Drug Concentration Monitoring Research Articles

Analytical validation of therapeutic drug monitoring (TDM) on AxSYM Abbott analyzer

Careful monitoring of drug concentration (therapeutic drug monitoring, TDM) is essential for a large number of drugs. The aim of this study was to evaluate analytical performance of Abbott AxSYM analyzer for therapeutic drug monitoring of theophylline, carbamazepine, phenobarbital and valproic acid. For the purpose of analytical validation following parameters were determined for all analytes: inaccuracy (bias), within-run and between-run imprecision and measurement uncertainty. Additionally, concentration of valproic acid was compared with the previously used analytical system (TDx FLx Abbott analyzer) for 30 patients’ samples. Inaccuracy results (bias) were as follows: for theophylline from –3.66% to –5.84% ; for carbamazepine –0.46% to 1.00% ; for phenobarbital –1.83% to –8.08% and for valproic acid from – 1.01% to –5.65%. The highest coefficient of variation (CV) for within run imprecision was observed for phenobarbital (7.07%) and the lowest for theophylline (2.71%). The highest CV for between run imprecision was observed for carbamazepine (4.73%) and the lowest for theophylline (2.94%). The highest measurement uncertainty was observed for phenobarbital assay (21.7%) and the lowest for carbamazepine (10.7%). Passing-Bablock regression analysis of valproic acid comparison on two analyzers showed statistically significant, but clinically insignificant deviation in slope of the regression equation (b = 1.121 ; 95% CI = 1.028– 1.197) ; however the Cusum linearity test proved that there was a linear relationship between two methods. In conclusion, analytical validation fulfilled all previously established criteria and could be implemented in a routine laboratory work.

Clinical Significance of Measuring the Blood Concentration of Itraconazole Oral Solution in the Field of Hematology

Some studies indicated that preventive therapy with Itraconazole oral solution (ITCZ-OS) significantly decreased the incidence of invasive fungal infection, whereas others emphasized that there was no significant decrease. On the other hand, a study involving patients with neutropenia showed a 15-fold increase in the blood concentration of Itraconazole (ITCZ). Therefore, when administering ITCZ-OS, which is more rapidly absorbed in the digestive tract compared to its conventional dosage forms, to patients with blood disease, the blood concentration of ITCZ should be measured to maintain its efficacy and safety. To promote the appropriate use of ITCZ-OS, we conducted blood drug concentration monitoring, and investigated its clinical significance. The subjects were 26 patients with blood diseases. The blood level of ITCZ was measured using HPLC. The mean blood level of ITCZ was 2396.5±1742.7 ng/ml (mean±S.D.). The mean blood level of hydroxy-ITCZ was 5384.4±3348.2 ng/ml. The dose was not correlated with the blood levels of ITCZ/hydroxy-ITCZ per body weight (R(2)=0.134, 0.154, p=0.094, 0.071). Furthermore, the blood levels of ITCZ and hydroxy-ITCZ per body weight were significantly higher in females (p=0.025, 0.010). In males, there was a correlation between the creatinine clearance and blood level of ITCZ per body weight (R(2)=0.319, p=0.044). The blood levels of ITCZ varied among the patients. In addition, when ITCZ-OS was administered at a daily dose of 200 mg (ITCZ), the blood levels of ITCZ exceeded a trough level at which this agent may be effective in patients with febrile neutropenia in whom fungal infection is suspected.

Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy

Optical spectroscopy was used to monitor changes in tumor physiology with therapy, and its influence on drug delivery and treatment efficacy for hyperthermia treatment combined with free doxorubicin or a low-temperature sensitive liposomal formulation. Monte Carlo-based modeling techniques were used to characterize the intrinsic absorption, scattering, and fluorescence properties of tissue. Fluorescence assessment of drug concentration was validated against HPLC and found to be significantly linearly correlated ( r = 0.88). Cluster analysis on the physiologic data obtained by optical spectroscopy revealed two physiologic phenotypes prior to treatment. One of these was relatively hypoxic, with relatively low total hemoglobin content. This hypoxic group was found to have a significantly shorter time to reach 3 times pre-treatment volume, indicating a more treatment resistant phenotype ( p = 0.003). Influence of tumor physiology was assessed in more detail for the liposomal doxorubicin + hyperthermia group, which demonstrated a highly significant correlation between pre-treatment hemoglobin saturation and tumor growth delay, and also between post-hyperthermia total hemoglobin content and tumor drug delivery. Finally, it was found that the doxorubicin concentration, measured in vivo using fluorescence techniques significantly predicted for chemoresponse (hazard ratio: 0.34, p = 0.0007). The ability to characterize drug delivery and tumor physiology in vivo makes this a potentially useful tool for evaluating the efficacy of targeted delivery systems in preclinical studies, and may be translatable for monitoring and predicting individual treatment responses in the clinic.

Therapeutic drug monitoring of naltrexone in alcohol dependent patients

Rationale: The µ-opiate receptor antagonist naltrexone is a new option for the treatment of alcohol dependence. It has been shown to reduce craving for alcohol and alcohol intake. Objective: The aim of this study was to relate plasma concentrations of naltrexone and its major active metabolite 6β-naltrexol in patients during treatment with naltrexone with clinical effects. Methods: A high performance liquid chromatographic method with column switching and spectrophotometric detection was established and validated and used for determination of naltrexone and 6β-naltrexol in plasma samples collected under steady state conditions. Results: Plasma concentrations exhibited high interindividual variabilities. The sum of concentrations naltrexone plus 6β-naltrexol correlated significantly with the reduction of alcohol intake. Receiver operating characteristics (ROC) analyses revealed significantly (p=0.043) higher rates of reduced alcohol drinking when plasma concentrations of naltrexone and 6β-naltrexol were above 16ng/ml. Conclusions: These data give evidence that monitoring of drug concentrations may be a useful option to improve the outcome of naltrexone treatment aiming to reduce alcohol consumption.

Pharmacokinetics of Erlotinib for the Treatment of High‐Grade Glioma in a Pediatric Patient with Cystic Fibrosis: Case Report and Review of the Literature

A 12-year-old girl with cystic fibrosis was diagnosed with a high-grade glioma after radiographic and biopsy results confirmed the primary intracranial lesion. She was treated with single-agent erlotinib during and after daily localized radiation therapy. Pharmacokinetic studies were conducted to assess the effect of pancreatic enzyme deficiency and intestinal malabsorption secondary to cystic fibrosis on the bioavailability of orally administered erlotinib, a lipophilic drug. Pharmacokinetic analysis of plasma samples from days 1 and 8 demonstrated that absorption of oral erlotinib was not affected by the patient's cystic fibrosis when the drug was given concomitantly with pancreatic enzyme replacement. When pediatric patients with cystic fibrosis are receiving erlotinib or other lipophilic oral drugs, continued supplementation of pancreatic enzymes is recommended, with therapeutic drug monitoring of plasma drug concentrations when feasible, and close observation for therapeutic responses and adverse effects.

Pharmacokinetic and pharmacodynamic monitoring of immunosuppressive drugs in solid organ transplant recipients

Current clinical immunosuppressive regimens consist of combinations of drugs, in order to allow a reduction in the individual drug doses as a means to widen the therapeutic interval and to reduce the likelihood of individual drug toxicity. Combining drugs with different mechanisms of action may result in additive or even synergistic effects, potentially allowing dose reduction of individual drugs. Within the field of solid organ transplantation there is an unprecedented interest in therapeutic drug monitoring of immunosuppressive drugs, not only for recently introduced drugs, but also for established agents such as azathioprine and cyclosporine. Pharmacokinetic monitoring usually focuses on reaching certain target drug concentrations. Such ranges have been developed by retrospective review of drug concentration data and their correlation with clinical outcome. Multicenter concentration-controlled clinical trials can provide a basis for designing future prospective TDM investigations. Ideally, added to these trials should be also one or more pharmacodynamic tests, to quantify the biological effect of the drugs applied. Although on theoretical grounds monitoring the pharmacodynamic effect makes more sense than monitoring drug concentrations, in daily practice pharmacodynamic monitoring is not performed. Defining optimal ranges for pharmacokientic and pharmacodynamic drug monitoring of immunosuppressive drugs may lead to further improvement of the safety and efficacy of our immunosuppressive regimens.

Therapeutic Drug Monitoring of Aminoglycosides in Neonates

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to extended-interval dosing. This evolution has also taken place in neonates. Neonates, however, display large interindividual differences in the pharmacokinetics of aminoglycosides due to developmental differences early in life. The volume of distribution of aminoglycosides shows a strong relationship with bodyweight, which tends to be larger (corrected for bodyweight) in more premature infants and those with sepsis. Renal clearance of aminoglycosides increases with gestational age and accelerates immediately after birth. Because of these developmental influences, there is great inter- and intraindividual variability in the volume of distribution and clearance of these drugs, and investigators have established aminoglycoside dosing regimens based on bodyweight and/or gestational age. Widely practised dosing regimens comprise 4-5 mg/kg bodyweight of gentamicin every 24-48 hours as a first dose, followed by dose adjustment based on therapeutic drug monitoring. Although formal toxicity studies are scarce, there is no evidence that aminoglycoside toxicity in neonates differs from that in adults. Monitoring of blood drug concentrations and intelligent reconstruction of individual pharmacokinetic behaviour using a population pharmacokinetic model, optimally chosen blood sampling times and appropriate pharmacokinetic software, help clinicians to quickly optimize aminoglycoside dosing regimens to maximize the clinical effect and minimize the toxicity of these drugs.

Irreversible CYP3A Inhibition Accompanied by Plasma Protein–Binding Displacement: A Comparative Analysis in Subjects With Normal and Impaired Liver Function

In this study, quinine was used as a probe substrate and erythromycin as a prototypical irreversible inhibitor of CYP3A to ascertain whether, like reversible CYP inhibition, the magnitude of irreversible inhibition is also strictly dependent on the status of liver function. The effect of erythromycin on oral quinine disposition was studied in 10 healthy subjects and in 20 patients with cirrhosis of the liver who had varying degrees of liver dysfunction. This effect was shown to be the result of two types of interaction: (i) irreversible inhibition of CYP3A-mediated quinine metabolism, the extent of which proved to be independent of liver function, and (ii) displacement of quinine from plasma protein-binding sites, the magnitude of the displacement increasing dramatically as liver function worsened. Such an interaction causes limited increases in the total concentration of the displaced drug but disproportionate increases in its free concentration; the latter increases are magnified by liver dysfunction, thereby requiring that the monitoring of free drug concentrations be made mandatory.

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

The successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. As the population of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel (57). Despite recent advances in antifungal pharmacology, the morbidity and mortality due to invasive fungal infections remain unacceptably high. Numerous factors determine the outcome of these infections, including the host immune state, pathogen variables including drug susceptibility, location of the infection, timing of diagnosis relative to initiation of antifungal therapy, management of the infection source (e.g., surgery or vascular catheter removal), and effective administration of the appropriate dose of the most potent and safe antifungal drug (Fig. ​(Fig.1).1). Few of these variables are under the control of the clinician. The choices of antifungal drug and dosing regimen are among the factors which the clinician can dictate. However, even if the appropriate drug and regimen are initiated, drug exposure at the site of infection may be inadequate due to pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed those anticipated and may result in toxicity. Many antifungal drugs exhibit marked variability in drug blood concentrations due to inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. An understanding of the pharmacokinetics and pharmacodynamics of these drugs has been demonstrated to be important to optimize drug choice and dosing regimen design. One tool to detect drug exposures outside of the therapeutic window is monitoring of drug concentration in blood. The utility of this tool to inform drug choice and dosing decisions is being increasingly explored. FIG. 1. Determinants for outcome of invasive mycoses. Several factors must be considered in determining the role of therapeutic drug monitoring in patient management (32, 86, 88). An accurate, rapid, and cost-effective drug assay must be readily available to the clinician. Two pharmacological features then determine the relevance of monitoring of concentrations of drug in blood. The foremost variable is an unpredictable drug dose-exposure relationship. Next, there must be a clear relationship between concentrations of drug in blood and either toxicity or treatment efficacy. Consideration of these pharmacological variables for available antifungal compounds is the focus of this review.

24 PHOTODYNAMIC THERAPY FOR SKIN CANCER WITH CHLORIN DERIVATIVES UNDER THE OUTPATIENT CONDITIONS

Photodynamic therapy (PDT) has slowly found its place in the treatment of human disease. Currently, photodynamic therapy is being explored as a treatment option for localized prostate cancer. PDT for the treatment of prostate cancer will require ablation of both malignant and non-malignant glandular epithelium. Ablation of both malignant and normal epithelium adds a new treatment dimension since traditionally PDT has not targeted normal epithelial tissue. PDT for prostate cancer as currently envisioned will present challenges in terms of in situ monitoring of light, drug concentration, pO2 levels and biologic endpoints. The introduction of vascular-targeted photosensitizers fundamentally alters the traditional axioms for successful PDT treatment by obviating the need for “selective” tumor localization. Should clinical trials demonstrate the utility of this approach, patients with organ-confined disease will benefit.

66 THE DIFFERENT RESPONSES OF THE MAIN SYMPTOMS OF INNER EAR EXHAUSTION TO A SPECIFIC HIGH DOSAGE LOW LEVEL LASER THERAPY

In this study we investigated the pharmacokinetics of a hematoporphyrin derivative (Photogem®) in Wistar rats using the fluorescence spectroscopy to evaluate the drug distribution in liver, kidney and skin tissues. The detection system is composed of a 532 nm exciting laser, a Y-type catheter for light delivery and collection, a monochromator and a computer for data acquisition. The analysis of the fluorescence spectra was based on the intensity of porphyrin emission bands from specific tissues of the investigated organ. A simple transport model is proposed to determine the accumulation and elimination times for each type of investigated tissue. The obtained results show the viability of the fluorescence spectroscopic technique for the drug concentration monitoring in different target tissues and related pharmacokinetics. These effects should be considered before any in vivo study of Photodynamic Therapy using Photogem®.

Fungal infections in lung transplant recipients

Despite numerous advances in lung transplantation, survival is still significantly compromised by a higher rate of infections. This review intends to provide an overview of the most common fungal infections afflicting lung transplant recipients, focusing on the most recent developments in diagnosis, therapy and prophylaxis. Although detection of galactomannan in serum has poor sensitivity for the diagnosis of invasive aspergillosis in lung transplant recipients, detection of galactomannan in the bronchoalveolar lavage of a lung transplant recipient, with a compatible clinical illness, is highly suggestive of invasive disease. New antifungal agents, with a broader spectrum of activity and a more tolerable side effect profile, have become available for the treatment and prophylaxis of fungal infections. Evidence suggests that, at least for voriconazole, monitoring of drug concentrations may be advisable to prevent clinical failure due to underdosing and toxicity due to excessive dosing. Fungal infections remain a significant cause of morbidity and mortality in lung transplant recipients; however, advances have been made in the recent years, which will allow earlier diagnosis and more effective and tolerated treatment.

Prescribing and Monitoring Clozapine in Christchurch

The aim of the study was to identify the pattern of usage of clozapine in Christchurch, New Zealand, including daily dose, indication and use of drug concentration monitoring. Patients (n=353) were identified retrospectively from the pharmacy computer system. Data gathered included patient demographics, the daily clozapine dose and the number of occasions that clozapine drug concentration monitoring occurred. In addition, each psychiatrist who had prescribed clozapine was surveyed, regarding their indications for the use of clozapine and their use of clozapine drug concentration monitoring. The majority (63%) of patients on clozapine were male. The mean age of the patients was 43 years (range 15-88 years). The mean daily dose of clozapine was 325 mg (range 12.5-900 mg). Patients over the age of 65 years were on a significantly lower dose (mean=143 mg, 95% CI=103-183 mg) compared with those under 65 years of age (mean=350 mg, 95% CI=330-370 mg). The median duration of treatment on clozapine was 4 years. Fifty-one percent of patients had undergone drug concentration monitoring, the majority on multiple occasions. In females, increasing age correlated with an increase in dose-corrected plasma clozapine concentrations (r(2)=0.29, p<0.001). This was not demonstrated in the male population. Of the psychiatrists surveyed, 44% prescribed clozapine for unlicensed indications and 79% used clozapine drug concentration monitoring in their patients. This was most commonly performed to assess compliance or confirm toxicity. The mean daily dose of clozapine of 325 mg was similar to that found in other studies. An age-related decline in dose was observed, probably due to different indications, with many of the elderly patients receiving clozapine for Parkinsonian related symptoms. There was also an age-related decline apparent in clearance in females. Clozapine was often used for unlicensed indications, and a clear majority of psychiatrists use drug concentration monitoring.

Tamoxifen and its Main Metabolites Serum and Tissue Concentrations in Breast Cancer Women

Because of a possible relationship between tamoxifen (T) concentrations and clinical effects, we initiated a preliminary investigation on serum and tissue concentrations of T and its main active metabolites, and 4-hydroxytamoxifen, in women with positive breast cancer estrogen receptor. One hundred forty-eight patients were studied: 80 were admitted for monitoring of therapeutic serum drug concentrations, 22 had tissue concentrations taken at surgery, and 46 patients had uterine mucosa levels measured at diagnostic hysteroscopy. Steady-state serum concentrations were reached after 1 month of continuous treatment, with desmethyltamoxifen being the highest represented derivative from the third week onward. There was no relationship between dose (in mg/kg body weight) and steady-state serum concentrations during therapeutic drug monitoring of patients. The highest tissue concentrations were observed in breast lymph-nodes, cancer tissue, and uterine mucosa. On the basis of these data, we speculate that T and its active metabolites may exert both a defensive role (ie, an obstacle to the diffusion of malignant cells through the local lymphatic system) and a harmful one (induction of uterine malignancies).

Application of the Cockcroft–Gault method to estimate lithium dosage requirement

The aim of the present study was to assess the precision and bias of a priori methods in the estimation of lithium dosage requirement among bipolar patients. The charts of 82 Diagnostic and Statistical Manual of Mental Disorder-fourth edition bipolar patients with previous history of lithium intoxication were reviewed. After excluding patients who had discontinued lithium treatment, 69 patients were entered to the study. Another 60 bipolar patients without history of lithium intoxication were also included in the study. The demographic data regarding factors thought to affect serum lithium concentrations, including gender, weight, and renal function, was retrospectively collected. Predicted daily lithium doses were calculated by using the new equation derived by the present authors and a priori methods proposed by Pepin et al., Zetin et al., Terao et al. and Keck et al. Mean error was calculated to assess the precision and bias of each a priori method. The Zetin method, the Terao method, and the Keck method had a significant tendency to overpredict dosage requirement. The Pepin method significantly underpredicted dosage. Only the 95% confidence interval of mean error of the present authors' equation was across zero. The present authors' equation represents a precise approach to estimate the lithium dose requirement and is easy to calculate. Regardless of the accuracy of each a priori method in predicting a patient's drug dosage, there is no substitute for proper serum drug concentration monitoring and good clinical judgment. Predictions made by any method should always be assessed clinically before applying its use in a patient.

Parallel Monitoring of Plasma and Intraluminal Drug Concentrations in Man After Oral Administration of Fosamprenavir in the Fasted and Fed State

The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

Effects of Daily Ingestion of Cranberry Juice on the Pharmacokinetics of Warfarin, Tizanidine, and Midazolam—Probes of CYP2C9, CYP1A2, and CYP3A4

Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.

Simultaneous determination of first‐line anti‐tuberculosis drugs and their major metabolic ratios by liquid chromatography/tandem mass spectrometry

Monitoring of anti-tuberculosis drug concentrations and dose adjustment can be helpful in cases that show poor response to treatment. Here, we describe a method that can rapidly and simultaneously measure the blood concentrations of four anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) and two major metabolic ratios (acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin) using high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A C18 reversed-phase column and gradients of methanol in 0.3% formic acid and water were used for HPLC separation. The drug concentrations were determined by multiple reaction monitoring in positive ion mode and the assay performance was evaluated. We determined peak concentration ranges for each drug and acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin ratios by analyzing 2-h post-dose samples in patients treated with standard dosing as a first-line treatment. The preparation of 20 samples including two steps of deproteinization with 50% and 100% methanol was performed within 20 min and chromatographic separation was achieved within 4 min/sample. Interassay calibration variability data obtained over concentrations of 0-8 microg/mL for isoniazid and ethambutol and 0-80 microg/mL for rifampicin and pyrazinamide showed a linear and reproducible curve. Within-run and between-run imprecision (CVs) were 1.9-5.5% and 3.5-10.5% and the lower limits of detection and quantification were 0.01-0.5 microg/mL and 0.05-1.0 microg/mL, respectively. The isoniazid concentration was found to be inversely correlated to the acetylisoniazid/isoniazid ratio (R=-0.739, P<0.001). The devised method allows for the simple, rapid, sensitive and reproducible quantification of isoniazid, rifampicin, pyrazinamide, ethambutol and their two metabolic ratios and should be helpful for therapeutic drug monitoring in tuberculosis patients.

Optical method for real-time monitoring of drug concentrations facilitates the development of novel methods for drug delivery to brain tissue

The understanding of drug delivery to organs, such as the brain, has been hampered by the inability to measure tissue drug concentrations in real time. We report an application of an optical spectroscopy technique that monitors in vivo the real-time drug concentrations in small volumes of brain tissue. This method will facilitate development of new protocols for delivery of drugs to treat brain cancers. The delivery of many anticancer drugs to the brain is limited by the presence of the blood-brain barrier (BBB). Mitoxantrone (MTX) is a water-soluble anticancer drug that poorly penetrates the BBB. It is preliminarily determined in an animal model that the brain tissue uptake of chemotherapy agents-in this demonstration, MTX-delivered intra-arterially is enhanced when the BBB is disrupted.

Management of Epilepsy during Pregnancy

Managing epilepsy during pregnancy is to balance the maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects of antiepileptic drugs (AEDs). A rational approach requires knowledge of such risks as well as an understanding of the effects of pregnancy on seizure control and of gestational effects on AED disposition. Uncontrolled tonic-clonic seizures are potentially hazardous to the mother and, although strict evidence is lacking, are generally also assumed to be more harmful to the fetus than are AEDs. However, infants who have been exposed to AEDs in utero run an increased risk of congenital malformations: approximately twice the rate reported in the general population. Earlier literature has largely failed to demonstrate differences in birth defect rates with different treatment regimens, which can be ascribed mainly to insufficient sample sizes. More recent data have indicated higher malformation rates with exposure to valproic acid compared with some other major AEDs. The teratogenic effects of valproic acid appear to be dose dependent, with higher risks at dosage levels >1000 mg/day. Polytherapy involving treatment with more than one AED also seems to be associated with an increased risk of birth defects compared with monotherapy. Recently, a few small-scale studies have investigated the possibility that exposure to AEDs in utero may adversely affect the postnatal cognitive development of the offspring. Some of these studies have suggested that valproic acid poses a higher risk compared with other AEDs in this respect. These signals are important, but must be interpreted with caution because of the methodological shortcomings of the studies and because adequately powered prospective studies are necessary to draw firm conclusions. More reassuring findings have emerged regarding the obstetric outcome of pregnancy and the risk of worsening of epilepsy during pregnancy. In particular, it seems that the risk of obstetric complications is not significantly increased. Furthermore, most of the women with epilepsy have no change in their seizure frequency during pregnancy. The disposition of many AEDs may change during pregnancy, reflected in declining plasma drug concentrations. This seems to be most pronounced for lamotrigine and possibly also for oxcarbazepine, and can result in break-through seizures. The common treatment strategy has been to use the appropriate AED for the woman's seizure disorder as monotherapy in the lowest effective dosage throughout pregnancy, the objective being to use AEDs in such a way that generalised tonic-clonic seizures are avoided but with minimised risks to the fetus, the newborn and the breast-fed infant. Valproic acid should be avoided if possible. Any major change in the treatment of a woman with epilepsy should ideally be completed before conception. Regular monitoring of drug concentrations is recommended during pregnancy, in particular for lamotrigine and oxcarbazepine.