Extension de temps QT
Effets indésirables des médicaments
Variantes ✨Pour l'évaluation intensive en calcul des variantes, veuillez choisir l'abonnement standard payant.
Explications pour les patients
Nous n'avons aucun avertissement supplémentaire pour l'association de nefazodon, alprazolam et de carbamazépine. Veuillez également consulter les informations spécialisées pertinentes.
|Carbamazépine||1.05 [1.05,1.57] 1||1.05||1|
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. Nous n'avons détecté aucune modification de l'exposition à la nefazodon, lorsqu'il est combiné avec la alprazolam (100%). Nous ne pouvons actuellement pas estimer l'influence de la carbamazépine. L'exposition à la carbamazépine augmente à 105%, lorsqu'il est associé à la nefazodon (105%) et à la alprazolam (100%). L'ASC est comprise entre 105% et 157% selon le
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La nefazodon a une faible biodisponibilité orale [ F ] de 20%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer de manière significative avec une interaction. La liaison aux protéines [ Pb ] est très forte à 99%. Le métabolisme s'effectue principalement via le CYP3A4.
La alprazolam a une biodisponibilité orale élevée [ F ] de 88%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à peu changer pendant une interaction. La demi-vie terminale [ t12 ] est de 11.7 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est modérément forte à 70.2% et le volume de distribution [ Vd ] est de 50 litres dans la fourchette moyenne, Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Le métabolisme s'effectue principalement via le CYP3A4.
La carbamazépine a une biodisponibilité orale moyenne [ F ] de 78%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est de 20 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est modérément forte à 77.2% et le volume de distribution [ Vd ] est très important à 90 litres, Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Le métabolisme a lieu via le CYP1A2, CYP2C8, CYP2C9 et le CYP3A4, entre autres.
|Les scores||∑ Points||nef||alp||car|
|Effets sérotoninergiques a||2||++||Ø||Ø|
Recommandation: Par mesure de précaution, les symptômes de surstimulation sérotoninergique doivent être pris en compte, notamment après augmentation de la dose et à des doses dans la plage thérapeutique supérieure.
Évaluation: La nefazodon module le système sérotoninergique dans une mesure modérée. Le risque de syndrome sérotoninergique peut être classé comme faible avec ce médicament si la posologie se situe dans la plage habituelle. Selon nos connaissances, ni la alprazolam ni la carbamazépine n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||nef||alp||car|
|Kiesel & Durán b||2||+||Ø||+|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à des doses dans l'intervalle thérapeutique supérieur.
Évaluation: La nefazodon et la carbamazépine n'ont qu'un effet léger sur le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la posologie se situe dans la plage habituelle. Selon nos résultats, la alprazolam n'augmente pas l'activité anticholinergique.
Extension de temps QT
Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la nefazodon, alprazolam et la carbamazépine.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||nef||alp||car|
|Mal de crâne||39.0 %||39.0||n.a.||n.a.|
|La nausée||25.0 %||18.5||n.a.||8.0|
|Problème de coordination||24.8 %||n.a.||24.8↓||n.a.|
Déficience de mémoire (24.3%): alprazolam
Dysarthrie (17.1%): alprazolam
Confusion (12.5%): alprazolam, nefazodon
Asthénie (10%): nefazodon
Crise d'épilepsie: nefazodon
Augmentation de l'appétit (19.9%): alprazolam
Gain de poids (14.9%): alprazolam
La dépression (11.7%): alprazolam, nefazodon
Effet de rebond: alprazolam
Vision floue (11.2%): carbamazépine, nefazodon
Diminution de la libido (10.2%): alprazolam
Réactions cutanées allergiques (10%): carbamazépine
Syndrome de Stevens-Johnson: alprazolam, carbamazépine, nefazodon
Nécrolyse épidermique toxique: carbamazépine
Vomissements (8%): carbamazépine
Hypotension orthostatique (3.4%): nefazodon
Bloc auriculo-ventriculaire: carbamazépine
Leucopénie (2%): carbamazépine
Œdème périphérique: carbamazépine
Insuffisance hépatique: alprazolam, nefazodon
Hépatite cholestatique: carbamazépine
Syndrome de disparition des voies biliaires: carbamazépine
Réaction d'hypersensibilité: carbamazépine, nefazodon
Néphrite tubulo-interstitielle: carbamazépine
Sur la base de vos
Abstract: The interaction between fluoxetine and carbamazepine was investigated in six normal, healthy male volunteers (aged 23 to 40 years). Subjects were given carbamazepine, 400 mg every morning, for 3 weeks. Venous carbamazepine blood samples were obtained at baseline and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the morning dose. Fluoxetine, 20 mg every morning, was then coadministered with carbamazepine for 7 days. Venous carbamazepine blood samples were again obtained as described. Carbamazepine and carbamazepine-10,11-epoxide (CBZE) were assayed by HPLC. Addition of fluoxetine resulted in a significant increase in the area under the concentration-time curve of carbamazepine (105.93 +/- 18.05 micrograms/ml.hr versus 134.97 +/- 12.15 micrograms/ml.hr; t = 3.284; df = 5; p = 0.022) and CBZE (11.6 +/- 1.93 micrograms/ml.hr versus 15.2 +/- 2.4 micrograms/ml.hr; t = 2.805; df = 5; p = 0.038). Both oral and intrinsic clearance of carbamazepine was decreased significantly on fluoxetine addition (3.87 +/- 0.68 L/hr versus 2.98 +/- 0.26 L/hr; t = 3.025; df = 5; p = 0.029 and 17.90 +/- 4.9 L/hr versus 11.92 +/- 1.4 L/hr; t = 3.037; df = 5; p = 0.029, respectively). No significant changes were determined for fraction of absorbed dose, volume of distribution, absorption rate constant, and elimination rate constant. These findings suggest that fluoxetine can inhibit the metabolism of carbamazepine. Careful monitoring of patients is recommended when these two drugs are coadministered.
Abstract: Alprazolam is a short-acting triazolobenzodiazepine with anxiolytic and antidepressant properties. It has a half-life of 10-15 hours after multiple oral doses. Approximately 20% of an oral dose is excreted unchanged in the urine. The major urinary metabolites are alpha-OH alprazolam glucuronide and 3-HMB benzophenone glucuronide. The objective of this study was to characterize the reactivity of alprazolam and three metabolites in the Abbott ADx and TDx urinary benzodiazepine assays compared with the EMIT d.a.u. benzodiazepine assay. Alprazolam (at 300 ng/mL) gave an equivalent response as the 300 ng/mL low control (nordiazepam). alpha-OH alprazolam gave an equivalent response to this control between 300-500 ng/mL and 4-OH alprazolam between 500-1000 ng/mL. The 3-HMB benzophenone was not positive even at 10,000 ng/mL. The ADx screening assay was positive in 26 of 31 urine specimens collected from alprazolam-treated patients. All 31 of these specimens were confirmed positive for alpha-OH alprazolam by GC/MS after enzymatic hydrolysis and formation of a TMS derivative. For the TDx, 27 of 31 specimens were positive for benzodiazepines and all 31 were confirmed by GC/MS. All 5 of the negative ADx specimens and 4 of 5 TDx specimens contained 150-400 ng/mL of alpha-OH alprazolam. In conclusion, both the ADx and TDx urine benzodiazepine assays are acceptable screening assays for alprazolam use when the alpha-OH alprazolam concentration is greater than 400 ng/mL.
Abstract: Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.
Abstract: Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.
Abstract: A number of drugs inhibit the metabolism of carbamazepine catalyzed by cytochrome P450, sometimes resulting in carbamazepine intoxication. However, there is little information available concerning the identity of the specific isoforms of P450 responsible for the metabolism of this drug. This study addressed the role of CYP3A4 in the formation of carbamazepine-10,11-epoxide, the major metabolite of carbamazepine. Results of the study showed that: (1) purified CYP3A4 catalyzed 10,11-epoxidation; (2) cDNA-expressed CYP3A4 catalyzed 10,11-epoxidation (Vmax = 1730 pmol/min/nmol P450, Km = 442 microM); (3) the rate of 10,11-epoxidation correlated with CYP3A4 content in microsomes from sixteen human livers (r2 = 0.57, P < 0.001); (4) triacetyloleandomycin and anti-CYP3A4 IgG reduced 10,11-epoxidation to 31 +/- 6% (sixteen livers) and 43 +/- 2% (four livers) of control rates, respectively; and (5) microsomal 10,11-epoxidation but not phenol formation was activated 2- to 3-fold by alpha-naphthoflavone and progesterone and by carbamazepine itself (substrate activation). These findings indicate that CYP3A4 is the principal catalyst of 10,11-epoxide formation in human liver. Experiments utilizing a panel of P450 isoform selective inhibitors also suggested a minor involvement of CYP2C8 in liver microsomal 10,11-epoxidation. Epoxidation by CYP2C8 was confirmed in incubations of carbamazepine with cDNA-expressed CYP2C8. The role of CYP3A4 in the major pathway of carbamazepine elimination is consistent with the number of inhibitory drug interactions associated with its clinical use, interactions that result from a perturbation of CYP3A4 catalytic activity.
Abstract: Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals. Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP). The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration. The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups. Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4. Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.
Abstract: BACKGROUND: St John's Wort is a popular herbal product used by approximately 7% of patients with epilepsy. Previous reports have described reductions in concentrations of CYP3A4 substrates indinavir and cyclosporine (INN, ciclosporin) associated with St John's Wort. OBJECTIVE: Our objective was to determine the effect of St John's Wort on steady state carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics. METHODS AND SUBJECTS: Eight healthy volunteers (5 men; age range, 24-43 years) participated in this unblinded study. Subjects received 100 mg of carbamazepine twice daily for 3 days, 200 mg twice daily for 3 days, and then 400 mg once daily for 14 days. Blood samples were collected before and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the dose on day 21. The subjects then took 300 mg of St John's Wort (0.3% hypericin standardized tablet) 3 times daily with meals and with carbamazepine for 14 days. On day 35, blood sampling was repeated. Plasma samples were analyzed for carbamazepine and carbamazepine-10,11-epoxide with HPLC. We compared carbamazepine and carbamazepine-10,11-epoxide noncompartmental pharmacokinetic parameter values before and after St John's Wort with a paired Student t test. RESULTS: We found no significant differences before or after the administration of St John's Wort in carbamazepine peak concentration (7.2 +/- 1 mg/L before versus 7.6 +/- 1.3 mg/L after), trough concentration (4.8 +/- 0.5 mg/L before versus 4.3 +/- 0.8 mg/L after), area under the plasma concentration-time curve (142.4 +/- 12.9 mg x h/L before versus 143.8 +/- 27.2 mg x h/L after), or oral clearance (2.8 +/- 0.3 L/h before versus 2.9 +/- 0.6 L/h after). Similarly, no differences were found in peak concentration (2 +/- 0.5 mg/L before versus 2.1 +/- 0.4 mg/L after), trough concentration (1.3 +/- 0.3 mg/L before versus 1.4 +/- 0.3 mg/L after), and area under the plasma concentration-time curve (37.5 +/- 7.4 mg x h/L before versus 41.9 +/- 10.3 mg x h/L after) of carbamazepine-10,11-epoxide. CONCLUSIONS: The results suggest that treatment with St John's Wort for 14 days did not further induce the clearance of carbamazepine.
Abstract: Nefazodone is an antidepressant with a relatively unique structure and mechanism of action. The current study was conducted to assess the potential for nefazodone to have metabolic drug interactions associated with cytochrome P450 (CYP) enzymes. Nefazodone is metabolised to hydroxynefazodone (OH-NEF), triazoledione (TD), and m-chlorophenylpiperazine (m-CPP), and OH-NEF is metabolised to TD and m-CPP. Correlations with enzyme activities in a panel of microsomes prepared from human livers, incubations with heterologously expressed human CYP enzymes, and incubations with enzyme inhibitors were used to study these metabolic pathways. The results suggest that the metabolism of NEF and OH-NEF to each of their active metabolites is catalysed mainly by CYP3A4, which is in agreement with clinical reports of drug--drug interactions of nefazodone with substrates and inhibitors of CYP3A4.
Abstract: OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: BACKGROUND: Roughly 20% of patients in hospital have impaired kidney function. This is frequently overlooked because of the creatinine-blind range in which early stages of renal failure are often hidden. Chronic kidney disease is divided into 5 stages (CKD 1 to 5). METHODS: Selective literature search. RESULTS: Methotrexate, enoxaparin and metformin are examples of drugs that should no longer be prescribed if the glomerular filtration rate (GFR) is 60 mL/min or less. With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. atenolol) or anticonvulsive (e.g. gabapentin) drugs, the advice is to use alternative preparations such as gliquidone, metoprolol or carbamazepine which are independent of kidney function. Drug dose adjustment should be considered with antimicrobial (e.g. ampicillin, cefazolin), antiviral (e.g. aciclovir, oseltamivir) and, most recently, also for half of all chemotherapeutic and cytotoxic drugs in patients with impaired kidney function (with e.g. cisplatin, for instance, but not with paclitaxel). CONCLUSION: Decisions concerning drug dose adjustment must be based on the pharmacokinetics but this is an adequate prerequisite only in conjunction with the pharmacodynamics. There are two different dose adjustment rules: proportional dose reduction according to Luzius Dettli, and the half dosage rule according to Calvin Kunin. The latter leads to higher trough concentrations but is probably more efficient for anti-infective therapy.
Abstract: Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half-life in patients at steady state have not been determined. We developed an intravenous, stable-labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety-two patients received a 100-mg infusion of SL-carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography-mass spectrometry, and concentration-time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half-life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.
Abstract: To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 22.214.171.124 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r=0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT-1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs.
Abstract: The aim of the present study was to investigate the distribution ofvariantsand, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). Theandpolymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose incarriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39. 15.46 ± 4.35 mg/kg;= 0.5]. Dose-normalized serum concentration of carbamazepine was higher in(mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL,= 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only innon carriers (r = 0.52,= 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect ofpolymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that thepolymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.