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
Surveillance de la fluconazole et de la ciclosporine recommandée.
Augmentation des niveaux de cyclosporineMécanisme: La ciclosporine est à la fois un substrat et un inhibiteur du CYP3A4 et de la P-glycoprotéine. Le fluconazole est un inhibiteur modérément puissant du CYP3A4 et est lui-même principalement métabolisé par le CYP3A4. En association, une augmentation des concentrations de ciclosporine peut survenir.
Effet: Dans une étude chez des patients après transplantation rénale qui étaient stables sous ciclosporine, il y a eu une augmentation de 1,3 fois de l'ASC de la ciclosporine (jour 2 par rapport à la valeur initiale) après l'administration de 200 mg / jour de fluconazole pendant 14 jours 1,7 fois (jour 4 par rapport à la ligne de base). Après avoir réduit la dose de cyclosporine de 50% au jour 8, l'ASC a chuté de manière significative à environ 80% de la valeur initiale. Cependant, la variabilité interindividuelle de l'augmentation était grande. Avec l'augmentation des concentrations de ciclosporine, le risque d'effets indésirables tels que des troubles gastro-intestinaux, des maux de tête, une tachycardie pouvant aller jusqu'à une insuffisance rénale et une neurotoxicité est augmenté.
Mesures: Si le fluconazole est utilisé chez des patients qui reçoivent déjà de la ciclosporine, les concentrations de ciclosporine doivent être étroitement surveillées (par exemple avant le début du traitement, après 2 jours, après 4 jours, régulièrement pendant le traitement, à l'arrêt). La dose doit être ajustée en fonction des contrôles de niveau. Une surveillance régulière des concentrations de ciclosporine est recommandée pendant toute la durée de l'association. Une attention particulière doit être portée aux signes d'augmentation des effets indésirables (surveillance étroite de la fonction rénale - détérioration de la fonction rénale, neuropathie / paresthésie). Si le traitement par fluconazole est à nouveau arrêté, la posologie de la ciclosporine doit être ajustée sous un contrôle étroit de la concentration: si la concentration de ciclosporine est réduite, l'effet immunosuppresseur pourrait sinon être limité et le risque de rejet de greffe augmenté.
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. L'exposition à la ciclosporine augmente à 137%, lorsqu'il est associé à la alogliptine (100%) et à la fluconazole (137%). L'exposition à la alogliptine augmente à 107%, lorsqu'il est associé à la ciclosporine (104%) et à la fluconazole (106%). Nous ne prévoyons aucun changement d'exposition à la fluconazole, lorsqu'il est associé à la ciclosporine (100%) et à la alogliptine (100%).
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La ciclosporine a une faible biodisponibilité orale [ F ] de 27%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer de manière significative avec une interaction. La demi-vie terminale [ t12 ] est de 13.35 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est 95.4% forte et le volume de distribution [ Vd ] est très important à 92 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 s'effectue principalement via le CYP3A4 et le transport actif se fait notamment via PGP.
La alogliptine a une biodisponibilité orale élevée [ F ] de 95%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à peu changer pendant une interaction. La demi-vie terminale [ t12 ] est de 21 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est très faible à 20% et le volume de distribution [ Vd ] est très important à 417 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. Environ 65.5% d'une dose administrée est excrétée inchangée par les reins et cette proportion est rarement modifiée par les interactions. Le métabolisme a lieu via le CYP2D6 et le CYP3A4, entre autres.
La fluconazole a une biodisponibilité orale élevée [ F ] de 90%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à peu changer pendant une interaction. La demi-vie terminale [ t12 ] est assez longue à 30 heures et des taux plasmatiques constants [ Css ] ne sont atteints qu’après plus de 120 heures. La liaison aux protéines [ Pb ] est très faible à 11.5% et le volume de distribution [ Vd ] est de 56 litres. Environ 80.0% d'une dose administrée est excrétée inchangée par les reins et cette proportion est rarement modifiée par les interactions. Le métabolisme ne se fait pas via les cytochromes communs.
|Les scores||∑ Points||cic||alo||flu|
|Effets sérotoninergiques a||0||Ø||Ø||Ø|
Évaluation: Selon nos connaissances, ni la ciclosporine, alogliptine ni la fluconazole n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||cic||alo||flu|
|Kiesel & Durán b||0||Ø||Ø||Ø|
Évaluation: Selon nos résultats, ni la alogliptine ni la fluconazole n'augmentent l'activité anticholinergique. L'effet anticholinergique de la ciclosporine est insignifiant.
Extension de temps QT
|Les scores||∑ Points||cic||alo||flu|
Évaluation: La fluconazole peut déclencher des arythmies ventriculaires potentiellement de torsades de pointes. Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la ciclosporine et la alogliptine.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||cic||alo||flu|
|Mal de crâne||20.3 %||10.0||4.3||7.5|
|La nausée||4.7 %||n.a.||n.a.||4.7|
|Infection respiratoire supérieure||4.5 %||n.a.||4.5||n.a.|
Crise d'épilepsie (3%): ciclosporine, fluconazole
Leucoencéphalopathie multifocale progressive: ciclosporine
Vomissements (1.7%): fluconazole
Hypertrophie gingivale: ciclosporine
Réaction d'hypersensibilité: alogliptine
Syndrome de DRESS: fluconazole
Sensation de brûlure dans les yeux: ciclosporine
Douleur dans les yeux: ciclosporine
Phosphatase alcaline élevée: fluconazole
ALT élevé: fluconazole
AST élevé: fluconazole
Insuffisance hépatique: alogliptine, fluconazole
Insuffisance cardiaque: alogliptine
Syndrome de Stevens-Johnson: alogliptine, fluconazole
Nécrolyse épidermique toxique: fluconazole
Syndrome hémolytique urémique: ciclosporine
Sur la base de vos
Abstract: The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37 degrees C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre-rifampin phase. Post-rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.
Abstract: 1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.
Abstract: To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.
Abstract: 1. The oral pharmacokinetics of fluconazole were studied in three groups of volunteers (n = 5) with various degrees of renal function (GFR greater than 70 ml min-1; 20-70 ml min-1; less than 20 ml min-1) and in a group of patients with chronic end-stage renal failure requiring regular haemodialysis. 2. The pharmacokinetics of fluconazole were markedly affected by impaired renal function with the elimination of half-life in Group III (GFR less than 20 ml min-1) being approximately three times that observed in normal volunteers (Group I). 3. Fluconazole renal clearance was positively correlated with GFR. 4. Non-renal clearance of fluconazole decreased with decreasing renal function. 5. Approximately 38% of the 50 mg dose of fluconazole was removed by haemodialysis extending over a 3 h period.
Abstract: Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life = 12.1 +/- 5.0 h, apparent volume of distribution at steady-state = 5.6 +/- 2.11 X kg-1, apparent clearance = 0.51 +/- 0.11 l X h-1 X kg-1. The time lag between drug ingestion and first blood level was short, 0.38 +/- 0.11 h. Drug absorption lasted for 2.8 +/- 1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.
Abstract: OBJECTIVE: To present cases supporting the hypothesis that fluconazole inhibition of cyclosporine metabolism is dose-dependent. DESIGN: Case reports. PATIENTS AND INTERVENTIONS: One renal-pancreatic transplant patient taking fluconazole 100 and 300 mg/d for 37 and 17 days, respectively; four bone marrow transplant recipients taking fluconazole 100 mg/d as antifungal prophylaxis and five other concurrent nonmatched recipients whose antifungal prophylactic agent is nystatin mouthwash. All of these patients underwent transplantation during the same period. RESULTS: There was a sharp rise in cyclosporine trough concentration (ng/mL), concentration:dose ratio (ng.mL-1/mg.kg-1), and serum creatinine concentration (mumol/L) in the renal-pancreatic transplantation patient taking fluconazole 300 mg/d. No such increase occurred at 100 mg/d. No significant alterations in cyclosporine concentration:dose ratio were seen in the patients undergoing bone marrow transplantation and receiving fluconazole 100 mg/d. CONCLUSIONS: The case of the renal-pancreatic transplantation patient shows a characteristic interaction profile, and it supports the hypothesis of a dose-dependent interaction between cyclosporine and fluconazole. Given the nephrotoxic potential of the immunosuppressant drug, dosage reduction and closer monitoring of cyclosporine concentrations and/or renal function in patients receiving fluconazole dosages greater than 200 mg/d must be considered.
Abstract: BACKGROUND: Cyclosporin (CsA) is metabolized primarily in the liver by cytochrome P-450 enzymes. Concomitant use of fluconazole can increase CsA concentrations by inhibiting this enzyme system and the effect seems to be dose dependent, with no interaction noted when fluconazole is used in a dose of 100 mg/day. Two previous investigations studying this interaction while using higher doses of fluconazole have provided inconsistent results. Recommendations advising an empirical 50% CsA dosage reduction in these patients have not been tested in a prospective trial. METHODS: We studied six renal transplant recipients on CsA immunosuppression in a prospective, unblinded, crossover trial. Baseline renal functions, CsA area under the curve (AUC), Cmax, Cmin, CsA clearance, and Tmax were compared with those 2, 4 and 7 days after starting fluconazole orally in a dose of 200 mg/day. From day 8 onwards, patients reduced CsA dose by 50% and the above parameters were repeated on day 14. RESULTS: CsA AUC increased from 2887 +/- 1729 ng.h/ml on day 0 to 3842 +/- 1975 ng.h/ml on day 2 (P < 0.05), 4750 +/- 1718 ng.h/ml on day 4 (P< 0.01) and then decreased to 4052 +/- 1687 ng.h/ml on day 7 (P<0.01). Following CsA dose reduction by 50%, the mean AUC decreased significantly to 2330 +/- 1602 ng x h/ml (P<0.01). The Cmax showed a significant increase from 701 +/- 345 ng/ml on day 0 to 941 +/- 326 ng/ml (P < 0.01) on day 4 but decreased from 768 +/- 292 ng/ml on day 7 to 498 +/- 289 ng/ml on day 14, P<0.01. The mean Cmin increased from 207 +/- 138 ng/ml on day 0 to 274 +/- 168 ng/ml on day 4. No significant changes were observed in CsA clearance and Tmax. On repeated-measurement ANOVA, only the AUC and Cmax on day 4 of fluconazole were significantly higher than day 0 (P<0.001). There was a large interindividual variability in the degree of drug interaction between patients. CONCLUSIONS: Fluconazole given orally in a dose of 200 mg/day is associated with significant increase in bioavailability of CsA. The maximum effect occurs on day 4 after starting fluconazole. Although repeated monitoring of CsA Cmin is convenient as opposed to repeated determination of AUC, changes in Cmin may not be sensitive enough to pick up this interaction. The increase in bioavailability of CsA is unpredictable in individual patients and all patients should be monitored with AUC near day 4 of treatment to guide CsA dosage reductions.
Abstract: A 25-year-old woman who was hospitalized for worsening endocarditis had a prolonged QT interval at baseline and developed monomorphic ventricular arrhythmias, which were managed successfully with pacing and antiarrhythmic therapy. Several days later, the patient started receiving high-dose fluconazole for fungemia and subsequently experienced episodes of torsades de pointes, a polymorphic ventricular arrhythmia associated with a prolonged QT interval or prominent U wave on the electrocardiogram. The arrhythmia developed in the presence of known risk factors. Clinicians should be aware of these risk factors and other relevant structural similarities with drugs that cause torsades de pointes so that they can recognize patients who may be at risk for fluconazole-associated arrhythmia.
Abstract: Cyclosporine and tacrolimus share the same pharmacodynamic property of activated T-cell suppression via inhibition of calcineurin. The introduction of these drugs to the immunosuppressive repertoire of transplant management has greatly improved the outcomes in organ transplantation and constitutes arguably one of the major breakthroughs in modern medicine. To this date, calcineurin inhibitors are the mainstay of prevention of allograft rejection. The experience gained from the laboratory and clinical use of cyclosporine and tacrolimus has greatly advanced our knowledge about the nature of many aspects of immune response. However, the clinical practice still struggles with the shortcomings of these drugs: the significant inter- and intraindividual variability of their pharmacokinetics, the unpredictability of their pharmacodynamic effects, as well as complexity of interactions with other agents in transplant recipients. This article briefly reviews the pharmacological aspects of calcineurin antagonists as they relate to the mode of action and pharmacokinetics as well as drug interactions and monitoring.
Abstract: Fluconazole is an antifungal medication that has been reported to cause prolongation of the QT interval and Torsades de Pointes (TdP) ventricular tachycardia in adults. We describe the case of an 11-year-old child treated with fluconazole who developed ventricular arrhythmia culminating in TdP. We discuss the possible roles played by genetic and environmental factors in this child's rhythm disturbances. After briefly summarizing similar cases from the adult literature, we outline the putative mechanism by which fluconazole may cause arrhythmia. This case should alert pediatricians to the possible risks of fluconazole use, especially in the presence of electrolyte abnormalities, diuretic use, therapy with other pro-arrhythmic agents, or suspicion of congenital Long-QT Syndrome.
Abstract: OBJECTIVE: Although the drug interaction between fluconazole and calcineurin inhibitors has been established, the influence of the route of fluconazole administration on its drug interaction with calcineurin inhibitors has yet to be fully examined. The aim of the present study is to examine whether different routes of fluconazole administration alter its drug interactions with intravenous calcineurin inhibitors. METHODS: In 53 recipients of allogeneic hematopoietic cell transplantation receiving calcineurin inhibitors intravenously, steady-state whole-blood levels of cyclosporine A (CsA) or tacrolimus were measured after the route of fluconazole (200 mg/day) administration was switched from intravenous to oral. RESULTS: The mean steady-state whole-blood level of CsA or tacrolimus significantly increased after the route of fluconazole administration was switched from intravenous to oral (CsA: to 394 +/- 28.4 from 362 +/- 17.8 ng/mL; tacrolimus: to 18.8 +/- 0.64 from 17.4 +/- 0.39 ng/mL, P < 0.05). CONCLUSION: This finding strongly suggests that oral fluconazole has a greater impact on its drug interactions with intravenous calcineurin inhibitors than intravenous fluconazole. Monitoring of blood levels of intravenous calcineurin inhibitors is recommended when the route of fluconazole administration is switched from intravenous to oral.
Abstract: PURPOSE: A case of torsades de pointes associated with fluconazole use is described. SUMMARY: A 68-year-old woman with a history of hypertension treated with 2.5 mg of indapamide for 16 months sought medical treatment after having two falls 1 month apart. A computed tomography scan and subsequent magnetic resonance imaging of the brain revealed a lesion in the left pons and middle cerebellar peduncle. Biopsy of the pontine lesion revealed large yeast forms and subsequently revealed Cryptococcus neoformans var. gattii. The patient was initially treated with conventional amphotericin B and flucytosine for six weeks. The first week of therapy was complicated by hypokalemia, hypomagnesemia, and an episode of atrial fibrillation that was managed with electrolyte replacement, commencement of metoprolol, and switching from conventional amphotericin B to amphotericin B lipid complex. After six weeks, liposomal amphotericin was discontinued and high-dose oral fluconazole was initiated. Six days after beginning fluconazole therapy, the patient had a generalized tonic-clonic seizure and suffered cardiopulmonary arrest. Postresuscitation, an electrocardiogram demonstrated a corrected Q-T interval of 556 msec. Recurrent episodes of torsades de pointes were also recorded postarrest. Fluconazole was discontinued at this time, and liposomal amphotericin B was resumed. Neurologic and electroencephalographic assessment conducted 48 hours postarrest revealed that significant neurologic damage had been sustained. Supportive care was withdrawn, and the patient died two days later. A postmortem examination revealed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma. CONCLUSION: Treatment with high-dose fluconazole was the probable cause of torsades de pointes in a patient with risk factors for this condition. The benefits and risks of using fluconazole should be carefully weighed for patients with risk factors for Q-T interval prolongation.
Abstract: Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials. Furthermore, because acute rejection and drug-related adverse events do occur despite routine application of CNI TDM, alternative approaches to better predict the dose-concentration-response relationship in the individual patient are being explored. Monitoring of CNI concentrations in lymphocytes and other tissues, determination of CNI metabolites, and CNI pharmacogenetics and pharmacodynamics are in their infancy but have the potential to become useful additions to conventional CNI TDM. Although MPA is usually administered at a fixed dose, there is a rationale for MPA TDM, and this is substantiated by the increasing knowledge of the many nongenetic and genetic factors contributing to the interindividual and intraindividual variability in MPA pharmacokinetics. However, recent, large, randomized clinical trials investigating the clinical utility of MPA TDM have reported conflicting data. Therefore, alternative pharmacokinetic (ie, MPA free fraction and metabolites) and pharmacodynamic approaches to better predict drug efficacy and toxicity are being explored. Finally, for MPA and tacrolimus, novel formulations have become available. For MPA, the differences in pharmacokinetic behavior between the old and the novel formulation will have implications for TDM, whereas for tacrolimus, this probably will not to be the case.
Abstract: Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: No Abstract available
Abstract: All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.
Abstract: Programmed cell death, which occurs through a conserved core molecular pathway, is important for fundamental developmental and homeostatic processes. The human iron-sulfur binding protein NAF-1/CISD2 binds to Bcl-2 and its disruption in cells leads to an increase in apoptosis. Other members of the CDGSH iron sulfur domain (CISD) family include mitoNEET/CISD1 and Miner2/CISD3. In humans, mutations in CISD2 result in Wolfram syndrome 2, a disease in which the patients display juvenile diabetes, neuropsychiatric disorders and defective platelet aggregation. The C. elegans genome contains three previously uncharacterized cisd genes that code for CISD-1, which has homology to mitoNEET/CISD1 and NAF-1/CISD2, and CISD-3.1 and CISD-3.2, both of which have homology to Miner2/CISD3. Disrupting the function of the cisd genes resulted in various germline abnormalities including distal tip cell migration defects and a significant increase in the number of cell corpses within the adult germline. This increased germ cell death is blocked by a gain-of-function mutation of the Bcl-2 homolog CED-9 and requires functional caspase CED-3 and the APAF-1 homolog CED-4. Furthermore, the increased germ cell death is facilitated by the pro-apoptotic, CED-9-binding protein CED-13, but not the related EGL-1 protein. This work is significant because it places the CISD family members as regulators of physiological germline programmed cell death acting through CED-13 and the core apoptotic machinery.
Abstract: A biowaiver is accepted by the Brazilian Health Surveillance Agency (ANVISA) for immediate-release solid oral products containing Biopharmaceutics Classification System (BCS) class I drugs showing rapid drug dissolution. This study aimed to simulate plasma concentrations of fluconazole capsules with different dissolution profiles and run population simulation to evaluate their bioequivalence. The dissolution profiles of two batches of the reference product Zoltec150 mg capsules, A1 and A2, and two batches of other products (B1 and B2; C1 and C2), as well as plasma concentration-time data of the reference product from the literature, were used for the simulations. Although products C1 and C2 had drug dissolutions < 85% in 30 min at 0.1 M HCl, simulation results demonstrated that these products would show the same in vivo performance as products A1, A2, B1, and B2. Population simulation results of the ln-transformed 90% confidence interval for the ratio ofand AUCvalues for all products were within the 80-125% interval, showing to be bioequivalent. Thus, even though the in vitro dissolution behavior of products C1 and C2 was not equivalent to a rapid dissolution profile, the computer simulations proved to be an important tool to show the possibility of bioequivalence for these products.