Intervallo QT lungo
Reazione avversa da farmaco (ADR)
|Mal di testa|
Varianti ✨Per l'analisi computazionale dettagliata delle varianti, si prega di selezionare l'abbonamento standard a pagamento.
Informazioni dei farmaci per i pazienti
Formalmente controindicato: midazolam e claritromicina
Secondo il riassunto svizzero delle caratteristiche del prodotto della midazolamEstratto del testo: … in terapia concomitante con induttori o inibitori del CYP3A molto potenti (ketoconazolo, itraconazolo, voriconazolo e inibitori della proteasi dell'HIV comprese le formulazioni potenziate con ritonavir) …
|Clobazam||1.45 [1.19,2.29] 1||1.45||n.a.|
I cambiamenti riportati in seguito all'esposizione corrispondono ai cambiamenti nell'area sottesa alla curva concentrazione plasmatica-tempo [ AUC ]. L'esposizione alla midazolam è aumentata del 297%, quando è co-somministrata con la claritromicina (760%) e la clobazam (72%). Questo può portare ad un aumento del tasso di incidenza di effetti indesiderati L'esposizione alla clobazam è aumentata del 145%, quando è co-somministrata con la claritromicina (145%). L' AUC è compreso tra lo 119% e il 229% in base al
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per calcolare i cambiamenti del singolo individuo esposto alle interazioni farmacologiche
La claritromicina ha una significativa biodisponibilità [ F ] orale pari al 53%, perciò attraverso un'interazione farmacologica la concentrazione plasmatica massima [Cmax] tende a cambiare di poco. L'emivita [ t12 ] del farmaco è piuttosto breve in 4.6 ore e lo stato stazionario [Css] si raggiunge molto velocemente. Il legame proteico [ Pb ] è piuttosto debole al 70% e il volume di distribuzione [ Vd ] è molto grande in 176 litri. Poiché la sostanza ha un basso tasso di estrazione epatica di 0.13, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può portare a un aumento dell'esposizione. Circa il 27.5% della dose somministrata è escreta inalterata attraverso le urine e in seguito alle varie interazioni farmacologiche questo valore raramente cambia. Il metabolismo avviene principalmente attraverso l'enzima CYP3A4 e il trasporto attivo avviene in particolare attraverso i trasportatori PGP e TRA8X8.
La clobazam ha un elevata biodisponibilità [ F ] orale pari al 87%, perciò nel corso di un'interazione farmacologica la concentrazione plasmatica massima [Cmax] tende a cambiare di poco. Il legame proteico [ Pb ] è moderatamente forte al 87%. Poiché la sostanza ha un basso tasso di estrazione epatica di 0.02, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può portare a un aumento dell'esposizione. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2B6, CYP2C19 e CYP3A4. e il trasporto attivo avviene in particolare attraverso i trasportatori PGP e TRA8X8.
La midazolam ha una bassa biodisponibilità orale [ F ] del 29%, motivo per cui il livello plasmatico massimo [Cmax] tende a cambiare fortemente con un'interazione. L'emivita [ t12 ] del farmaco è piuttosto breve in 4.1 ore e lo stato stazionario [Css] si raggiunge molto velocemente. Il legame proteico [ Pb ] è moderatamente forte al 94.3% e il volume di distribuzione [ Vd ] è molto grande in 147 litri, per cui, con un significativo tasso di estrazione epatico dello 0.57, hanno importanza sia il flusso ematico a livello del fegato [Q] sia le variazioni di legame alle proteine plasmatiche [Pb]. Il metabolismo avviene principalmente attraverso l'enzima CYP3A4 e il trasporto attivo avviene in particolare attraverso i trasportatori UGT1A4 e TRA8X8.
|Effetti serotoninergici a||0||Ø||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la claritromicina, clobazam né la midazolam potenziano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la claritromicina né la clobazam causano un aumento dell'attività anticolinergica. L'effetto anticolingerico della midazolam non è rilevante.
Intervallo QT lungo
Valutazione: La claritromicina potrebbe causare tachicardia ventricolare a torsione di punta. Non è noto se la clobazam e la midazolam siano in grado di prolungare l'intervallo QT
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||cla||clo||mid|
|Mal di testa||15.4 %||9.0||n.a.||7.0↑|
|Disturbo del gusto||13.5 %||13.5||n.a.||n.a.|
|Comportamento aggressivo||8.5 %||n.a.||8.5||0.01↑|
Insonnia (5.5%): clobazam, claritromicina
Sedazione (5.5%): clobazam
Disartria (3.5%): clobazam
Effetto hangover: midazolam
Cognizione alterata: midazolam
Diarrea (5.5%): claritromicina
Dolore addominale (4.5%): claritromicina
Dispepsi (4%): claritromicina
Diarrea da Clostridium difficile: claritromicina
Tosse (5%): clobazam
Depressione respiratoria: midazolam, clobazam
Infezione del tratto urinario (3.5%): clobazam
Insufficienza cardiaca: midazolam
Sindrome di Stevens Johnson: clobazam, claritromicina
Necrolisi epidermica tossica: clobazam, claritromicina
Reazione di ipersensibilità: clobazam
Reazione anafilattica: claritromicina
Epatite colestatica: claritromicina
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Abstract: Midazolam is a short-acting water-soluble benzodiazepine (at pH less than 4), a member of a new class of imidazobenzodiazepine derivatives. At physiological pH the drug becomes much more lipid soluble. Water solubility minimises pain on injection and venous thrombosis compared with diazepam administered in organic solvent. Midazolam is a hypnotic-sedative drug with anxiolytic and marked amnestic properties. To date it has been used mostly by the intravenous route, for sedation in dentistry and endoscopic procedures and as an adjunct to local anaesthetic techniques. It has proved less reliable than thiopentone, but preferable to diazepam, as an intravenous induction agent and is unlikely to replace the other well established drugs. However, due to the cardiorespiratory stability following its administration, midazolam is useful for anaesthetic induction in poor-risk, elderly and cardiac patients. The short elimination half-life (1.5-3.5h) and the absence of clinically important long acting metabolites make midazolam suitable for long term infusion as a sedative and amnestic for intensive care, but clinical trials have yet to be completed. Thus, a combination of properties make midazolam a useful addition to the benzodiazepine group.
Abstract: The pharmacokinetic interaction between clobazam and cimetidine was studied in 9 healthy male volunteers in an open-labelled study. After a single oral dose of clobazam 30 mg, a wash-out period of 14 days was followed by daily doses of cimetidine 1 g for one week. Thereafter a single oral dose of clobazam 30 mg was again given. The plasma concentrations of clobazam and its main metabolite N-desmethyl-clobazam were measured by gas-chromatography. The area under the curve (AUC0-infinity) of plasma clobazam level was significantly larger after pretreatment with cimetidine and the elimination half life of clobazam was significantly longer. There were no statistically significant differences in Cmax and tmax for plasma clobazam. The plasma levels of N-desmethyl-clobazam did not show any significant change after the intake of cimetidine.
Abstract: OBJECTIVE: To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam. METHODS: Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam. RESULTS: In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged. CONCLUSIONS: Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.
Abstract: Erythromycin, clarithromycin, and azithromycin are clinically effective for the treatment of common respiratory and skin/skin-structure infections. Erythromycin and azithromycin are also effective for treatment of nongonococcal urethritis and cervicitis due to Chlamydia trachomatis. Compared with erythromycin, clarithromycin and azithromycin offer improved tolerability. Clarithromycin, however, is more similar to erythromycin in pharmacokinetic measures such as half-life, tissue distribution, and drug interactions. Misunderstandings about differences among the macrolides (erythromycin and clarithromycin) and the azalide (azithromycin) in terms of pharmacokinetics and pharmacodynamics, spectrum of activity, safety, and cost are common. The uptake and release of these compounds by white blood cells and fibroblasts account for differences in tissue half-life, volume of distribution, intracellular:extracellular ratio, and in vivo potency. Although microbiologic studies reveal that gram-positive pathogens are equally susceptible to these agents, significantly more isolates of Haemophilus influenzae are susceptible to azithromycin than to erythromycin or clarithromycin. Concentrations achieved at the infection site and duration above the minimum inhibitory concentration are as important as in vitro activity in determining in vivo activity against bacterial pathogens. Analysis of safety data indicates differences among these agents in drug interactions and use in pregnancy. Analysis of safety data reveals pharmacokinetic drug interactions for erythromycin and clarithromycin with theophylline, terfenadine, and carbamazepine that are not found with azithromycin. Both erythromycin and azithromycin are pregnancy category B drugs; clarithromycin is a category C drug. The numerous differences in pharmacokinetics, microbiology, safety, and costs among erythromycin, clarithromycin, and azithromycin can be used in the judicious selection of treatment for indicated infections.
Abstract: We have examined the effect of fentanyl on the pharmacokinetics of midazolam in patients undergoing orthopaedic surgery. Thirty patients were allocated randomly to receive fentanyl 200 micrograms and midazolam 0.2 mg kg-1 (fentanyl group, n = 15) or placebo and midazolam 0.2 mg kg-1 (placebo group, n = 15) in a double-blind manner for induction of anaesthesia. Anaesthesia was maintained with nitrous oxide and isoflurane. Systemic clearance of midazolam was decreased by 30% (P = 0.002) and elimination half-time was prolonged by 50% (P = 0.04) in the fentanyl group compared with the placebo group. There were no differences in the distribution half-time or volume of distribution at steady state between the two groups. These findings indicate that elimination of midazolam was inhibited by fentanyl during general anaesthesia.
Abstract: To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not affect other pharmacokinetic parameters.
Abstract: No Abstract available
Abstract: OBJECTIVE: To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. RESULTS: Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. CONCLUSION: The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.
Abstract: Clarithromycin is a macrolide antibacterial that differs in chemical structure from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability (52 to 55%), increased plasma concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and 2.41 to 2.85 mg/L after multiple 250 and 500 mg doses, respectively), and a longer elimination half-life (3.3 to 4.9 hours) to allow twice daily administration. In addition, clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14-hydroxyclarithromycin. The reported mean values of total body clearance and renal clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h, respectively. In patients with severe renal impairment, increased plasma concentrations and a prolonged elimination half-life for clarithromycin and its metabolite have been reported. A dosage adjustment for clarithromycin should be considered in patients with a creatinine clearance < 1.8 L/h. The recommended goal for dosage regimens of clarithromycin is to ensure that the time that unbound drug concentrations in the blood remains above the minimum inhibitory concentration is at least 40 to 60% of the dosage interval. However, the concentrations and in vitro activity of 14-hydroxyclarithromycin must be considered for pathogens such as Haemophilus influenzae. In addition, clarithromycin achieves significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, respectively. Further studies are needed to determine the importance of these concentrations of clarithromycin at the site of infection. Clarithromycin can increase the steady-state concentrations of drugs that are primarily depend upon CYP3A metabolism (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be clinically important for drugs that have a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are potent enzyme inducers and several small studies have suggested that these agents may significantly decrease serum clarithromycin concentrations. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with older macrolides such as erythromycin and troleandomycin.
Abstract: Two cases of QT prolongation and torsades de pointes (TdP) are presented. The patients had been taking clarithromycin (400 mg/day) for respiratory disease. Although erythromycin is reportedly associated with TdP, this is the first report of clarithromycin associated with TdP in the absence of other drugs already known to produce QT prolongation.
Abstract: Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.
Abstract: This investigation determined the ability of alfentanil miosis and single-point concentrations to detect various degrees of CYP3A inhibition. Results were compared with those for midazolam, an alternative CYP3A probe. Twelve volunteers were studied in a randomized 4-way crossover, targeting 12%, 25%, and 50% inhibition of hepatic CYP3A. They received 0, 100, 200, or 400 mg oral fluconazole, followed 1 hour later by 1 mg intravenous midazolam and then 15 microg/kg intravenous alfentanil 1 hour later. The next day, they received fluconazole, followed by 3 mg oral midazolam and 40 microg/kg oral alfentanil. Dark-adapted pupil diameters were measured coincident with blood sampling. Area under the plasma concentration-time curve (AUC) ratios (fluconazole/control) after 100, 200, and 400 mg fluconazole were (geometric mean) 1.3*, 1.4*, and 2.0* for intravenous midazolam and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (*significantly different from control), indicating 16% to 21%, 31% to 36%, and 43% to 53% inhibition of hepatic CYP3A. Single-point concentration ratios were 1.5*, 1.8*, and 2.4* for intravenous midazolam (at 5 hours) and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (at 4 hours). Pupil miosis AUC ratios were 0.9, 1.0, and 1.2*. After oral dosing, plasma AUC ratios were 2.3*, 3.6*, and 5.3* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil; plasma single-point ratios were 2.4*, 4.5*, and 6.9* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil, and alfentanil miosis ratios were 1.1, 1.9*, and 2.7*. Plasma concentration AUC ratios of alfentanil and midazolam were equivalent for detecting hepatic and first-pass CYP3A inhibition. Single-point concentrations were an acceptable surrogate for formal AUC determinations and as sensitive as AUCs for detecting CYP3A inhibition. Alfentanil miosis could detect 50% to 70% inhibition of CYP3A activity, but was less sensitive than plasma AUCs. Further refinements are needed to increase the sensitivity of alfentanil miosis for detecting small CYP3A changes.
Abstract: OBJECTIVE: Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. RESULTS: Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. CONCLUSION: When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.
Abstract: BACKGROUND AND OBJECTIVE: Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. METHODS: Healthy men and nonpregnant women aged 18-45 years with a body mass index of </=30 kg/m(2) each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum observed drug plasma concentration (C(max)). Safety and tolerability were also assessed. RESULTS: A total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the C(max) or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the C(max) of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events. CONCLUSIONS: Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.
Abstract: AIMS: To compare midazolam kinetics between plasma and saliva and to find out whether saliva is suitable for CYP3A phenotyping. METHODS: This was a two way cross-over study in eight subjects treated with 2 mg midazolam IV or 7.5 mg orally under basal conditions and after CYP3A induction with rifampicin. RESULTS: Under basal conditions and IV administration, midazolam and 1'-hydroxymidazolam (plasma, saliva), 4-hydroxymidazolam and 1'-hydroxymidazolam-glucuronide (plasma) were detectable. After rifampicin, the AUC of midazolam [mean differences plasma 53.7 (95% CI 4.6, 102.9) and saliva 0.83 (95% CI 0.52, 1.14) ng ml(-1) h] and 1'-hydroxymidazolam [mean difference plasma 11.8 (95% CI 7.9 , 15.7) ng ml(-1) h] had decreased significantly. There was a significant correlation between the midazolam concentrations in plasma and saliva (basal conditions: r = 0.864, P < 0.0001; after rifampicin: r = 0.842, P < 0.0001). After oral administration and basal conditions, midazolam, 1'-hydroxymidazolam and 4-hydroxymidazolam were detectable in plasma and saliva. After treatment with rifampicin, the AUC of midazolam [mean difference plasma 104.5 (95% CI 74.1, 134.9) ng ml(-1) h] and 1'-hydroxymidazolam [mean differences plasma 51.9 (95% CI 34.8, 69.1) and saliva 2.3 (95% CI 1.9, 2.7) ng ml(-1) h] had decreased significantly. The parameters separating best between basal conditions and post-rifampicin were: (1'-hydroxymidazolam + 1'-hydroxymidazolam-glucuronide)/midazolam at 20-30 min (plasma) and the AUC of midazolam (saliva) after IV, and the AUC of midazolam (plasma) and of 1'-hydroxymidazolam (plasma and saliva) after oral administration. CONCLUSIONS: Saliva appears to be a suitable matrix for non-invasive CYP3A phenotyping using midazolam as a probe drug, but sensitive analytical methods are required.
Abstract: AIMS: Midazolam (MDZ) is a benzodiazepine used as a CYP3A4 probe in clinical and in vitro studies. A glucuronide metabolite of MDZ has been identified in vitro in human liver microsome (HLM) incubations. The primary aim of this study was to understand the in vivo relevance of this pathway. METHODS: An authentic standard of N-glucuronide was generated from microsomal incubations and isolated using solid-phase extraction. The structure was confirmed using proton nuclear magnetic resonance (NMR) and (1)H-(13)C long range correlation experiments. The metabolite was quantified in vivo in human urine samples. Enzyme kinetic behaviour of the pathway was investigated in HLM and recombinant UGT (rUGT) enzymes. Additionally, preliminary experiments were performed with 1'-OH midazolam (1'-OH MDZ) and 4-OH-midazolam (4-OH MDZ) to investigate N-glucuronidation. RESULTS: NMR data confirmed conjugation of midazolam N-glucuronide (MDZG) standard to be on the alpha-nitrogen of the imidazole ring. In vivo, MDZG in the urine accounted for 1-2% of the administered dose. In vitro incubations confirmed UGT1A4 as the enzyme of interest. The pathway exhibited atypical kinetics and a substrate inhibitory cooperative binding model was applied to determine K(m) (46 microM, 64 microM), V(max) (445 pmol min(-1) mg(-1), 427 pmol min(-1) mg(-1)) and K(i) (58 microM, 79 microM) in HLM and rUGT1A4, respectively. From incubations with HLM and rUGT enzymes, N-glucuronidation of 1'-OH MDZ and 4-OH MDZ is also inferred. CONCLUSIONS: A more complete picture of MDZ metabolism and the enzymes involved has been elucidated. Direct N-glucuronidation of MDZ occurs in vivo. Pharmacokinetic modelling using Simcyp illustrates an increased role for UGT1A4 under CYP3A inhibited conditions.
Abstract: STUDY OBJECTIVE: To investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers. DESIGN: Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials. SETTING: Clinical research unit. PARTICIPANTS: Fifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. INTERVENTION: In the first drug-drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on clobazam and its active metabolite N-desmethylclobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4-19, to study clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4. MEASUREMENTS AND MAIN RESULTS: In the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0-∞) ) 54% and decreased clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-∞) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N-CLB has 3-4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-∞) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures. CONCLUSION: These findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.
Abstract: The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.
Abstract: PURPOSE: To develop a physiologically based pharmacokinetic model in adults and children for clobazam, its active metabolite norclobazam and stiripentol and to account for significant clinical interaction that has been reported when clobazam and stiripentol are co-administered. METHODS: A PBPK model with ten compartments was developed. An in vitro-in vivo extrapolation technique was used to scale clearance in children for clobazam and norclobazam and clearance parameters for stiripentol were obtained from fitting. Other drug and system parameters were obtained from the literature. RESULTS: The tissue/blood partition coefficients adequately predict observed volume of distribution for clobazam and stiripentol. In a clinical study in children where clobazam was administered alone and co-administered with stiripentol, the predicted and observed minimum concentration at steady state (mean and 95% confidence interval) during clobazam monotherapy were 0.19 (0.05-0.49 mg/L) and 0.20 (0.17-0.23 mg/L), respectively, and predicted and observed norclobazam concentrations were 0.49 (0.16-1.38 mg/L) and 0.95 (0.91-0.99 mg/L), respectively. From an interaction study with stiripentol the predicted stiripentol concentration was 10.12 (2.51-39.36 mg/L) and the observed concentration was 10.0 (8.3-11.7 mg/L); the predicted clobazam concentration was 0.29 (0.07-1.05 mg/L) and the observed concentration was 0.31 (0.24-0.38 mg/L); and the predicted norclobazam concentration was 2.30 (0.45-5.53 mg/L) and the observed concentration was 4.32 (3.77-4.87 mg/L). CONCLUSIONS: The PBPK model adequately described observed data and the extent of interaction between clobazam/norclobazam and stiripentol.
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: Clobazam (CLB) is a 1,5-benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox-Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single- and multiple-dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N-desmethylclobazam. The half-life of CLB after a single oral dose ranges from 36 to 42 hours; the half-life of N-desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox-Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.
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.