Extensión de tiempo QT
Efectos adversos de las drogas
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Áreas de aplicación
Explicaciones para pacientes
No tenemos advertencias adicionales para la combinación de teofilina, cimetidina y rifabutina. Consulte también la información especializada pertinente.
Los cambios en la exposición mencionados se refieren a cambios en la curva de concentración plasmática-tiempo [AUC]. La exposición a teofilina aumenta al 131%, cuando se combina con cimetidina (145%) y rifabutina (93%). No detectamos ningún cambio en la exposición a cimetidina. Actualmente no podemos estimar la influencia de teofilina y rifabutina. La exposición a rifabutina aumenta al 124%, cuando se combina con teofilina (100%) y cimetidina (124%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La teofilina tiene una alta biodisponibilidad oral [ F ] del 85%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar poco durante una interacción. La vida media terminal [ t12 ] es de 7 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 28 horas. La unión a proteínas [ Pb ] es bastante débil al 40% y el volumen de distribución [ Vd ] es de 36 litros en el rango medio, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede aumentar la exposición. El metabolismo tiene lugar a través de CYP1A2, CYP2D6, CYP2E1 y CYP3A4, entre otros..
La cimetidina tiene una biodisponibilidad oral media [ F ] del 65%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es bastante corta a las 1.6333333 horas y se alcanzan rápidamente niveles plasmáticos constantes [ Css ]. La unión a proteínas [ Pb ] es muy débil al 19% y el volumen de distribución [ Vd ] es muy grande a 91 litros. El metabolismo no tiene lugar a través de los citocromos comunes. y el transporte activo se realiza en parte a través de BCRP y PGP.
La rifabutina tiene una baja biodisponibilidad oral [ F ] del 20%, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La vida media terminal [ t12 ] es bastante larga a las 45 horas y los niveles plasmáticos constantes [ Css ] solo se alcanzan después de más de 180 horas. La unión a proteínas [ Pb ] es moderadamente fuerte al 85% y el volumen de distribución [ Vd ] es muy grande a 595 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede aumentar la exposición. El metabolismo tiene lugar principalmente a través de CYP3A4. y el transporte activo tiene lugar en particular a través de OATP1B1.
|Efectos serotoninérgicos a||0||Ø||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la teofilina, cimetidina ni la rifabutina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||2||+||+||Ø|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: Teofilina y cimetidina solo tienen un efecto leve sobre el sistema anticolinérgico. El riesgo de síndrome anticolinérgico con este medicamento es bastante bajo si la dosis se encuentra en el rango habitual. Según nuestros hallazgos, la rifabutina no aumenta la actividad anticolinérgica.
Extensión de tiempo QT
Recomendación: Asegúrese de minimizar los factores de riesgo influibles. Las alteraciones electrolíticas, como los bajos niveles de calcio, potasio y magnesio, deben compensarse. Se debe usar la dosis efectiva más baja de cimetidina.
Clasificación: La cimetidina puede prolongar potencialmente el tiempo QT y, si hay factores de riesgo, se pueden favorecer las arritmias del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT para teofilina y rifabutina.
Efectos secundarios generales
|Efectos secundarios||∑ frecuencia||teo||cim||rif|
|Diarrea por clostridium difficile||1.0 %||n.a.||n.a.||+|
|Sentido del gusto alterado||1.0 %||n.a.||n.a.||+|
Fibrilación auricular: teofilina
Reacciones alérgicas de la piel: teofilina
Lupus eritematoso: rifabutina
Reacción anafiláctica: teofilina
Dolor de cabeza: teofilina
Hemorragia intracraneal: teofilina
Aumento de la frecuencia de la micción: teofilina
Orina descolorida: rifabutina
Microdepósitos corneales: rifabutina
Síndrome de Stevens-Johnson: teofilina
Con base en sus
Referencias de literatura
Abstract: We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.
Abstract: To investigate a possible interaction between norfloxacin and theophylline, eight healthy nonsmoking volunteers (mean age 27 +/- 5.3 years) were administered aminophylline, 5 mg/kg, before and after a 6-day course of norfloxacin, 400 mg every 12 hours, and changes in pharmacokinetic parameters were measured and compared. Norfloxacin induced significant decreases in theophylline clearance (14.9%; p less than 0.01) and the terminal phase slope (13.3%; p less than 0.02) and increased the AUC (16.6%; p less than 0.01). The apparent volume of distribution at steady state was unchanged. The greatest norfloxacin-induced individual change in theophylline clearance was a reduction of 28.6%. Given these findings, we advise that, for patients who are treated with theophylline and are subsequently treated with norfloxacin, adjustment of the theophylline dosage may be necessary in some patients to minimize the risk of theophylline toxicity.
Abstract: In 42 subjects with chronic obstructive lung disease receiving chronic oral theophylline therapy, the venous whole blood theophylline concentration was closely related to the total plasma theophylline concentrations (r = 0.976, p less than 0.001). The blood/plasma concentration ratio was 0.85 +/- 0.13 and was not related to the haematocrit or the free fraction of theophylline in plasma. The red blood cell theophylline concentration was closely related and numerically similar to the free plasma concentration. This indicates that the free plasma concentration is the most important determinant of red blood cell concentration, and that binding of drug by red blood cells or active uptake into erythrocytes is unlikely to occur. Whole blood concentration can be used to predict plasma theophylline concentration in subjects with obstructive lung disease in situations where preparation of plasma is inconvenient. The therapeutic range for whole blood concentration is approximately 8.5-17 mg/L.
Abstract: The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily erythromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography. The mean +/- SD pharmacokinetic parameters for each phase of study were as follows: apparent volume of distribution (L/kg) 0.45 +/- 0.05 (control), 0.41 +/- 0.05 (experimental); clearance (ml . min/kg) 0.83 +/- 0.17 (control), 0.60 +/- 0.11 (experimental); elimination half-life (hr) 6.65 +/- 1.88 (control), 8.10 +/- 1.58 (experimental). Erythromycin significantly affected the elimination half-life and clearance of theophylline (p less than 0.05). The apparent volume of distribution was unaffected (p greater than 0.05). Therefore patients being administered theophylline appear to be at added risk for the development of toxicity when erythromycin is added to the therapeutic regimen.
Abstract: The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.
Abstract: The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.
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: Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy. However, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study, involving 12 adult male volunteers, compared the effects of 14-day courses of rifampin and rifabutin on clearance of theophylline, a substrate for the hepatic microsomal enzyme CYP1A2. Subjects were given oral theophylline solution (5 mg/kg of body weight) on day 1 and then randomized to receive daily rifampin (300 mg) or rifabutin (300 mg) on days 3 to 16. Theophylline was readministered as described above on day 15. The first treatment sequence was followed by a 2-week washout period; subjects then received the alternative treatment. Theophylline concentrations were determined for 46 h after each dose, and pharmacokinetic parameters were determined. One subject developed flu-like symptoms while taking rifabutin and withdrew voluntarily. Results from the remaining 11 subjects are reported. Compared with the baseline, the mean area under the concentration-time curve (AUC) (+/- standard deviation) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 micrograms . h/ml, P <0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/- 45 micrograms.h/ml). Baseline theophylline AUCs before each treatment phase were not different. A comparison of equal doses of rifampin and rifabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is significantly less following rifabutin treatment than it is following rifampin treatment. However, the relative induction potency for other metabolic enzymes remains to be investigated.
Abstract: Biotransformation of rifabutin, an antibiotic used for treatment of tuberculosis in patients infected with the human immunodeficiency virus (HIV), and its interactions with some macrolide and antifungal agents were studied in human intestinal and liver microsomes. Both liver and enterocyte microsomes metabolized rifabutin to 25-O-deacetylrifabutin, 27-O-demethylrifabutin, and 20-, 31-, and 32-hydroxyrifabutin. The same products (except 25-O-deacetylrifabutin) were formed by microsomes from lymphoblastoid cells that contained expressed CYP3A4. The apparent Michaelis-Menten constant (Km); approximately 10 to 12 mumol/L) and maximal velocity (Vmax; approximately 100 pmol/min/mg of protein) values for CYP-mediated metabolism were similar in liver and enterocyte microsomes. Deacetylation of rifabutin (Km approximately 16 to 20 mumol/L and Vmax approximately 50 to 100 pmol/min/mg of protein) was catalyzed by microsomal cholinesterase. Clarithromycin, ketoconazole, and fluconazole inhibited CYP-mediated metabolism of rifabutin in enterocyte microsomes equally or more potently than in liver microsomes but had no effect on cholinesterase activity. Azithromycin did not inhibit in vitro metabolism of rifabutin. This study provides evidence that CYP3A4 and cholinesterase are major enzymes that biotransform rifabutin in humans and that intestinal CYP3A4 contributes significantly to rifabutin presystemic first-pass metabolism and drug interactions with macrolide and antifungal agents.
Abstract: Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P = 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.
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: Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the concentration-time curve of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together with rifabutin. Patients should be monitored for adverse effects of rifabutin administered concomitantly with clarithromycin and/or fluconazole.
Abstract: This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.
Abstract: OBJECTIVE: To examine the potential effect of daidzein on CYP1A2 activity and on the pharmacokinetics of theophylline by inhibiting its metabolism. METHODS: The experiment was conducted in a single-blind, placebo-controlled, parallel study. The caffeine metabolic ratio (CMR) used as an indicator of CYP1A2 function was completed at baseline and after daidzein or placebo co-administration. A single dose of 100 mg theophylline was taken by all 20 volunteers on day 3. Thereafter, volunteers were allocated for one of two regimens. One group received 200 mg daidzein twice daily for 10 days. The other group received placebo. On day 12, the test group received 200 mg daidzein with 100 mg theophylline; the parallel group received 100 mg theophylline with placebo. RESULTS: The baseline value of CMR between test group and control group did not show a difference (P=0.215). The percentage decrease in CMR ranged from -50% to 20%, with an average value of -19.8+/-19.7%. The percentage decrease in test group was statistically significant (P=0.009), and no significant changes were shown in the control group (t=0.12, P=0.914). By comparing the pharmacokinetic parameters of theophylline before and after daily treatment with daidzein, the effect of daidzein on the metabolism of theophylline was evident. Comparing the kinetics parameters of theophylline of day 1 (without co-medication) with those of day 12 (10-day daidzein), the AUC(0-48), AUC(0- infinity ), C(max) and t(1/2) were significantly increased by 33.57+/-21.75% (CI, 1.21-1.46, P< 0.05), 33.77+/-21.45% (CI, 1.20-1.46, P<0.05), 23.54+/-16.93% (CI, 1.23-1.52, P< 0.05) and 41.39+/-45.92% (t=-3.19, P=0.011), respectively. The pharmacokinetic parameters of theophylline within the placebo group showed no statistically significant difference (P >0.05). CONCLUSIONS: Daidzein, a principal isoflavone in soybean, in higher doses may inhibit CYP1A2 activity in vivo, and physicians should be aware of potential drug-food interactions.
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: BACKGROUND AND OBJECTIVES: In vivo inhibition of cytochrome P450 (CYP) 1A2 by fluvoxamine causes a reduction in the clearance of the high-extraction drug lidocaine, which decreases in proportion to the degree of liver dysfunction. The objectives of this study were (1) to evaluate the effect of liver cirrhosis on the inhibition by fluvoxamine of the metabolic disposition of theophylline, a CYP1A2 substrate with a low-extraction ratio, to assess whether decreased sensitivity to CYP1A2 inhibition in liver disease is a general characteristic of CYP1A2 substrates, regardless of their pharmacokinetic properties, and (2) to investigate the mechanism(s) underlying the effect of liver dysfunction on CYP1A2 inhibition. METHODS: The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild liver dysfunction (Child class A) and 10 with severe liver dysfunction (Child class C), according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 7 days; in the other phase they received one 50-mg fluvoxamine dose for 2 days and two 50-mg fluvoxamine doses, 12 hours apart, in the next 5 days. On day 6, 4 mg/kg of theophylline was administered orally 1 hour after the morning fluvoxamine dose. Concentrations of theophylline and its metabolites, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, were then measured in plasma and urine up to 48 hours. RESULTS: Fluvoxamine-induced inhibition of theophylline clearance decreased from 62% in healthy subjects to 52% and 12% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CYP1A2-mediated formations of 3-methylxanthine and 1-methyluric acid were almost totally inhibited in control subjects, whereas they were only reduced by one third in patients with Child class C cirrhosis. Inhibition of 1,3-dimethyluric acid formation, which is catalyzed by CYP1A2 and CYP2E1, progressively decreased from 58% in healthy subjects to 43% and 7% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CONCLUSIONS: The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elimination is a general phenomenon, independent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less and less important as liver function worsens. Two mechanisms, as follows in order of importance, are responsible for the effect of liver dysfunction: (1) decreased sensitivity to fluvoxamine of CYP1A2-mediated biotransformations in the cirrhotic liver, probably resulting from reduced uptake of the inhibitory drug, and (2) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.
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: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Abstract: OBJECTIVES: Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir. PATIENTS AND METHODS: A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776. RESULTS: The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co-administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infected patients. CONCLUSIONS: The benefits to HIV/TB co-infected patients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability.
Abstract: Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).
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.