valproic acid - pharmacokinetics

24
Dr.Abdallah Rabba Shereen Rawajbeh Sondos Hassouneh Areej Abu Hanieh 1

Upload: areej-abu-hanieh

Post on 21-Jan-2018

180 views

Category:

Health & Medicine


0 download

TRANSCRIPT

Dr.Abdallah Rabba

Shereen Rawajbeh

Sondos Hassouneh

Areej Abu Hanieh1

Valproic acid (VPA) is a broad-spectrum,

carboxylic acid-derived anticonvulsant that has

been used in the treatment of first line therapy of

mania ,epilepsy, bipolar disease, schizophrenia,

and migraine headache.

2

- It comes in several different preparations

and salt forms:

3

For example :

Divalproex sodium is a mixture of equal parts of

the acid and sodium salts of valproic acid.

The delayed-release (Depakote) and extended-

release (Depakote ER) formulations are not

bioequivalent.1 A 20 percent increase in the daily

dose is recommended when switching from

Depakote to Depakote ER to account for the

differences in rate and extent of absorption.

4

5

Dosing initial oral dosing for patients 10 years of age and

older is 10–15 mg/kg/day. Dosing intervals for the

oral and parenteral preparations are typically

every 8–12 hours (although dosing every 6 hours

may be needed in some patients), Who are those

patients ?

with the exception of the extended-release

formulation, which can be administered once

daily.

6

Dosing : The daily dose can be titrated weekly by 5–10

mg/kg/day to a maximum recommended dose of

60 mg/kg/day.

Loading doses are not recommended for the oral

VPA formulations due to intolerable

gastrointestinal side effects.

Intravenous loading doses of valproate sodium 25

mg/kg are commonly given for patients in status

epilepticus.

Intravenous loading doses can be given at a rate

of 1.5–3 mg/kg/min, but faster rates of up to 6

mg/kg/min appear to be safe.

7

Therapeutic drug monitoring

(TDM)

Is used in conjunction with the clinical exam to

optimize seizure control and minimize toxicity.

Measuring serum concentrations is routinely

performed via immunoassay ( what is

immunoassay ?), and the therapeutic range is

reported as 50–100 mcg/mL, although individual

patients may have optimal responses outside

these ranges.

8

Toxicity : Concentrations higher than 150 mcg/mL are

associated with a high incidence of CNS side effects. Free (unbound) concentrations are also available with a therapeutic range reported to be 6–22 mcg/mL with toxicity occurring above 50 mcg/mL.

Diurnal variations in the serum concentration of VPA have been reported, so it is important to be consistent when sampling in order to properly compare levels and adjust dosing regimens. Clearance tends to be higher in the evening compared to the morning times in both young adults and elderly subjects , Why ? , so trough levels are recommended before the morning dose.

9

Bauer, Larry A., et al. "Valproic acid clearance: unbound

fraction and diurnal variation in young and elderly

adults." Clinical Pharmacology & Therapeutics 37.6 (1985):

697-700.

10

BIOAVAILABILITY:

All of the formulations of valproic acid have

bioavailabilities near 100 percent (F = 1),

reflecting the absence of a first-pass effect

in the liver.

The enteric-coated formulation has a

bioavailability of approximately 90 percent

(F = 0.9)

Valproate sodium is rapidly converted to

valproic acid in the stomach and then

readily absorbed via the gastrointestinal

tract. 11

Peak concentrations are achieved within

0.5–2 hours after oral administration. The

presence of food will delay the peak

concentration but not the extent of

absorption.

The volume of distribution in adults is

reported to range from 0.1 to 0.4

L/kg, indicating that VPA remains primarily

within the intravascular and extracellular

space. The volume of distribution tends to

increase with higher doses due to

saturable protein binding.

12

cerebrospinal

fluid

10%

breast milk

1–10%

VPA

saliva

1%

placenta can increase

the risk of neural tube

defects (pregnant

women)

13

VPA is approximately 90–95 percent protein bound, primarily to serum albumin. The free fraction of VPA ranges from 6 to 10 percent.

protein binding depends on serum concentration, serum albumin, age, and end-organ failure

The free fraction has been reported to be increased in elderly patients (10.7%) versus younger adults (6.4%).14

At concentrations above 70 mcg/mL, VPA displays a higher free fraction with minimal changes in total concentration.

Renal failure may increase the free fraction to 18 percent while cirrhosis can increase it to 29 percent. Caution must be used when interpreting total VPA serum levels in these patients because they can be falsely low while their free levels may be therapeutic or higher.

In addition, VPA may displace other highly protein-bound drugs, such as phenytoin; therefore, free phenytoin levels should be monitored when these drugs are given concomitantly

15

METABOLISM

VPA is primarily metabolized in the liver via

glucuronidation (40%), β-oxidation, and ω-

oxidation (20%) and then eliminated via the

kidneys, with less than 3 percent of the drug

excreted in the urine unchanged.

VPA is characterized as a low-extraction drug with

its clearance being independent of hepatic blood

flow. Many of the metabolites are thought to be

responsible for anticonvulsant activity as well as

toxicity

16

17

METABOLISM

VPA has an average elimination half-life of 11

hours and follows first-order kinetics. The mean

plasma clearance for total VPA is reported to be

approximately 6–7 mL/hr/kg in adults (range 5–10

mL/hr/kg), which may be decreased in patients

with renal or hepatic failure, and increased in

patients taking concomitant hepatic enzyme-

inducing agents.

Total clearance increases with higher doses due

to saturable protein binding, which leads to a

higher free fraction and more unbound drug

available for metabolism (assuming normal

hepatic function). 18

VPA acts as a substrate and inhibitor of various

cytochrome P450 enzymes, reflecting a high

potential for drug interactions

Enzymes That Metabolize VPA

Enzymes That VPAInhibits

Enzymes That VPAInduces

CYP2A6, 2B6, 2C9, 2C19, 2E1

CYP2C9 (weak), 2C19 (weak), 2D6 (weak), 3A4

(weak)

CYP2A6 (weak)

19

Drug interaction Several drugs significantly influence the clearance of VPA

including aspirin, caffeine, and various antibiotics. Aspirin and caffeine act by displacing VPA binding to serum proteins, inhibiting its clearance. Though this may be used to reduce the daily dose of VPA, it can also increase the risk of toxicity of VPA .

Carbapenem antibiotics increase the glucuronidation of VPA and increase clearance .The risk for hepatotoxicity with VPA is greatest in infants under 2 years old treated with additional drugs

Drugs that activate cytochrome P450 enzymes increase the clearance of VPA, increase the amount of N-acetylcysteineconjugates of VPA and may have the greatest risk for hepatoxicity.

VPA can also influence the clearance and metabolism of other drugs. A significant interaction can occur with coadministration of lamotrigine, where VPA doubles its half- life and increases risk of the ADRs Stevens-Johnson syndrome and toxic epidermal necrolysis. Interaction with topiramate, another AED, has been shown to increase risk for hyperammonia and encephalopathy .

20

VPA also interferes with HIV medications

zidovudine lopinavir and ritonavir ,patients

receiving valproic acid may require a zidovudine

dosage reduction to maintain unchanged serum

zidovudine concentrations

21

Drugs That DECREASE VPA Concentration

Drugs That May INCREASE VPA Concentration

Bile acid–binding resins –decreased absorptionCarbamazepine – hepatic metabolism inducedCarbapenem antibiotics –multiple mechanismsLamotrigine – hepatic metabolism inducedPhenytoin – hepatic metabolism inducedPhenobarbital – hepatic metabolism inducedRifampin – hepatic metabolism inducedRitonavir – hepatic metabolism inducedSevelamer – decreased absorption

Aspirin (high dose) – protein binding displacement/decreased intrinsic clearanceCimetidine – hepatic metabolism inhibitedMacrolides – unknown mechanismFelbamate – hepatic metabolism inhibited

22

QUESTION

JJ is a 54-year-old woman admitted with acute

kidney injury from interstitial nephritis. Her

baseline serum creatinine is 0.9 mg/dL, and

currently it is 2.3 mg/dL. She has a history of

seizures for which she takes Depakote 250 mg

PO TID.

What is the best recommendation for dose

adjustments in a patient with renal insufficiency?

23

24