Pharmacokinetics of salmeterol fluticasone powder inhalation

Adult salmeterol/fluticasone propionate, adolescent patients aged 65,438+02 and over 65,438+02: After healthy adult subjects take this product, the plasma peak concentration of fluticasone propionate will reach 65,438+0 within 0 to 2 hours, while the plasma peak concentration of salmeterol will reach about 5 minutes later. In a single-dose crossover trial, 14 healthy adult subjects received more than the recommended dose of this product. The following three 2- inhalation therapies were given: 50mg/500mg of this product, 500mg of fluticasone propionate dry powder and 50mg of salmeterol dry powder, or 500mg of fluticasone propionate dry powder alone. The average plasma peak concentrations of fluticasone propionate and salmeterol were 107, 94 and 120 pg/mL, respectively, which indicated that the systemic exposure of fluticasone propionate and salmeterol had no significant change. In a repeated dosing trial, 45 adolescents and adults with asthma received the highest recommended dose of this product. The following inhalation treatments were given twice a day: 50mg/500mg of this product, 500mg of fluticasone propionate dry powder and 50mg of salmeterol dry powder, or 500mg of fluticasone propionate dry powder alone. The average steady-state plasma peak concentrations of fluticasone propionate were 57, 73 and 70 pg/mL, respectively, indicating that the systemic exposure of fluticasone propionate had no significant change. The plasma concentration of salmeterol was not detected in this experiment. There was no significant change in fluticasone propionate and salmeterol in feces. After taking this product, the average terminal half-life of fluticasone propionate is 5.33 to 7.65 hours, which is similar to the terminal half-life reported when inhaling salmeterol or using fluticasone propionate alone (average 5.30 to 6.95438+0 hours). There is no report on the terminal half-life of salmeterol after giving this product or inhaling fluticasone propionate. Children patients: In a clinical trial of asthmatic children aged 4 to 1 1 year, 6 1 patients took 50 mg and 100mg of fluticasone propionate twice a day, and the concentration of fluticasone propionate was detected 20 to 40 minutes after inhaling dry powder. The plasma concentration is very low, ranging from never detected (about 80% of plasma samples) to 88 pg/mL. The average peak plasma concentrations of fluticasone propionate at 50 mg and 100 mg dosage levels were 5 and 8 pg/ml, respectively. Special population: There is no routine pharmacokinetic study to find gender differences. In special population, such as elderly patients, patients with liver or kidney injury, such research has not been carried out. Drug interaction: In repeated and single dose studies, there is no obvious evidence that there is drug interaction between fluticasone propionate and salmeterol after inhalation. In animals and humans, there is no evidence that the simultaneous use of salmeterol and fluticasone propionate by inhalation will affect the pharmacokinetics of these two components. Therefore, from the point of view of pharmacokinetics, these two components can be considered separately. In a placebo-controlled, cross-over drug interaction study involving 15 healthy volunteers, simultaneous use of SEREVENT(50mcg, inhaled twice a day) and ketoconazole (400mg, taken orally once a day) for 7 days resulted in a significant increase in plasma exposure of salmeterol (Cmax was 1.4 times, AUC was 650). After repeated administration, the accumulation of salmeterol did not increase. Three subjects withdrew from the combination of this product and ketoconazole because of prolonged QTc interval or palpitation with sinus tachycardia. Other 12 subjects used ketoconazole at the same time had no clinically significant effect on heart rate, blood potassium or QTc interval (see Precautions and Drug Interaction). Salmeterol: Salmeterol acts locally in the lung, so the plasma level is not used as a therapeutic index. In addition, information about the pharmacokinetics of salmeterol is limited, because the plasma concentration of salmeterol is very low (about 200pg/ml or lower) after inhalation of therapeutic dose, and it is technically difficult to detect the drug in plasma. Hydroxynaphthoic acid can be detected in systemic circulation after routine use of salmeterol, and its steady-state concentration reaches about 100ng/ml. This concentration is 1000 times lower than the steady-state level observed in the toxicity study. After long-term (more than 12 months) conventional drug treatment, no harmful effects were observed in patients with airway obstruction. Absorption: Because the therapeutic dose is very small, after inhaling the recommended dose of salmeterol (50mg salmeterol inhaled dry powder twice a day), the system level is very low or uncertain. Seven patients with asthma were given 50mg salmeterol inhalation dry powder twice a day for a long time. The plasma concentration of salmeterol can be measured within 5 ~ 45 minutes, and the average peak concentration within 20 minutes is 65438±067 pg/mL. There was no livestock accumulation after repeated administration. Distribution: In vitro, the binding rate of salmeterol to plasma protein is 96% on average, and the concentration of salmeterol per ml of plasma ranges from 8 to 7722 ng, which is much higher than that achieved after the therapeutic dose of salmeterol is given. Metabolism: Salmeterol is metabolized mainly by hydroxylation, and then eliminated mainly by feces. No significant amount of prototype salmeterol was found in urine or feces. Excretion: Two healthy adult subjects took orally 1mg of radiolabeled salmeterol, and about 25% and 60% of radiolabeled salmeterol were excreted in urine or feces within 7 days respectively. The half-life of terminal clearance is about 5.5 hours. Xanax has no obvious pharmacological activity. The protein binding rate is high (]99%) and the half-life is 1 1 day. Special population: patients with liver injury: Because salmeterol is mainly metabolized by the liver, liver function damage will lead to the accumulation of salmeterol in plasma, so patients with liver disease should be closely monitored. Others: There is no formal pharmacokinetic study of salmeterol in other special populations. Fluticasone Propionate: To evaluate the absolute bioavailability of fluticasone Propionate at each inhalation dose from the study containing pharmacokinetic data after inhalation, or from the study containing pharmacokinetic data after intravenous administration, or by comparing the pharmacokinetic data in this study. In healthy adult subjects, the absolute bioavailability of fluticasone propionate with different inhalation devices was evaluated: Accuhaler/Diskus was 7.8%, Diskhaler was 9.0%, Evohaler inhaled fluticasone propionate was 65,438 00.9%, and salmeterol was 65,438 00.9%. It has been observed that patients with asthma or chronic obstructive pulmonary disease have reduced their systemic exposure after inhaling fluticasone propionate. Absorption: Fluticasone propionate acts locally on the lung, so the plasma level cannot predict its therapeutic effect. For labeled and unlabeled drugs, oral dose studies show that the oral bioavailability of fluticasone propionate can be ignored ([1%) due to incomplete absorption in intestine and liver and systemic metabolism. On the contrary, most fluticasone propionate delivered to the lungs is absorbed by the whole body. Fluticasone propionate was administered through a quasi-receptor device, and its systemic bioavailability was about 65438 08%. Adult asthma patients (N = 1 1) were given 500mg of fluticasone propionate twice a day through a quasi-inhaler, and the steady-state plasma peak concentration of fluticasone propionate changed from no display to 266pg/mL. The average plasma concentration was 1 10pg/mL. Patients with chronic obstructive pulmonary disease inhale fluticasone propionate 250mg twice a day with a quasi-inhaler. The average steady-state plasma concentration was 53pg/mL (ranging from 19.3 to 159.3pg/mL). After intravenous administration, fluticasone propionate has a rapid initial treatment period, which is related to its high fat solubility and tissue binding rate. Its distribution capacity is 4.2 liters/kg. The average binding rate of fluticasone propionate to human plasma protein is 965438 0%, and the binding to red blood cells is weak and reversible, but it has no obvious binding to human corticosteroid transfer protein. Metabolism: the overall clearance rate of fluticasone propionate is high (average 1093 mL/min), and the renal clearance rate is lower than 0.02% of the overall clearance rate. The only circulating metabolite found in human body is formed through cytochrome P450 3A4 pathway, and fluticasone propionate is 17β? Carboxylic acid derivatives. Compared with in vitro and maternal drugs, the affinity of this metabolite to glucocorticoid receptor in human lung cell fluid is low (about 1/2000), and its pharmacological activity can be ignored in animal experiments. Other metabolites found in in vitro experiments using cultured human liver tumor cells were not found in human body. Exclusion: Fluticasone propionate has many exponential kinetic parameters after intravenous administration, and its terminal clearance half-life is about 7.8 hours. Less than 5% of the oral dose of radioactive label is excreted from urine in the form of metabolites, while the rest is excreted from feces in the form of metabolites and maternal drugs. Special population: liver injury: because fluticasone propionate is mainly eliminated by liver metabolism, liver injury will lead to the accumulation of fluticasone propionate in plasma. Therefore, patients with liver disease should be closely monitored when taking this product. Gender: Nine women and 16 male asthma patients were given 500mg fluticasone propionate dry powder twice a day by quasi-inhaler, and 14 women and 43 male COPD patients were given 250 or 500mg twice a day to obtain comprehensive pharmacokinetics. No overall difference in pharmacokinetics of fluticasone propionate was observed. Age: Fifty-seven COPD patients (aged from 40 to 82) used 250 or 500mg fluticasone propionate twice a day, and no correlation between age and systemic exposure was observed. Others: There is no formal pharmacokinetic study for other special populations. Drug interaction: Fluticasone propionate is the substrate of cytochrome P450 3A4. According to a multi-dose, crossover drug interaction study involving 18 healthy volunteers, it is not recommended to use fluticasone propionate in combination with potent cytochrome P450 3A4 inhibitors and ritonavir. Fluticasone propionate water-soluble nasal spray (200mg) and ritonavir (100mg twice a day) were used together for 7 days. In most subjects, the plasma concentration ([10 pg/mL) was not detected after the water-soluble fluticasone propionate nasal spray was used alone, but the peak concentration Cmax (average 65438) could be monitored. 10.8 to 14. 1 pg/ml] and AUC(0-t) are 8.43 pg HR/ml[ range, 4.2 to 18.8 pg? Hours/ml]). After ritonavir was combined with water-soluble fluticasone propionate nasal spray, the Cmax and AUC(0-t) of fluticasone propionate increased to 365,438+08 pg/ml (range, 65,438+065,438+00 ~ 648 pg/ml) and 3/kl respectively. Hr/mL (range, 1207. 1 to 5662.0 pg? Hours/ml). The obvious increase of plasma exposure of fluticasone propionate led to the obvious increase of plasma cortisol area under AUC (86%). Other potent cytochrome P450 3A4 inhibitors and fluticasone propionate should be used with caution. In a drug interaction study, combined oral inhalation of fluticasone propionate (1000mg) and ketoconazole (200 mg once a day) will increase the plasma exposure of fluticasone propionate and decrease the AUC of plasma cortisol, but it has no effect on urinary excretion of cortisol. In another multi-dose drug interaction study, the combination of oral inhalation of fluticasone propionate (500mg twice daily) and erythromycin (333mg three times daily) did not affect the pharmacokinetics of fluticasone propionate.