Changes in lamotrigine pharmacokinetics during pregnancy and the puerperium

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.     

The relation between primidone and phenobarbitone blood levels

A dose of primidone or one fifth of the same weight of phenobarbitone produced equal levels of phenobarbitone in the blood.     

Brain concentrations of phenytoin,phenobarbitone and primidone in epileptic patients

Summary Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10–14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.     

Simultaneous quantitative gas-chromatographic analysis of ethosuximide, phenobarbitone, primidone and diphenylhydantoin.

1 Therapeutic serum concentrations of ethosuximide, phenobarbitone, primidone, and dipheylhydantoin were assayed from 1 ml of human serum. The extraction procedure was common to all four drugs and three internal standards. 2 Subsequent isothermal gas chromatographic analysis of serum extracts produced well resolved peaks for the underivatized quantitation of ethosuximide and phenobarbitone. Primidone and diphenylhydantoin were determined as methylated derivatives. 3 Mean coefficients of variation for the assay of each drug were less 7% on a newly packed and conditioned column and less than 10% after the technique had been in continuous use for 3 months. 4 The advantage of quantitation relative to peak area ratios rather than peak height ratios was minimal for the determination of ethosuximide, primidone and diphenylhydantoin but appeared significant for the assay of phenobarbitone.     

Urinary metabolites of phenobarbitone, primidone, and their N-methyl and N-ethyl derivatives in humans.

1. Phenobarbitone (1) and three of its N-alkyl derivatives, and primidone (10) and four of its N-alkyl derivatives, were orally administered separately to two human volunteers. Total urine was collected for approximately 2 weeks following each dose, and the drugs and their metabolites were assayed by g.l.c.-mass spectrometry. 2. Recoveries in the phenobarbitone series increased from approximately 40% to approximately 50% as alkylation of (1) increased. There was a linear relationship between the extent of p-hydroxylation and the lipophilicity (log P) of the substrates. The increased total recovery was largely attributable to increased p-hydroxylation. 3. Urinary recoveries in the primidone series decreased from approximately 80% for (10) to approximately 30% for its diakyl derivatives, despite a slight increase in p-hydroxylation with increasing alkylation (and increasing lipophilicity). The decreased recovery was mainly the result of decreased urinary excretion of the drug.     

Complications during pregnancy, labor and puerperium in women with increased BMI at pregnancy term

The aim of this study was to analyse perinatal complications in woman with increased BMI at pregnancy term. Study included 23190 women who gave singleton birth during a 10-year period in our institution. Maternal databases were reviewed for pregnancy, labor and delivery complications and early maternal postpartum morbidity. Women with increased BMI at pregnancy term had a significantly higer incidence of postterm pregnancy, gestational diabetes, pregnancy-induced hypertension and third trimester hemorrhage, compared to normal weight women (p 0.000). Women with increased BMI had significantly more labor induction with prostaglandins (p 0.001 and 0.000) and elective caesarean (p 0.025 and 0.000). Also, overweight and obese women had higher incidence of operative delivery: caesarean section (p 0.000) and vacuum extraction (p 0.000). The incidences of postpartum febrility (p 0.057, 0.000, 0.002) and trombophlebits (p 0.013) were also significantly higher. We can conclude that prepregnancy normal weight women with increased BMI during pregnancy need special follow-up and counseling in pregnancy and delivery.     

Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium

The treatment of epilepsy in pregnancy is particularly challenging in that the fetal and maternal risks associated with maternal seizures need to be balanced against the potential teratogenic effects of antiepileptic drugs (AEDs). Pregnancy is known to affect the pharmacokinetics of older-generation AEDs. Understanding such alterations is important in the effort to optimise drug therapy since they may affect seizure control as well as fetal drug exposure. Therapeutic drug monitoring has therefore been recommended to control for changes in the disposition of the older-generation AEDs during pregnancy. Much less is known about gestation-induced alterations in the pharmacokinetics of the newer AEDs that have been introduced in the last 15 years. Lamotrigine is by far the most extensively studied of the newer AEDs. Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of >300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is available on the pharmacokinetics during pregnancy of other newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate or zonisamide). Given the importance of maintaining optimal treatment of epilepsy during pregnancy, therapeutic drug monitoring appears to be justified for lamotrigine and oxcarbazepine in particular. Systematic studies of the effects of pregnancy on the pharmacokinetics of the other newer-generation AEDs are urgently needed.     

Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium

Twenty-four epileptic women were followed-up during late pregnancy, labor, and early puerperium in order to detect possible alterations in serum protein binding of antiepileptic drugs (AEDs). The total and free concentrations of carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) in maternal serum were measured. In addition, the concentrations of albumin, alpha 1-acid glycoprotein (AGP), and free fatty acids (FFA) were also measured. Total AED concentrations during labor were influenced by changes in drug dosages; total PHT increased during the first puerperal weeks. During labor the free fraction of CBZ remained stable, whereas PHT and particularly VPA free fractions increased. This phenomenon was parallel to the increase in FFA concentration; FFA concentrations decreased again during the first days postpartum. Albumin and AGP concentrations were low during pregnancy and labor, and increased after delivery. The total umbilical CBZ and PHT concentrations were not significantly different from maternal concentrations. The total VPA concentration in umbilical serum was significantly higher than that in maternal serum. The free fraction of CBZ was higher and that of PHT and VPA lower in umbilical than in maternal serum at delivery. Umbilical cord serum had a higher albumin but a lower AGP and FFA concentration than maternal serum. The changes in PHT and particularly VPA free fraction associated with changes in FFA concentration should be considered when assessing the total concentration of these drugs in maternal and umbilical serum.     

A safety evaluation of aripiprazole for treating schizophrenia during pregnancy and puerperium

Introduction: Aripiprazole (ARI) is a second-generation antipsychotic acting as a dopamine-serotonin system stabilizer and partial agonist at D₂ receptors. The drug is indicated in several and severe psychiatric disorders which are particularly frequent in women during the childbearing age.

Area covered: A systematic review of studies investigating the reproductive safety of ARI.

Expert opinion: For first trimester use, reviewed data provide no clear evidence about the safety of the drug for the developing fetus. However, a decline of plasma levels (PLs) throughout the pregnancy compared with PLs before pregnancy was observed. This finding suggests the need to increase the dosage during pregnancy in order to maintain stable PLs. If used during late pregnancy, some signals exist suggesting that ARI may worse neonatal outcomes. Hence, clinicians should consider withdrawing the drug before the last month of pregnancy to reduce the risks of neonatal complications. However, such risks must be weighed against the risks of woman’s symptom deterioration. In any case, parturition should happen in hospitals equipped with well-organized neonatal intensive care units. No information is available on the impact of antenatal exposure to ARI on the main neurodevelopmental milestones. Infant exposure to the drug through maternal milk may increase the risk of insufficient milk production and neonatal somnolence.     

The safety of medications for the treatment of bipolar disorder during pregnancy and the puerperium

Risks associated with pharmacological treatment of bipolar disorder are heightened during reproductive events. Treatments need to be planned with the mutual agreement of both the treating physician and the patient and tailored to the needs of the individual so as to minimise risk while providing adequate treatment. Conventional treatments have all been associated with teratogeny in first trimester exposure, lithium with cardiac malformation and valproate and carbamazepine with neural tube malformations. There have been an insufficient number of first trimester exposures to the newer anticonvulsant mood stabilisers, lamotrigine and oxcarbazepine, to determine whether there is a safety advantage in switching to these agents. Increasingly, atypical antipsychotics are being suggested as useful agents for the treatment of bipolar disorder. While not known to be teratogenic, there are other reproductive safety concerns associated with these agents. Bipolar disorder patients may be prescribed antidepressants, and many of these agents are associated with a low safety risk during reproductive events, however data regarding use of these agents are currently equivocal. Adverse outcomes from inadequate pharmacological prophylaxis have been documented for both the mother and the baby. Risks and benefits need to be carefully balanced based on an accurate review of the evidence.     

Practical management of lupus nephritis in pregnancy and the puerperium

Pregnancy represents a major challenge in the management of patients with systemic lupus erythematosus, with substantial risks to both mother and baby. Over the past 40 years there have been major improvements in outcomes. This partly relates to the discovery of the antiphospholipid syndrome, which has transformed management of lupus pregnancy, but also due to more effective drugs and better obstetric practice. Despite these advances, significant maternal and fetal morbidity may still occur in patients with lupus nephritis, and there remain ongoing challenges in order to improve outcomes further. In this article we focus on the challenges facing lupus nephritis patients considering pregnancy, and discuss how we approach practical management issues in relation to the current literature.     

Practical management of lupus nephritis in pregnancy and the puerperium

Pregnancy represents a major challenge in the management of patients with systemic lupus erythematosus, with substantial risks to both mother and baby. Over the past 40 years there have been major improvements in outcomes. This partly relates to the discovery of the antiphospholipid syndrome, which has transformed management of lupus pregnancy, but also due to more effective drugs and better obstetric practice. Despite these advances, significant maternal and fetal morbidity may still occur in patients with lupus nephritis, and there remain ongoing challenges in order to improve outcomes further. In this article we focus on the challenges facing lupus nephritis patients considering pregnancy, and discuss how we approach practical management issues in relation to the current literature.     

PB:PRM ratio in patients with epilepsy treated with primidone

Phenobarbitone (PB) and primidone (PRM) plasma concentrations were measured in 88 patients of both sexes with different types of epilepsy and treated with PRM, alone or in association with carbamazepine (CBZ), phenytoin (PHT), ethosuximide (ESM) or valproic acid (VPA). A correlation was observed between the dose and the levels of both PRM and PB. Plasma PB:PRM ratio was high variable, especially interindividually. These changes seemed to be linked to age and particularly to pharmacological associations. In fact, PB:PRM ratio was increased with CBZ, ESM, VPA and PHT respectively. Moreover, a correlation was observed between the PB:PRM ratio and PHT plasma levels. The possibility of monitoring PB and PRM plasma levels during long-term treatment with PRM is discussed.     

Changes in respiratory function tests during pregnancy

Anatomical, physiological and biochemical adaptations that occur during pregnancy are profound. Changes in respiratory physiology are a part of the same process. In the present study of 70 selected women, 50 pregnant and nonpregnant control, it was found that out of seven parameters studied five showed changes. There were changes in respiratory frequency, tidal volume, vital capacity, inspiratory capacity and expiratory reserve volume. Maximum voluntary ventilation and timed vital capacity did not change. RF, VT, VC and IC rose significantly while ERV had a significant fall. These changes may be affecting ante-intranatal behaviour of pregnant women and their pregnancy outcome.