Pharmacokinetics of valproate in pregnancy: mother-foetus-newborn S v e i n I. J o h a n n e s s e n

Introduction An increased risk of seizures during and immediately after labour has been recognized in women with epilepsy, and there is growing interest in a more subtle m a n a g e m e n t of antiepileptic drug t h e r a p y during pregnancy [1 2]. The reasons for this increased risk of seizures are not fully understood, b u t m a n y factors, including alterations in antiepileptic drug kinetics, weight gain, decreased albumin levels as well as patients' noncompliance with therapy, have been suspected [3 4]. Despite the teratogenic potential of valproate (VPA) it r e m a i n s a useful drug, especially in certain types of epilepsy, and continues to be administered in p r e g n a n c y [5 6]. At c o n s t a n t drug dosage the s e r u m level of most antiepileptic drugs tends to decrease during pregnancy, but r e t u r n s to p r e p r e g n a n t level within the first m o n t h after delivery. This is of clinical importance because low s e r u m levels m a y provoke seizures. Longitudinal studies of the pharmacokinetics of antiepileptic drugs during p r e g n a n c y are few since such studies are difficult to perform for technical, ethical, and legal reasons. Therefore, little information is available concerning antiepileptic disposition and protein binding during pregnancy, especially with regard to VPA [7-10].

whereas the salts are generally absorbed in the small intestine. There is no evidence t h a t the absorption of VPA is altered during pregnancy [10 11].

Drug distribution There are m a r k e d changes in the body composition during pregnancy [8]. Factors which could modify drug distribution in pregnancy are the increased p l a s m a volume and the increased cardiac output due to a higher h e a r t b e a t frequency and a greater stroke volume. The p l a s m a volume increases by about 50%, and the cardiac output increases by about 30%. Total body fluid increases greatly during pregnancy, with i n t r a v a s c u l a r volume and extracellular fluid both showing large increases. The volume of distribution (V) rises with increases in extracellular fluid, fat content and the expanding foetal compartment. During steady-state t h e r a p y with VPA during pregnancy, an increase in a p p a r e n t volume of distribution has been determined by m e a n s of laC-label]ed VPA [12]. VPA is readily distributed to all tissues and is present in high concentration in blood, liver and kidney. It also distributes rapidly to the foetus. The a p p a r e n t volume of distribution is in the order of 0.14-0.20 1/kg in adults.

Drug absorption

Drug protein binding

Gastric tone and motility are reduced during pregnancy, resulting in delayed e m p t y i n g of the stomach. N a u s e a and vomiting are other symptoms occurring during pregnancy which affect drug ingestion and absorption, especially during the first trimester. VPA tablets/capsules are available in an acid form and as various salts including sodium and m a g n e s i u m . In general, the absorption is complete since VPA is quite water-soluble. The acid form is rapidly absorbed from the stomach,

The degree of s e r u m protein binding is an imp o r t a n t d e t e r m i n a n t of drug disposition and response [13]. The desired t h e r a p e u t i c s e r u m level r a n g e for a drug usually refers to total drug concentration, and drug regimens are adjusted to m a i n t a i n steady-state concentrations based on t h a t total. If the binding of the drug is altered due to a change in p l a s m a composition (altered proteins and/or binding inhibitors), dose adjustm e n t s based on the total s e r u m levels m a y no longer be valid.

Johannessen SI. Pharmacokinetics of valproate in pregnancy: mother-foetus-newborn. Pharm Weekbl [Sci] 1992;14(3A):114-7.

Abstract

S.I. Johannessen: The National

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the halflife of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.

Centre for Epilepsy, N-1301 Sandvika, Norway.

Accepted May 1991.

Keywords Biological availability Fetus Lactation Metabolism Pharmacokinetics Placental transfer Protein binding

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The physiological changes that occur in pregnancy include a reduction in the levels of the two major drug-binding proteins, albumin and alacid glycoprotein, potentially altering the fraction of free drug. Serum albumin level is decreased during pregnancy, resulting in fewer binding sites for acidic drugs. Therefore, a decrease in drug-binding corresponding to the fall in albumin level would be expected. A reduction in serum protein-binding capacity correlates positively with gestational age. VPA is extensively (average 90%) bound to serum proteins. The unbound fraction of VPA in serum increases with increasing concentrations as a result of saturation of binding sites. When total concentrations reach the upper limit of the assumed therapeutic range, the free fraction may increase by about 50%. Furthermore, VPA can be partially displaced from protein-binding sites by circulating free fatty acids, which gradually increase during pregnancy [14]. The serum protein binding of VPA is significantly decreased in pregnant women. Up to a two-fold increase in the free fraction has been observed [15]. Therapeutic concentrations of other antiepileptic drugs do not appear to alter VPA binding to a clinically important extent [16]. The decrease in protein-binding capacity will result in increased plasma clearance, giving decreased total serum levels. Other changes during pregnancy, e.g. increases in renal clearance and metabolic capacity, increased tissue binding, altered receptor sensitivity and an increase in body water, may counteract the effect of altered drug binding [13].

Drug metabolism Pregnancy is accompanied by changes in almost every aspect of metabolism. There are a number of changes that occur in the liver during pregnancy, and these affect drug metabolism. Changes in liver enzymes are also likely during pregnancy, but are not well understood. The drugs are cleared from the body mainly by metabolism, and during pregnancy the clearance is acccelerated because of increased hepatic activity, as a result of the induction of the hepatic microsoma! drug-metabolizing system [17]. Increased circulating progesterone is known to induce the system, whereas estrogens are strong inhibitors. Thus, an increased metabolic rate of the drug may partly depend upon a balance between the effects of progesterone and estrogens. The large interindividual variation of plasma clearance observed may be explained by the varying ratio of the hormones among individuals. In pregnancy and labour the body becomes a complex physiological unit consisting of the mother, the placenta, and the foetus. The foeto-placental unit increases the volume of distribution of drugs which are administered to the mother and also contributes to drug metabolism. During pregnancy the extracellular fluid and tissue volume also expand and all together might lead to the decrease in serum drug level that is observed with an unaltered drug dosage [10]. VPA is extensively metabolized in the liver 14(3A) 1992

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through several metabolic pathways, and a number of compounds have been identified, of which the main two metabolites are 2-n-propyl-2pentenoate (A2-VPA) and 3-keto-2-n-propylpentanoate (3-keto-VPA) [18]. The half-life of VPA is in the range of 10 h [19]. Concomitant treatment with enzyme-inducing antiepileptic drugs reduces the half-life, but VPA itself exhibits no enzyme-inducing potential. However, VPA may inhibit the metabolism of other antiepileptic drugs. The halfdife of VPA is shorter in children than in adults [20-22]. There is some suggestion that during pregnancy VPA metabolism may be significantly altered. There is an increased clearance of VPA during the third trimester which may have multiple mechanisms. These may simply include an increased metabolism of VPA to its metabolites, but there may also be some increased renal clearance. Several studies have suggested that total VPA levels fall, but that free fractions increase during pregnancy [23 24]. Recent studies support these findings [25 26]. Despite an upward dose adjustment in some patients, total VPA levels declined as the pregnancy proceeded, especially later in the pregnancy and at delivery, but free levels did not. Free fractions in the plasma and clearances increased, but intrinsic clearances, which were adjusted for changes in body-weight, remained unchanged. These findings suggest that the actual metabolism of VPA is not altered by pregnancy and that the changes of the plasma clearance were due primarily to decreased protein binding. The altered binding is probably not only due to changes in albumin concentrations, but also to the increased free fatty acid levels. These observations suggest that in a given patient, free VPA levels will not change significantly as pregnancy advances if the total daily dose in mg/kg body-weight is kept constant. However, a dose reduction after delivery may be necessary to avoid toxicity.

Antiepileptic drugs in the foetus, the newborn, and breast milk VPA readily crosses the placental barrier [7]. In contrast to other antiepileptic drugs, the foetal plasma level of VPA is higher than the maternal plasma level, with a ratio of 1.3-4.6. The reason for the accumulation of VPA in the foetal blood is not clear. It has been suggested that the foetus may act as a deep compartment, active transport mechanisms across the placenta may be involved, or protein binding of VPA may be higher in foetal than in maternal plasma. In a recent study [26] it was also observed that the free fraction of VPA was significantly lower in umbilical than in maternal serum at delivery. Umbilical cord serum had a higher albumin but a lower al-acid glycoprotein and free fatty acids concentration than maternal serum. The umbilico-maternal difference in the free fraction of VPA is probably due to the difference in free fatty acid concentrations. The magnitude of this phenomenon is not negligible. High total foetal levels do not indicate high levels of free VPA. Also, the metabolites of VPA undergo pla115

cental transfer, and its two main metabolites (A2-VPA, 3-keto-VPA) were found to be present in cord plasma in higher concentrations t h a n in m a t e r n a l plasma [7]. The elimination half-life of VPA following placental transfer is in the range of 10 to 70 h, considerably longer t h a n in adults. The neonatal elimination of the two main metabolites is similar to t h a t of V.PA, and the metabolic pattern in the neonate's urine is similar to t h a t in adult urine. The long half-life of VPA in neonates m a y suggest t h a t the enzymes responsible for VPA metabolism are not induced in utero to the same extent as in neonates exposed to enzyme-inducing antiepileptic drugs. VPA also appears to inhibit the enzyme~inducing effects of some other antiepileptics, giving a complex metabolic pattern in these neonates [7]. The concentration of antiepileptic drugs in breast milk varies inversely with the degree of protein binding in serum [27]. Since antiepileptic drugs do not bind to breast milk protein, it is only the free fraction which appears in breast milk. VPA appears in breast milk in concentrations as low as 3% of the simultaneous values in serum. Small amounts of the 3-keto-VPA have also been found in breast milk. The presence of VPA in milk is not likely to cause any problems since the breast-feeding infant would be receiving only about 2% of the m a t e r n a l dose normalized to body-weight [7 27].

Therapeutic drug monitoring in pregnancy The rationale for monitoring drugs in pregnancy is, of course, the same as t h a t for any patient group. It depends on a strong correlation between the unbound concentration of drug at the receptor site and the drug response. For m a n y drugs variations in patient response are a result of pharmacokinetic r a t h e r t h a n pharmacodynamic differences, and in pregnancy these differences are often amplified [28 29]. The unbound fraction of VPA in serum increases due to saturable binding [30]. Due to the marked fluctuations in serum VPA levels, the unbound fraction also changes during a dosage interval, and the d o s e - c o n c e n t r a t i o n relationship of the drug may be non-linear at higher concentrations [31]. Since only the unbound fraction is available to produce biological effects at the receptor sites, serum levels of total (free and bound) VPA would not be expected to reflect accurately the concentration of pharmacologically active drug, and this suggests t h a t optimal therapeutic monitoring should be based upon the m e a s u r e m e n t of free drug [32]. However, so far there seems to be a consensus t h a t free VPA levels do not appear to be more useful t h a n total levels in predicting seizure control [33 34]. Consequently, free level monitoring should be reserved for special indications [32 35]. As discussed above several pharmacokinetic parameters of antiepileptic drugs, including VPA, are altered during pregnancy, delivery, and puerperium. Total VPA serum levels decrease as pregnancy proceeds, but the changes in free, active concentrations m a y be insignificant. Thus it is not necessary to modify drug doses

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according to changes in total concentrations, but it is important to ensure patients' compliance [25 26]. During pregnancy, preferably both total and free VPA serum levels should be closely monitored (once a m o n t h if possible) to determine the lowest effective dose and to avoid the h a r m of seizures and drugs to the mother and foetus. After delivery the serum levels should be monitored the first m o n t h since a dose reduction may be necessary to prevent toxicity [10 36].

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Pharmacokinetics of valproate in pregnancy: mother-foetus-newborn.

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of anti...
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