels from 44 mg/L to 5 mg/L within 24 hours of being given meropenem, despite being given greater doses of valproic acid. Other reports " describe reductions in valproate levels in several other patients when they were also given meropenem three of them developed seizures. . ... 

Two children taking valproic acid rapidly developed severe dyskinesias and bruxism after the first and second dose of methylphenidate, respectively. Valproate appears to potentiate the effects of methylphenidate, possibly by a pharmacokinetic mechanism, or because of additive dopaminergic effects. The authors of the re-... 

However, a bipolar patient with multidrug addiction had a decrease in plasma valproic acid levels of more than 50% shortly after starting an antiretroviral regimen including efavirenz. Even though the valproate dose was increased to 4 g daily, it was found diffrcult to achieve a target plasma level of 50 mg/dL. About 3 months later, following a valproate dose reduction to 1.5 g daily due to adverse effects, his level was unaltered, at 52 mg/dL. ... 

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