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 abirateron, pioglitazona y teofilina. Consulte también la información especializada pertinente.
Los cambios en la exposición mencionados se refieren a cambios en la curva de concentración plasmática-tiempo [AUC]. No detectamos ningún cambio en la exposición a abirateron, cuando se combina con teofilina (100%). Actualmente no podemos estimar la influencia de la pioglitazona. La exposición a pioglitazona aumenta al 146%, cuando se combina con abirateron (146%) y teofilina (100%). La exposición a teofilina aumenta al 107%, cuando se combina con abirateron (108%) y pioglitazona (99%).
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 abirateron tiene una biodisponibilidad oral media [ F ] del 50%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es de 18 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 72 horas. La unión a proteínas [ Pb ] es muy fuerte al 99.8% y el volumen de distribución [ Vd ] es muy grande a 2815 litros, El metabolismo tiene lugar principalmente a través de CYP3A4..
La pioglitazona tiene una alta biodisponibilidad oral [ F ] del 83%, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar poco durante una interacción. La vida media terminal [ t12 ] es de 8.3 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 33.2 horas. La unión a proteínas [ Pb ] es muy fuerte al 99% y el volumen de distribución [ Vd ] es de 36 litros en el rango medio, El metabolismo tiene lugar a través de CYP2C19, CYP2C8 y CYP3A4, entre otros..
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..
|Efectos serotoninérgicos a||0||Ø||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la abirateron, pioglitazona ni la teofilina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||1||Ø||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: La teofilina solo tiene 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, ni la abirateron ni la pioglitazona aumentan la actividad anticolinérgica.
Extensión de tiempo QT
La abirateron puede aumentar potencialmente el tiempo de QT, pero no sabemos acerca de las arritmias torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT para pioglitazona y teofilina.
Efectos secundarios generales
|Efectos secundarios||∑ frecuencia||abi||pio||teo|
|Edema periférico||20.0 %||20.0||n.a.||n.a.|
|Infeccion de las vias respiratorias altas||13.2 %||n.a.||13.2||n.a.|
|ALT elevado||13.0 %||13.0||n.a.||n.a.|
|AST elevado||13.0 %||13.0||n.a.||n.a.|
|Infección del tracto urinario||10.0 %||10.0||n.a.||n.a.|
Sepsis (5.5%): abirateron
Reacciones alérgicas de la piel: teofilina
Reacción anafiláctica: teofilina
Fibrilación auricular (2.6%): abirateron, teofilina
Angina de pecho (1.6%): abirateron
Insuficiencia cardiaca: pioglitazona
Aumento de peso: pioglitazona
Dolor de cabeza: teofilina
Hemorragia intracraneal: teofilina
Visión borrosa: pioglitazona
Edema macular: pioglitazona
Aumento de la frecuencia de la micción: teofilina
Síndrome de Stevens-Johnson: teofilina
Con base en sus
Referencias de literatura
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: 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: 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: 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: BACKGROUND AND OBJECTIVE: The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans. METHODS: In a randomized, double-blind, 4-phase crossover study, 12 healthy volunteers took either 600 mg gemfibrozil or 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily for 4 days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative excretion of pioglitazone and its metabolites into urine were measured for up to 48 hours. RESULTS: Gemfibrozil alone raised the mean total area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of pioglitazone 3.2-fold (range, 2.3-fold to 6.5-fold; P < .001) and prolonged its elimination half-life (t (1/2) ) from 8.3 to 22.7 hours ( P < .001) but had no significant effect on its peak concentration (C max ) compared with placebo (control). Gemfibrozil increased the 48-hour excretion of pioglitazone into urine by 2.5-fold ( P < .001) and reduced the ratios of the active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil decreased the area under the plasma concentration-time curve from time 0 to 48 hours [AUC(0-48)] of the metabolites M-III and M-IV by 42% ( P < .05) and 45% ( P < .001), respectively, but their total AUC(0-infinity) values were reduced by less or not at all. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. The mean area under the concentration versus time curve to 49 hours [AUC(0-49)] of itraconazole was 46% lower ( P < .001) during the gemfibrozil-itraconazole phase than during the itraconazole phase. CONCLUSIONS: Gemfibrozil elevates the plasma concentrations of pioglitazone, probably by inhibition of its CYP2C8-mediated metabolism. CYP2C8 appears to be of major importance and CYP3A4 of minor importance in pioglitazone metabolism in vivo in humans. Concomitant use of gemfibrozil with pioglitazone may increase the effects and risk of dose-related adverse effects of pioglitazone. However, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction.
Abstract: AIMS: The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans. METHODS: In a randomized, two-phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M-IV and M-III into urine were measured up to 48 h. RESULTS: Rifampicin decreased the mean total area under the plasma concentration-time curve (AUC(0-infinity)) of pioglitazone by 54% (range 20-66%; P = 0.0007; 95% confidence interval -78 to -30%) and shortened its dominant elimination half-life (t(1/2)) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (C(max)) or time to peak (t(max)) was observed. Rifampicin increased the apparent formation rate of M-IV and shortened its t(max) (P < 0.01). It also decreased the AUC(0-infinity) of M-IV (by 34%; P = 0.0055) and M-III (by 39%; P = 0.0026), shortened their t1/2 (M-IV by 50%; P = 0.0008, and M-III by 55%; P = 0.0016) and increased the AUC(0-infinity) ratios of M-IV and M-III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M-IV/pioglitazone and M-III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M-XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M-XI to pioglitazone by 240% (P = 0.0020). CONCLUSIONS: Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.
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: We studied the effects of the CYP2C8 inhibitor trimethoprim and CYP2C8 genotype on the pharmacokinetics of the antidiabetic pioglitazone. In a randomized crossover study, 16 healthy volunteers with the CYP2C8(*)1/(*)1 (n = 8), (*)1/(*)3 (n = 5), or (*)3/(*)3 (n = 3) genotype ingested 160 mg of trimethoprim or placebo twice daily for 6 days. On day 3, they ingested 15 mg of pioglitazone. The effects of trimethoprim on pioglitazone were characterized in vitro. Trimethoprim raised the area under the plasma pioglitazone concentration-time curve (AUC(0-infinity)) by 42% (p < 0.001) and decreased the formation rates of pioglitazone metabolites M-IV and M-III (p < 0.001). During the placebo phase, the weight-adjusted AUC(0-infinity) of pioglitazone was 34% smaller in the CYP2C8(*)3/(*)3 group and 26% smaller in the CYP2C8(*)1/(*)3 group than in the CYP2C8(*)1/(*)1 group (p < 0.05). Trimethoprim inhibited M-IV formation in vitro (inhibition constant 38.2 muM), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.
Abstract: BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common liver disease associated with obesity and diabetes. NASH is a progressive disorder that can lead to cirrhosis and liver failure. Insulin resistance and oxidative stress are thought to play important roles in its pathogenesis. There is no definitive treatment for NASH. OBJECTIVES: PIVENS is conducted to test the hypotheses that treatment with pioglitazone, a thiazolidinedione insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvement in hepatic histology in non-diabetic adults with biopsy proven NASH. DESIGN: PIVENS is a randomized, multicenter, double-masked, placebo-controlled trial to evaluate whether 96 weeks of treatment with pioglitazone or vitamin E improves hepatic histology in non-diabetic adults with NASH compared to treatment with placebo. Before and post-treatment liver biopsies are read centrally in a masked fashion for an assessment of steatohepatitis and a NAFLD Activity Score (NAS) consisting of steatosis, lobular inflammation, and hepatocyte ballooning. The primary outcome measure is defined as either an improvement in NAS by 2 or more in at least two NAS features, or a post-treatment NAS of 3 or less, and improvement in hepatocyte ballooning by 1 or more, and no worsening of fibrosis. METHODS: PIVENS enrollment started in January 2005 and ended in January 2007 with 247 patients randomized to receive either pioglitazone (30 mg q.d.), vitamin E (800 IU q.d.), or placebo for 96 weeks. Participants will be followed for an additional 24 weeks after stopping the treatment. The study protocol incorporates the use of several validated questionnaires and specimen banking. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB) which was established for monitoring the accumulated interim data as the trial progresses to ensure patient safety and to review efficacy as well as the quality of data collection and overall study management. (ClinicalTrials.gov number, NCT00063622).
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: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.
Abstract: Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.
Abstract: Pioglitazone is a thiazolidinedione antidiabetic with actions similar to those of rosiglitazone. It is used in the management of type 2 diabetes mellitus and is prepared by reducing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene]-2,4-thiazolidinedione with sodium borohydride in the presence of a cobalt ion and dimethyl glyoxime. Ultraviolet spectroscopy shows maximum absorption at 270nm. Infrared spectroscopy shows principal peaks at wave numbers 3082, 2964, 1736, 1690, 1472, 1331, 1254, 1040, 841, 728cm(-1) (KBr disk). The determination method by high-performance liquid chromatography was linear over the range of 25-1500ng/mL of pioglitazone in plasma (r(2)>0.999). The within- and between-day precision values were in the range of 2.4-6.8%. The limit of quantitation of the method was 25ng/mL. It is well absorbed with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5h. It is metabolized by the hepatic cytochrome P450 enzyme system. Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
Abstract: Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.
Abstract: Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.
Abstract: We present a case of a 77 year-old gentleman with previous coronary artery bypass grafting, admitted to hospital with recurrent torsades de pointes (TdP) due to abiraterone-induced hypokalaemia and prolonged QTc. The patient was on abiraterone and prednisone for metastatic prostate cancer. He required multiple defibrillations for recurrent TdP. Abiraterone is a relatively novel drug used in metastatic prostate cancer and we discuss this potential adverse effect and its management in this unusual presentation.
Abstract: BACKGROUND: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background. OBJECTIVES: The first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners. METHODS: PBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network. RESULTS: The newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C,) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI C,ratios (C,during DDI/C,control) are within twofold of the observed values. CONCLUSIONS: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.