Estensione di tempo QT
Effetti avversi del farmaco
Varianti ✨Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
Spiegazioni per i pazienti
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla alprazolam aumenta al 172%, se combinato con eritromicina (170%) e fluoxetina (101%). Questo può portare a un aumento degli effetti collaterali. L'esposizione alla eritromicina aumenta al 101%, se combinato con alprazolam (100%) e fluoxetina (101%). Non abbiamo rilevato alcun cambiamento nell'esposizione alla fluoxetina, se combinato con alprazolam (100%). Al momento non possiamo stimare l'influenza della eritromicina.
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La eritromicina ha una bassa biodisponibilità orale [ F ] del 24%, motivo per cui il livello plasmatico massimo [Cmax] tende a cambiare fortemente con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 2.3 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 73% e il volume di distribuzione [ Vd ] è di 56 litri, ecco perché, con una velocità di estrazione epatica media di 0,9, sono rilevanti sia il flusso sanguigno epatico [Q] che una variazione del legame proteico [Pb]. Il metabolismo avviene principalmente tramite CYP3A4 e il trasporto attivo avviene in parte tramite MRP2 e PGP.
La alprazolam ha un'elevata biodisponibilità orale [ F ] del 88%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è di 11.7 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 46.8 ore. Il legame proteico [ Pb ] è moderatamente forte al 70.2% e il volume di distribuzione [ Vd ] è di 50 litri nell'intervallo medio, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene principalmente tramite CYP3A4.
La fluoxetina ha una biodisponibilità orale media [ F ] del 60%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è di 24 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 96 ore. Il legame proteico [ Pb ] è moderatamente forte al 94.5% e il volume di distribuzione [ Vd ] è molto grande a 2275 litri, ecco perché, con una velocità di estrazione epatica media di 0,9, sono rilevanti sia il flusso sanguigno epatico [Q] che una variazione del legame proteico [Pb]. Il metabolismo avviene tramite CYP2C19, CYP2C9, CYP2D6 e CYP3A4, tra gli altri.
|Effetti serotoninergici a||2||Ø||Ø||++|
Raccomandazione: Come misura precauzionale, devono essere presi in considerazione i sintomi della sovrastimolazione serotoninergica, specialmente dopo aver aumentato la dose e alle dosi nell'intervallo terapeutico superiore.
Valutazione: La fluoxetina modula il sistema serotoninergico in misura moderata. Il rischio di una sindrome serotoninergica può essere classificato basso con questo farmaco se il dosaggio rientra nell'intervallo abituale. Secondo le nostre conoscenze, né la eritromicina né la alprazolam aumentano l'attività serotoninergica.
Raccomandazione: Il rischio di effetti collaterali anticolinergici come visione offuscata, confusione e tremore aumenta con questa terapia. Se possibile, la terapia deve essere modificata o il paziente deve essere attentamente monitorato per altri sintomi come Vengono monitorati costipazione, midriasi e ridotta vigilanza.
Valutazione: Insieme, la fluoxetina (moderare) e la alprazolam (blando) aumentano l'attività anticolinergica. Secondo i nostri risultati, la eritromicina non aumenta l'attività anticolinergica.
Estensione di tempo QT
Valutazione: In combinazione, eritromicina e fluoxetina possono potenzialmente innescare aritmie ventricolari di tipo torsione di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la alprazolam.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||eri||alp||flu|
|Problema di coordinamento||24.8 %||n.a.||24.8||n.a.|
|Compromissione della memoria||24.3 %||n.a.||24.3||n.a.|
|Aumento dell'appetito||19.9 %||n.a.||19.9||n.a.|
Rinofaringite (19.5%): fluoxetina
Costipazione (17.1%): alprazolam
Diarrea (13.9%): eritromicina, fluoxetina
Perdita di appetito (11.3%): eritromicina, fluoxetina
Dispepsi (8%): fluoxetina
Dolore addominale: eritromicina
Diarrea da Clostridium difficile: eritromicina
Disartria (17.1%): alprazolam
Astenia (14%): fluoxetina
Tremore (8%): fluoxetina
Confusione (6%): alprazolam
Convulsioni: eritromicina, fluoxetina
Aumento di peso (14.9%): alprazolam
Depressione (11.7%): alprazolam
Ansia (9%): fluoxetina
Nervosismo (8.5%): fluoxetina
Effetto rimbalzo: alprazolam
Riduzione della libido (10.2%): alprazolam
Visione offuscata: fluoxetina
Perdita dell'udito: eritromicina
Aritmia ventricolare: eritromicina
Sindrome di Stevens Johnson: eritromicina, alprazolam
Necrolisi epidermica tossica: eritromicina
Eritema multiforme: fluoxetina
Epatite colestatica: eritromicina
Insufficienza epatica: eritromicina, alprazolam
Reazioni allergiche della pelle: eritromicina
Reazione anafilattica: fluoxetina
Nefrite tubulointerstiziale: eritromicina
Tempo di sanguinamento prolungato: fluoxetina
Sulla base delle vostre
Abstract: No Abstract available
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: No Abstract available
Abstract: No Abstract available
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: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Abstract: A 48-year-old man presented to the emergency department with confusion, agitation, diaphoresis, and muscle rigidity after beginning treatment with fluoxetine, a serotonin reuptake inhibitor. He had discontinued treatment with tranylcypromine, a monoamine oxidase inhibitor, 2 weeks earlier. The constellation of findings was diagnostic of the serotonin syndrome.
Abstract: Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite norfluoxetine ranges from 7 to 15 days. Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction). In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment. On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine above 500 micrograms/L appear to be associated with a poorer clinical response than lower concentrations. Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine increased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the 'serotonergic syndrome'. This is because of synergistic pharmacodynamic effects and the influence of fluoxetine on the bioavailability of these compounds.
Abstract: BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.
Abstract: No Abstract available
Abstract: AIMS: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects. METHODS: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography. RESULTS: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively. CONCLUSIONS: The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.
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: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
Abstract: BACKGROUND: Serotonin syndrome is a rare but serious complication of treatment with serotonergic agents. In its severe manifestations, death can ensue. Early recognition and aggressive management are crucial to mitigating the syndrome. Often the presentation can be subtle and easy to miss. CASE REPORTS: We present 2 cases of serotonin syndrome seen in the psychiatric consultation service of a busy academic hospital. Both patients had favorable outcomes because of early recognition and aggressive management. CONCLUSION: Physicians should carefully consider and rule out the clinical diagnosis of serotonin syndrome when presented with an agitated or confused patient who is taking serotonergic agents.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.