Verlängerung der QT-Zeit
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Abacavir wird zur Behandlung von HIV- Infektionen (humaner Immunmangel-Virus- Infektionen) eingesetzt und zusammen mit anderen HIV-Medikamenten oral als Tablette oder Lösung eingenommen. Abacavir ist ein Virustatikum und gehört zur Klasse der nukleosidischen Reverse-Trankskriptase-Inhibitoren (NRTI). Es hemmt das für die Virusvermehrung notwendige Enzym "Reverse Transkriptase". Somit kommt es zur Abnahme der Viruslast. Ein Gentest (auf HLA B5701) kann anzeigen, ob bei einer Person ein höheres Risiko für die Entwicklung einer Überempfindlichkeit (mit Symptomen wie Hautausschlag, Erbrechen und Atemnot) besteht.
Die Warnhinweise werden für die Kombination mehrerer Wirkstoffe überprüft. Für die einzelnen Substanzen konsultieren Sie bitte die entsprechende Fachinfo.
Da nur Abacavir ohne weitere Substanzen eingeben wurde, können keine pharmakokinetischen Interaktionen detektiert werden.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Abacavir hat eine hohe orale Bioverfügbarkeit [ F ] von 83%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell wenig verändern. Die terminale Halbwertszeit [ t12 ] ist mit 1 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 49% eher schwach und das Verteilungsvolumen [ Vd ] ist mit 61 Liter gross, Die Metabolisierung erfolgt nicht über die gängigen Cytochrome und der aktive Transport erfolgt zum Teil über BCRP, MRP4 und PGP.
|Serotonerge Effekte a||0||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöht Abacavir nicht die serotonerge Aktivität.
|Kiesel & Durán b||0||Ø|
Bewertung: Gemäss unseren Erkenntnisse erhöht Abacavir nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Für Abacavir ist uns kein QT-Zeit verlängerndes Potential bekannt.
|Infektion der oberen Atemwege||5.0 %||5.0|
Stevens Johnson-Syndrom: Abacavir
Toxische epidermale Nekrolyse: Abacavir
Steatose der Leber: Abacavir
Basierend auf Ihren
Abstract: STUDY OBJECTIVES: Study A: to determine the absolute bioavailability of a single 300-mg abacavir hemisulfate tablet. Study B: to determine the bioequivalence of two oral abacavir formulations (300-mg hemisulfate tablet, 100-mg succinate caplet), the effect of food on the bioavailability of the 300-mg hemisulfate tablet, and the bioavailability of the hemisulfate tablet relative to the hemisulfate solution. DESIGN: Phase I, randomized, open-label, balanced two- (study A) and three- or four-period (study B), crossover studies. SETTING: Two clinical research centers. SUBJECTS: Six men infected with the human immunodeficiency virus (HIV), aged 27-39 years (study A), and 18 HIV-infected men and women, aged 21-50 years (study B). INTERVENTIONS: In study A, all subjects received a single, oral 300-mg tablet of abacavir hemisulfate or a single, intravenous infusion of abacavir hemisulfate 150 mg over 60 minutes. In study B, all subjects received each of three single-dose treatments: three 100-mg abacavir succinate caplets in a fasted state, one 300-mg abacavir hemisulfate tablet in a fasted state, and one 300-mg abacavir hemisulfate tablet with a high-fat breakfast. Twelve subjects in study B also received a fourth treatment of abacavir hemisulfate 300 mg as an oral solution in a fasted state. Plasma samples collected for 24 hours (study A) or 12 hours (study B), and urine samples collected for 12 hours (study A) were analyzed by validated high-performance liquid chromatographic methods. MEASUREMENTS AND MAIN RESULTS: Abacavir pharmacokinetic parameters were calculated using standard, noncompartmental methods. In study A, the geometric least square (GLS) mean absolute bioavailability of oral abacavir was 83% (range 65-107%). In study B, the hemisulfate tablet was bioequivalent to the succinate caplet, but its time to maximum concentration (Tmax) occurred 30 minutes earlier. Administration of the abacavir hemisulfate tablet with food had no effect on area under the curve from time zero to infinity (AUC0-infinity), decreased maximum concentration (Cmax) by 26%, and delayed Tmax by 38 minutes. The relative bioavailability (GLS mean AUC0-infinity ratio) of the 300-mg abacavir hemisulfate tablet to solution was 101%, Cmax was 11% lower, and Tmax was unchanged. The most common drug-related adverse events associated with abacavir were nausea, vomiting, abdominal pain, and headache, all of which were mild. CONCLUSION: Based on our results, abacavir is safe and well tolerated and can be administered with or without meals.
Abstract: Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi of [(14)C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.
Abstract: Abacavir is a carbocyclic 2'-deoxyguanosine nucleoside reverse transcriptase inhibitor that is used as either a 600-mg once-daily or 300-mg twice-daily regimen exclusively in the treatment of HIV infection. Abacavir is rapidly absorbed after oral administration, with peak concentrations occurring 0.63-1 hour after dosing. The absolute bioavailability of abacavir is approximately 83%. Abacavir pharmacokinetics are linear and dose-proportional over the range of 300-1200 mg/day. To date, one study has assessed the steady-state pharmacokinetics of abacavir following a 600-mg once-daily regimen, and reported a geometric mean steady-state abacavir peak concentration of 3.85 microg/mL. Although this concentration is higher than the steady-state abacavir peak concentration reported following a 300-mg twice-daily regimen (0.88-3.19 microg/mL, depending on the study), the geometric mean steady-state abacavir exposure over 24 hours was similar following these regimens. Coadministration with food has no significant effect on abacavir exposure; therefore, abacavir may be administered with or without food.The apparent volume of distribution of abacavir after intravenous administration is approximately 0.86 +/- 0.15 L/kg, suggesting that abacavir is distributed to extravascular spaces. Binding to plasma proteins is about 50% and is independent of the plasma abacavir concentration. Abacavir is extensively metabolized by the liver; less than 2% is excreted as unchanged drug in the urine. Abacavir is primarily metabolized via two pathways, uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, resulting in the inactive glucuronide metabolite (361W94, ~36% of the dose recovered in the urine) and the inactive carboxylate metabolite (2269W93, approximately 30% of the dose recovered in the urine). The remaining 15% of abacavir equivalents found in the urine are minor metabolites, each less than 2% of the total dose. Faecal elimination accounts for about 16% of the dose. The terminal elimination half-life of abacavir is approximately 1.5 hours. The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate (CBV-TP). When assessed by validated high-performance liquid chromatography electrospray ionization tandem mass spectrometry, CBV-TP has been shown to have a long elimination half-life (>20 hours), supporting once-daily dosing. The mean CBV-TP trough concentrations do not differ following abacavir 600-mg once-daily and 300-mg twice-daily regimens. Limited data are available for abacavir in subjects with renal dysfunction or hepatic impairment. Abacavir pharmacokinetics in HIV-infected subjects with end-stage renal disease were found to be no different from those observed in healthy adults; this finding was consistent with the kidney being a minor route of abacavir elimination. A study of abacavir pharmacokinetics in hepatically impaired adults (Child-Pugh score of 5-6) showed that the abacavir area under the plasma concentration-time curve and elimination half-life were 89% and 58% greater, respectively, suggesting that the daily dose of abacavir should be reduced in patients with mild hepatic impairment (Child-Pugh score of 5-6). Abacavir pharmacokinetics have not been studied in patients with higher Child-Pugh scores. Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes, nor does it inhibit these enzymes. Therefore, clinically significant drug interactions between abacavir and drugs metabolized by CYP enzymes are unlikely. The potential for drug interactions is no different when abacavir is used as a once-daily regimen versus a twice-daily regimen. No clinically significant drug interactions have been observed between recommended doses of abacavir and lamivudine, zidovudine, alcohol (ethanol) or methadone.
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.