QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of saquinavir and cimetidine. Please also consult the relevant specialist information.
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. We did not detect any change in exposure to saquinavir. We cannot currently estimate the influence of cimetidine. We did not detect any change in exposure to cimetidine. We cannot currently estimate the influence of saquinavir.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Saquinavir has a low oral bioavailability [ F ] of 4%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 7 hours and constant plasma levels [ Css ] are reached after approximately 28 hours. The protein binding [ Pb ] is 98% strong and the volume of distribution [ Vd ] is very large at 700 liters, The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via MRP2, OATP1A2 and PGP.
Cimetidine has a mean oral bioavailability [ F ] of 65%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.6333333 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 19% and the volume of distribution [ Vd ] is very large at 91 liters. The metabolism does not take place via the common cytochromes and the active transport takes place partly via BCRP and PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither saquinavir nor cimetidine increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Cimetidine only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our findings, saquinavir does not increase anticholinergic activity.
QT time prolongation
Rating: In combination, saquinavir and cimetidine can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||saq||cim|
|Abdominal pain||6.0 %||6.0||n.a.|
|Atrioventricular block||0.0 %||0.0||n.a.|
|Stevens johnson syndrome||0.0 %||0.0||n.a.|
|Diabetes mellitus||0.0 %||0.0||n.a.|
|Hemolytic anemia||0.0 %||0.0||n.a.|
Immune reconstitution syndrome: saquinavir
Psychosis: saquinavir, cimetidine
Based on your
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: No Abstract available
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Saquinavir mesylate (SQV) is the first-in-class and prototypical HIV protease inhibitor (PI) used in the treatment of HIV infection. SQV undergoes extensive hepatic metabolism and intestinal and bile secretion, and has poor and variable oral bioavailability. In previous studies, our group and others have described the interactions between SQV and absorptive and secretory efflux transporters such as MRP1, MRP2, and P-gp. However, the potential role of absorptive influx transporters such as OATP-A (SLC21A3) has not yet been reported for SQV. In the study presented here, the role of OATP-A in the influx transport of SQV was studied using a hepatic cell model, Hep G2, and Xenopus laevis oocytes overexpressing human OATP-A. In Hep G2 cells, SQV transport was found to be (i) concentration-dependent and saturable, (ii) temperature-sensitive, and (iii) proton (pH)- and sodium-independent. While GF120918, a specific inhibitor of P-gp, and MK571, a MRP transporter family inhibitor, significantly enhanced SQV uptake, estrone 3-sulfate, a substrate of OATP-A, significantly inhibited SQV uptake by Hep G2 cells. The observation that inhibitors of P-gp, MRP, or OATP-A have opposite effects on SQV uptake in polarized Hep G2 cells is consistent with their functions as hepatic efflux or influx transporters. In X. laevis oocytes into which OATP-A cRNA had been injected, the level of uptake of SQV was significantly greater than the level of uptake by oocytes into which water had been injected and was concentration-dependent and saturable (Km = 36.4+/-21.8 microM). This is the first report showing that SQV influx transport is directly facilitated by OATP-A. Given the wide body distribution of OATP-A, the current results suggest a potentially important role for OATP-A in the absorption and disposition of SQV in vivo. The data also suggest that in human hepatocytes basolaterally located OATP-A (influx transporter) may act in concert with apically located P-gp and/or MRP2 (efflux transporters) for the vectorial transport and excretion of SQV into bile.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: No Abstract available
Abstract: The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.
Abstract: OBJECTIVE: To evaluate the literature on protease inhibitor (PI)-associated QT interval prolongation and risk for torsade de pointes in patients infected by HIV. DATA SOURCES: Primary literature was identified through MEDLINE (1950-August 2011) and EMBASE (1980-August 2011), using the following search terms: antiretroviral agents, HIV, protease inhibitors, QTc, QT prolongation, and torsade de pointes. STUDY SELECTION AND DATA EXTRACTION: English-language case reports of antiretroviral therapy-associated QT interval prolongation, studies of healthy volunteers, or studies that evaluated the impact of PIs on QT interval in patients infected with HIV were reviewed and selected. Article bibliographies and conference abstracts were also reviewed. DATA SYNTHESIS: Several case reports, as well as in vitro data, have implicated PIs as a potential cause of QT interval prolongation and/or torsade de pointes. Saquinavir, therapeutically boosted with the potent CYP3A4 inhibitor ritonavir, was the only PI shown to be associated with significant QT interval prolongation in studies with healthy volunteers. While 1 case control study in HIV-infected patients found that nelfinavir or efavirenz, a nonnucleoside reverse transcriptase inhibitor, increased the risk of QT interval prolongation, larger prospective studies have not demonstrated any significant increase in QT interval following exposure to PIs. Similar risk factors for QT interval prolongation seen in non-HIV-infected patients, such as older age, female sex, ethnicity, cardiac conditions, diabetes mellitus, and concomitant use of other QT interval-prolonging medications, especially methadone, were risk factors identified in studies of HIV-infected patients. CONCLUSIONS: PIs do not appear to independently predispose patients to QT interval prolongation. However, other risk factors (both HIV-related and non-HIV-related) may increase the risk of QT interval prolongation. Available data suggest that baseline and follow-up electrocardiogram monitoring are unnecessary precautions, but may be considered in patients who are initiating PI therapy and are on multiple medications with proarrhythmic potential and/or have multiple comorbidities, increasing the risk.
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.