Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations

Although epilepsy affects men and women equally, there are many women's health issues in epilepsy, especially for women of childbearing age. These issues, which include menstrual cycle influences on seizure activity (catamenial epilepsy), interactions of contraceptives with antiepileptic drugs (AEDs), pharmacokinetic changes during pregnancy, teratogenicity and the safety of breastfeeding, challenge both the woman with epilepsy and the many healthcare providers involved in her care. Although the information in the literature on women's issues in epilepsy has grown steeply in recent years, there are many examples showing that much work is yet to be done. The purpose of this article is to review these issues and describe practical considerations for women of childbearing age with epilepsy. The article addresses the established or "first-generation" AEDs (phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide and valproic acid) and the "second-generation" AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). Although a relationship between hormones and seizure activity is present in many women, good treatment options for catamenial epilepsy remain elusive. Drug interactions between enzyme-inducing AEDs and contraceptives are well documented. Higher dosages of oral contraceptives or a second contraceptive method are suggested if women use an enzyme-inducing AED. Planned pregnancy and counselling before conception is crucial. This counselling should include, but is not limited to, folic acid supplementation, medication adherence, the risk of teratogenicity and the importance of prenatal care. AED dosage adjustments may be necessary during pregnancy and should be based on clinical symptoms, not entirely on serum drug concentrations. Many groups have turned their attention to women's issues in epilepsy and have developed clinical practice guidelines. Although the future holds promise in this area, many questions and the need for progress remain.     

A survey of pharmacokinetic data from pregnant women

Published results of pharmacokinetic studies (terminal half-life, t 1/2 beta, elimination constant, kappa e1; apparent volume of distribution in beta-phase, Vd beta and plasma clearance, CLp) in pregnant and non-pregnant women have been compiled and compared. Most of the data relate to the results of pharmacokinetic studies with 20 drugs in women at full-term pregnancy, i.e. about 40 weeks gestation. A review of these data failed to reveal any consistent overall trend in any of the pharmacokinetic parameters listed and no generally applicable changes in the disposition of the drugs as a result of pregnancy can be characterised. However, pregnancy associated changes appear to be discernible in the elimination patterns of certain drugs, for example, ampicillin, caffeine, diazepam, phenytoin and thiopentone, but the factors producing these changes can still only be suggested.     

Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women

Aim

Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.

Methods

Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (C_max) and oral clearances (CL/F).

Results

PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).

Conclusions

Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.     

Safety considerations when prescribing immunosuppression medication to pregnant women

Introduction: In the past two decades, the number of women with autoimmune and inflammatory diseases experiencing a pregnancy has significantly increased in parallel with the enormous advances in the diagnosis and management of these disorders. However, information regarding the safety of immunosuppressive agents comes from case reports and case series and no controlled trials are available.

Areas covered: We performed a review of the literature using MEDLINE. The term ‘pregnancy’ was searched in combination with all the principal immunomodulant/immunosuppressive drugs used in rheumatic diseases.

Expert opinion: A large number of reports suggest that azathioprine, cyclosporine, hydroxychloroquine and steroids are relatively safe during pregnancy, whereas methotrexate, cyclophosphamide, mycophenolate mofetil and leflunomide are contraindicated. Data about the safety of biological agents are scant, but a growing number of publications suggest that at least TNF inhibitors could be prescribed when benefits outweigh the potential risks. Nevertheless, we cannot draw definite conclusions, as this information has not been confirmed in controlled trials. Prospective registries, some of which are already in place, are invaluable resources to answer many questions, especially on the incidence of fetal malformations. Finally, outcome studies on the offspring especially in regard to immune system and psychomotor development will shed light on long-term safety.     

Characterizing pregnant drug-dependent women in treatment and their children

Alcohol and other drug use during pregnancy represents a major public health concern. This article characterizes a sample of 240 pregnant opioid- or cocaine-dependent women enrolled in the initial residential component of a comprehensive substance abuse treatment program for pregnant women. Data were collected using the Addiction Severity Index, Psychosocial History Form, and Structured Clinical Interview for DSM-III-R. Patients' substance use history, psychiatric comorbidity, social support network, employability, current and previous pregnancies, child custody arrangements, and the father of the current pregnancy, are described to assist providers in tailoring treatment to the specific needs of this population.     

Rectal drug administration: clinical pharmacokinetic considerations

The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. Drawbacks of rectal drug administration include the interruption of absorption by defaecation and lack of patient acceptability. The mechanism of drug absorption from the rectum is probably no different to that in the upper part of the gastrointestinal tract, despite the fact that the physiological circumstances (e.g. pH, fluid content) differ substantially, Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g. in children), but absorption from suppositories is generally slower and very much dependent on the nature of the suppository base, the use of surfactants or other additives, particle size of the active ingredient, etc. There is some evidence that hepatic first-pass elimination of high clearance drugs is partially avoided after rectal administration, e.g. lignocaine. This can be explained by the rectal venous blood supply: the upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Plasma concentration data following rectal administration of representatives of several classes of drugs are reviewed: anticonvulsants, non-narcotic analgesics and non-steroidal anti-inflammatory agents, hypnosedatives and anaesthetics, strong analgesics, theophylline and derivatives, corticosteroids, antibacterial agents, thiazinamium, promethazine, hyoscine-N-butyl-bromide, streptokinase, progesterone, ergotamine tartrate and levodopa. Only limited number of cases has it been adequately shown that the rectal route of administration gives plasma concentrations which are comparable to the oral route. Potentially the rectal route offers the same possibilities as the oral route, but the influence of the formulation seems to be very critical. It is also likely that the future novel drug delivery systems with zero order release characteristics will be applied rectally. Interesting preliminary results have already been obtained with theophylline administered by 2ml osmotic pumps.     

Cigarettes and drug therapy: pharmacokinetic and pharmacodynamic considerations

Cigarette smoking-induced alterations in drug absorption, distribution, metabolism, excretion, and effectiveness are reviewed. Drug therapy can be affected pharmacokinetically by polyaromatic hydrocarbons and pharmacodynamically by nicotine. Pentazocine and phenylbutazone show increased metabolism in smokers and may have to be given in higher dosages. Smokers experience less pain relief with propoxyphene than do nonsmokers. Codeine, meperidine, and morphine are unaffected pharmacokinetically, and the effect on acetaminophen is probably not clinically important. Carbamazepine, phenytoin, and phenobarbital are not influenced. Heparin metabolism is elevated in smokers; this effect may necessitate modest increases in dosage. Warfarin clearance is increased, but this is not associated with a change in prothrombin time. Pindolol and propranolol are unaffected pharmacokinetically, but direct effects of nicotine may interfere with blood pressure control. Smoking transiently diminishes the diuretic effect of furosemide, inconsistently affects protein binding of lidocaine, and has no effect on prednisone, prednisolone, or dexamethasone. The metabolism of estrogens to less active metabolites is increased. Smoking is associated with decreased subcutaneous absorption of insulin and increased dosage requirements. Healing of GI ulcers with histamine H2-receptor antagonists may be compromised in smokers; sucralfate is probably more useful. Imipramine, benzodiazepines, chlorpromazine, and glutethimide may be influenced, and theophylline metabolism is accelerated. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many drugs.     

Assessment of bisphenol A exposure in Korean pregnant women by physiologically based pharmacokinetic modeling

The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 μg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.     

儿童和妊娠合并糖尿病患者中胰岛素类似物的应用

糖尿病是一种因胰岛B细胞分泌功能受损和（或）胰岛素作用缺陷,导致胰岛素分泌绝对或相对不足而引发的以血糖升高为特征的代谢疾病。随着经济的飞速发展和生活方式的改变．近20年来全球糖尿病的发病率急剧上升^[1-3]。与此同时,糖尿病在特殊人群即儿童和妊娠妇女中的发病率也明显上升^[4-5]。     

Glucosamine therapy for knee osteoarthritis: pharmacokinetic considerations

Knee osteoarthritis is the most common form of arthritis. Given the aging of the world's population, the burden of this disease is expected to increase significantly over the next few decades. As a pharmacological agent, glucosamine has been investigated for the treatment of symptoms and progression of knee osteoarthritis, demonstrating symptomatic and disease-modifying effects. However, among the glucosamine studies conducted to date in knee osteoarthritis, there have been conflicting results due to differences and/or weaknesses in study design and sample size, in addition to product formulation, salt and quality. This review describes the current knowledge regarding the pharmacokinetics of glucosamine to provide a means for the interpretation of the pharmacodynamic and clinical efficacy results obtained in the different clinical trials.     

Glucosamine therapy for knee osteoarthritis: pharmacokinetic considerations

Knee osteoarthritis is the most common form of arthritis. Given the aging of the world’s population, the burden of this disease is expected to increase significantly over the next few decades. As a pharmacological agent, glucosamine has been investigated for the treatment of symptoms and progression of knee osteoarthritis, demonstrating symptomatic and disease-modifying effects. However, among the glucosamine studies conducted to date in knee osteoarthritis, there have been conflicting results due to differences and/or weaknesses in study design and sample size, in addition to product formulation, salt and quality. This review describes the current knowledge regarding the pharmacokinetics of glucosamine to provide a means for the interpretation of the pharmacodynamic and clinical efficacy results obtained in the different clinical trials.     

临床试验的伦理审查:妇女和孕妇

孕妇以及育龄期妇女参加临床试验,涉及她们本人、妊娠、胎儿和由胎儿长成的人、以及她们生育力的风险和受益,伦理委员会审查时需要有一些特殊的考虑.涉及妇女临床研究的特殊伦理审查问题主要包括：研究期间有怀孕的可能,其本身不能作为排除或限制育龄期妇女参加生物医学研究的理由;详尽讨论研究对孕妇和胎儿的风险,是妇女做出参加临床研究理性决定的先决条件;涉及孕妇临床研究的特殊伦理审查问题主要包括：风险和受益的判断应同时考虑研究对孕妇及胎儿两方面的风险与受益,并结合研究的类别进行考虑;只有当研究是针对孕妇或胎儿特有的健康需要,或针对孕妇总体的健康需要,并且如果合适,有来自动物实验、尤其是关于致畸和致突变风险的可靠证据予以支持,才能在孕妇群体中实施研究.     

Treatment of anxiety and depression in transplant patients: pharmacokinetic considerations

Depressive and anxiety disorders appear during the transplant process due to psychological stressors, medications and physiological disturbances. Treatment is necessary to prevent impact on patient compliance, morbidity and mortality. Psychotropic medications provide an effective option, although most are only available as oral formulations. Because of this, they are more susceptible to alterations in pharmacokinetic behaviour arising from organ dysfunction in the pretransplant period. Kinetics are also an issue when considering potential drug-drug interactions before and after transplantation.Prior to transplant, organ dysfunction can change the pharmacokinetic behaviour of some psychotropic agents, requiring adjustment of dosage and schedules. Thoracic or abdominal organ failure may reduce drug absorption through disturbances in intestinal motility, perfusion and function. Cirrhotic patients experience increased drug bioavailability due to portosystemic shunting, and thus dosage is adjusted downward. In contrast, dosage needs to be raised when peripheral oedema expands the drug distribution volume for hydrophilic and protein-bound agents. Drug clearance for most psychotropic medications is dependent upon hepatic metabolism, which is often disrupted by endstage organ disease. Selection of drugs or their dosage may need to be adjusted to lower the risk of drug accumulation. Further adjustments in dosage may be called for when renal failure accompanies thoracic or abdominal organ failure, resulting in further impairment of clearance.Studies regarding the treatment of anxiety and depressive disorders in the medically ill are limited in number, but recommendations are possible by review of clinical and pharmacokinetic data. Selective serotonin reuptake inhibitors are well tolerated and efficacious for depression, panic disorder and post-traumatic stress disorder. Adjustments in dosage are required when renal or hepatic impairment is present. Among them, citalopram and escitalopram appear to have the least risk of drug-drug interactions. Paroxetine has demonstrated evidence supporting its use with generalised anxiety disorder. Venlafaxine is an alternative option, beneficial in depression, post-traumatic stress and generalised anxiety disorders. Nefazodone may also be considered, but there is some risk of hepatotoxicity and interactions with immunosuppressant drugs. Mirtazapine still needs to be studied further in anxiety disorders, but can be helpful for depression accompanied by anorexia and insomnia. Bupropion is effective in the treatment of depression, but data are sparse about its use in anxiety disorders. Psychostimulants are a unique approach if rapid onset of antidepressant action is desired. Acute or short-term anxiolysis is obtained with benzodiazepines, and selection of particular agents entails consideration of distribution rate, half-life and metabolic route.     

Ziprasidone and the QTc interval: pharmacokinetic and pharmacodynamic considerations

Many psychotropic medications might cause prolongation of the QTc interval; however, antipsychotics have recently come under increasing scrutiny in this regard. Ziprasidone, a newly marketed second-generation antipsychotic, was initially delayed in approval by the FDA due to its propensity to prolong the QTc interval in patients with schizophrenia. While ziprasidone does prolong the QTc interval, safety, concomitant medication, and overdose data present little reason to consider ziprasidone a major risk factor for Torsades de Pointes thus far. The paucity of data regarding this agent, however, and its use in those with additional risk factors for QTc-interval prolongation are striking. The risk for this phenomenon has not been studied in patients with concomitant disease states that might be associated with QTc-interval prolongation or in those taking metabolic inhibitors which might inhibit aldehyde oxidase. Little is known about a major metabolic route of ziprasidone, oxidation by aldehyde oxidase. Finally, experience with other agents associated with QTc-interval prolongation raises the possibility that both the type and number of individuals studied to date might not be sufficient to reveal problems with ziprasidone. This paper will review the literature concerning real and theoretical implications of pharmacokinetic and pharmacodynamic interactions with ziprasidone, particularly with regard to these effects on the QTc interval.     

Exposure to violence among substance-dependent pregnant women and their children

This study examined the prevalence of exposure to violence among drug-dependent pregnant women attending a multidisciplinary perinatal substance abuse treatment program. Participants (N = 715) completed the Violence Exposure Questionnaire within 7 days after their admission to the program. Their rates of lifetime abuse ranged from 72.7% for physical abuse to 71.3% for emotional abuse to 44.5% for sexual abuse. Their rates of abuse remained high during their current pregnancy, ranging from 40.9% for emotional abuse to 20.0% for physical abuse to 7.1% for sexual abuse. Nearly one third of the women reported having physical fights with their current partner (lifetime), and 25% of these women reported that children were present during those physical fights. A total of 30% of the women perceived a need for counseling regarding exposure to violence for themselves and 15% perceived a need for counseling for their children. Study findings confirm previous reports of high rates of abuse and violence exposure among substance-abusing pregnant women and their strong need for counseling for psychosocial sequelae. This study affirmed the value of routine screening for violence exposure in this at-risk population as well as the need to train therapists in specific strategies for helping such women address this complex array of problems.     

Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations

Therapeutic drug monitoring of any pharmacologic agent should be considered when there is both significant pharmacokinetic variability and strong, clinically relevant, exposure-effect relationships. Many antifungal drugs exhibit marked variability in drug concentration as a result of inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. For each of the available antifungal drugs, both preclinical and clinical trials have exhibited a relationship between serum concentrations and treatment efficacy. For a smaller subset of compounds, a similar relationship has been identified for the toxicity. The kinetic variability among patients falls outside the therapeutic window for a group of four antifungal compounds. This review summarizes the current literature on therapeutic drug monitoring for these antifungal agents.