Influence of a Fat-Rich Meal on the Pharmacokinetics of a New Oral Formulation of Cyclosporine in a Crossover Comparison with the Market Formulation

The influence of a fat-rich meal on the pharmacokinetics of cyclosporine from a new oral formulation (Sandimmune Neoral) was compared in a randomized, four-way crossover study to the currently marketed formulation (Sandimmune) in 24 healthy male volunteers. Single oral doses of 300 mg Sandimmune and 180 mg Sandimmune Neoral were each administered once under fasting conditions and once 30 min after starting a high-fat meal. Serial blood samples were obtained over a 48-hr period after each administration, and whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay method. Food had a marked effect on cyclosporine absorption from Sandimmune manifested by a nearly doubled time to reach the peak concentration and a 37% increase in the area under the curve. This was associated with significant elevations in subsequent whole-blood cyclosporine concentrations compared to the fasting administration. For Sandimmune Neoral the influence was less pronounced. The maximum concentration was decreased by 26%, without a relevant change in the time to reach the peak; the area under the curve showed a slight reduction of 15%. The relatively minor influence of a fat-rich meal on the absorption of cyclosporine from Sandimmune Neoral is advantageous when individualizing a dosage regimen under clinical and out-patient administration conditions.     

Cyclosporine bioavailability of Neoral and Sandimmune in white and black de novo renal transplant recipients. Neoral Study Group

Black renal transplant recipients have inferior graft outcomes when compared to whites. The relative bioavailability of cyclosporine (CsA) with the Sandimmune (SIM) formulation is lower in black recipients when compared to whites. To study relative CsA bioavailability in the Neoral formulation, 18 black and 78 white de novo renal transplant recipients were randomized in a multicenter, double-blind, parallel group study to receive either SIM or Neoral capsules twice a day for 12 weeks. After an overnight fast, CsA whole blood levels (TDx) were collected during 12 hours after the morning dose and 12 hours after the evening dose with a standardized meal. Pharmacokinetic profiles were obtained at the end of weeks 1, 4, 8, and 12. Initial CsA dose was 5 mg/kg twice a day; subsequent doses were titrated to target trough CsA levels. Area under the blood concentration vs. time curve (AUC), peak blood concentration (Cmax) and time to Cmax(Tmax) were obtained from 16 black and 73 white patients. Food conditions (fed and fasting) were averaged, and data was dose-normalized. For black recipients, Neoral was significantly more bioavailable than SIM only during week 1; there was also a consistent trend to higher cyclosporine bioavailability at weeks 4, 8, and 12. For whites, there were significant differences in favor of Neoral at all time periods. No significant differences in relative bioavailability were noted between races for either SIM or Neoral except for a higher Cmax in white patients given Neoral. Neoral is better absorbed than SIM in both blacks and whites. These data suggest that Neoral is the superior CsA preparation for all racial groups.     

Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction.

Everolimus is an immunosuppressant intended for use with cyclosporine in acute-rejection prophylaxis following organ transplantation. The possibility of a drug interaction of cyclosporine on everolimus was assessed. In this randomized, two-period, crossover study, 24 healthy subjects received a single oral dose of 2 mg everolimus alone and with one of two cyclosporine formulations: either 175 mg Neoral or 300 mg Sandimmune. The single doses of Neoral and Sandimmune were chosen to yield similar average areas under the concentration-time curve (AUC). Treatments were separated by a 14-day washout period. Cyclosporine AUCs were similar for both formulations (p = 0.53), whereas the peak concentration (Cmax) was significantly higher for Neoral (p = 0.02). Simultaneous administration of Neoral with everolimus increased everolimus Cmax and AUC by 82% and 168%, respectively (p = 0.0001). Coadministration of Sandimmune with everolimus did not affect everolimus Cmax (p = 0.59) but increased everolimus AUC by 74% on average (p = 0.0001). Everolimus elimination half-lives were unchanged in the presence of both cyclosporine formulations. The everolimus AUC increase with Neoral coadministration was significantly greater than the AUC increase with Sandimmune (p = 0.008). However, there was no apparent association between cyclosporine Cmax and the change in everolimus AUC with cyclosporine coadministration. If Neoral or Sandimmune is removed from an everolimus-cyclosporine immunosuppressive regimen, a two- to three-fold decrease in everolimus exposure is expected. Therapeutic monitoring of everolimus concentrations would be helpful after the removal of cyclosporine to individually titrate everolimus exposure.     

Population pharmacokinetics of cyclosporine in cardiopulmonary transplant recipients

A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune) or a microemulsion (Neoral). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals [CI] 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 - 11.3 x ITRA + 23.5 x CF + 0.129 x (WT - 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population.     

A limited sampling strategy for the estimation of 12-hour SangCya and neoral AUCs in renal transplant recipients

Neoral and SangCya are new cyclosporine formulations with more consistent pharmacokinetic profiles than the older formulation of cyclosporine, Sandimmune. Limited sampling strategies have been derived to estimate the full area under the curve (AUC) for both Neoral and Sandimmune. In addition, no limited sampling strategy has been derived for SangCya, and no rigorous prospective testing has been done on any of these formulas. The authors studied 32 renal transplant patients who received Neoral and then SangCya during a formulation conversion study. Full AUCs were drawn on all patients (twice while on Neoral, once while on SangCya). Abbreviated formulas were derived using linear regression models and then tested for the prediction error. The authors found that several abbreviated formulas offer excellent estimations of the full AUC for both SangCya and Neoral. The generated formulas worked equally well with either formulation. In addition, the authors found that limited sampling strategies using a 1.5-hour sample may predict a full AUC more accurately than those that use a 2-hour sample. The use of these abbreviated formulas allows for a convenient and accurate estimate of CsA exposure.     

Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients

The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.     

Comparative bioavailability of the microemulsion formulation of cyclosporine (Neoral) with a generic dispersion formulation (Cicloral) in young healthy male volunteers

The aim of this study was to compare the bioavailability of cyclosporine (CyA) from the generic dispersion formulation Cicloral (CIC) with the microemulsion formulation Neoral (NEO) and the original Sandimmune (SIM) capsules after single doses of 100, 300, or 600 mg of drug, respectively. The study was performed according to an open 3-period cross-over design with 12 young healthy male volunteers for each dosage. The concentrations of CyA and its main metabolites were determined by high performance liquid chromatography in whole blood and urine up to 48 hours postdosing. Peak concentrations and area under the time-concentration curve were greater for the NEO and CIC formulations compared with SIM, and the mean bioavailability of CIC was significantly (P<0.05) lower compared with NEO. The bioavailability of SIM compared with NEO was 54% to 71%, in agreement with previous results. Bioequivalence was not demonstrated between CIC (test) and NEO (reference) as the 90% confidence intervals were outside the 80% to 125% guidelines based on log-transformed AUCs, and were 75.2% to 87.7% at 100 mg, 79.2% to 91.8% at 300 mg, and 76.6% to 94.5% at 600 mg doses. The respective values for Cmax were 78.9% to 94.6%, 80.7% to 95.0%, and 71.4% to 84.1%. A good correlation was demonstrated between the urinary recovery of CyA and the AUC4. Therefore, the urinary recovery of CyA may be helpful as a surrogate parameter for the systemic exposure of patients to CyA. Whereas the relative amount of hydroxylated metabolites (AM1, AM9, AM1c) was similar for all formulations and doses, the urinary recovery of the N-demethylated metabolite AM4N decreased with increasing dose indicating saturable metabolism. No relationship could be demonstrated between CYP3A activity using dextromethorphan as a probe for the metabolic clearance of CyA.     

Cyclosporine bioequivalence study: quantification using fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA)

OBJECTIVE: The aim of study was to compare the bioavailability of 2 cyclosporine capsule formulations (100 mg; Sigmasporin Microoral from Novaquímica Divis?o Nature's Plus Farmacêutica Ltd., Brazil, as test formulation and Sandimmune Neoral from Novartis Biociências S.A., Brazil, as reference formulation) in 24 healthy male volunteers. METHODS: The study was open, randomized, with a 2-period crossover, a 1-week washout interval between doses. Blood samples were obtained over a 12-hour interval after each oral administration of cyclosporine (2 capsules of 100 mg of each formulation). Cyclosporine blood concentrations were quantified using a fluorescence polarization immunoassay (FPIA) method provided by Abbott Axsym System and Cyclo-Trac SP. Whole-blood radioimmuoassay (RIA) kit was provided by DiaSorin. These assays provided concentration-time curves for cyclosporine in blood concentration from which the following pharmacokinetic parameters were obtained: AUC(last), AUC(inf), Cmax. RESULTS: Geometric mean and 90% confidence intervals (CI) of Microoral/Neoral as percent ratios were 94.5% (90.8-98.4%) for AUC(last), 93.8% (89.7-98.1%) for AUC(inf), and 98.1% (94.5-101.8%) for Cmax when cyclosporine was determined using FPIA and 96.1% (91.9 to 100.6%) for AUC(last), 95.2% (90.2-100.5%) for AUC(inf), and 99.4% (96.4-102.4%) for Cmax using RIA. CONCLUSION: Since the 90% CI for Cmax, AUC(last) and AUC(inf) ratio were within the 80-125% interval proposed by US-FDA, it is concluded that Sigmasporin Microoral 100 mg capsule formulation is bioequivalent to Sandimmune Neoral 100 mg capsule formulation with regard to both rate and the extent of absorption.     

环孢素A pH敏感性纳米粒的制备与大鼠口服药代动力学

目的研究环孢素A(CyA) pH敏感性纳米粒的制备工艺与口服药代动力学性质。方法采用改良的乳化-溶剂扩散技术(QESD)制备CyA pH敏感性纳米粒；经大鼠灌胃给药，HPLC法测定全血药物浓度，计算口服相对生物利用度。结果经3P87程序拟合，确定CyA在大鼠体内的药代动力学过程为二室模型；与Neoral微乳相比，CyA-E100，CyA-L100，CyA-L100-55和CyA-S100纳米粒的相对生物利用度分别为94.8%，115.2%，113.6%和132.5%。结论经统计分析，CyA-S100纳米粒可以显著改善CyA的生物利用度(P<0.05)，而CyA-L100-55纳米粒，CyA-L100纳米粒和CyA-E100纳米粒与Neoral微乳相比无显著性差异。实验结果表明,pH敏感性纳米粒有望成为促进蛋白、多肽类药物及难溶性药物口服吸收的有效载体。     

Abbreviated pharmacokinetic profiles in area-under-the-curve monitoring of cyclosporine therapy in de novo renal transplant patients treated with Sandimmune or Neoral. Neoral study group

Trough cyclosporine (CsA) blood levels obtained just before administration of the next dose are monitored to guide dosage adjustments. However, these levels may not be the best indicator of total drug exposure. In a study of de novo renal transplant patients, pharmacokinetic profiles of CsA after administration of the traditional CsA formulation (Sandimmune [CsA-SIM] Novartis, E. Hanover, NJ) or the new formulation, cyclosporine capsules for microemulsion (Neoral [CsA-ME] Novartis, E. Hanover, NJ), were compared at 1, 4, 8, and 12 weeks posttransplantation under fasting and fed conditions. The data were analyzed to assess the degree of correlation between total drug exposure, indicated by the area under the concentration-versus-time curve at the end of a 12-hour dosing interval (AUC12h), and drug exposure calculated from concentrations obtained at different time points (abbreviated AUC [AAUC]). With AAUCs calculated from trough levels and levels at 4 hours postdose, the average degree of correlation with AUC12h was r = 0.915 for CsA-ME and r = 0.853 for CsA-SIM. The degree of correlation was smaller with CsA-SIM and additional sampling times may be required. With CsA-ME, these two sampling time points appear to provide a reliable indication of total CsA exposure; CsA-ME may thus provide advantages in terms of blood level monitoring and patient management.     

Pharmacokinetic Profile and Variability of Cyclosporine versus Neoral in Patients with Cystic Fibrosis after Lung Transplantation

Various factors may influence bioavailability and blood concentrations of cyclosporine, a problem that may be compounded by diseases such as cystic fibrosis in which impaired absorption through the gastrointestinal tract is common. Neoral, a microemulsion formulation of cyclosporine, has improved bioavailability and more stable blood concentrations than earlier formulations. We conducted a prospective, open, crossover study to examine whether these findings held true in 12 clinically stable patients with cystic fibrosis who had undergone lung transplantation at least 6 months earlier. In the first arm, patients continued their usual dosage of cyclosporine twice/day. In the second arm they received Neoral for at least 1 week before having blood studies. For each arm whole blood trough concentrations were drawn for 7–10 successive days, together with a pharmacokinetic study with concentrations drawn at times zero, 1, 2, 3, 4, 6, 12, and 24 hours. Variance was assessed from morning concentrations. Area under the curve from zero to 12 hours (AUC12), maximum concentration (C_max), and time to C_max (T_max) were calculated for each arm. Eleven subjects completed the protocol. The daily variance for Neoral was significantly less than for cyclosporine (p=0.04). The AUC₁₂ for Neoral and cyclosporine were 4164 ± 1467 and 5318 ± 1670 μg·L/hour (p=0.09), respectively. Respective C_max were 613 ± 242 and 931 ± 458 μg/L (p=0.08) and relative C_max and AUC₁₂ were 1.91 and 1.47 (p<0.05). Thus Neoral had a superior pharmacokinetic profile and less day-to-day variability in patients with cystic fibrosis who had undergone lung transplantation.     

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80–0.94) or missed the criterion only marginally (90% confidence interval of c _max 0.75–0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules.     

Peppermint oil enhances cyclosporine oral bioavailability in rats: comparison with D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) and ketoconazole.

Peppermint oil inhibits cyclosporine metabolism in vitro. The current work compared the effects of peppermint oil, ketoconazole, and D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) on cyclosporine oral bioavailability. Male Sprague-Dawley rats were administered cyclosporine (25 mg/kg) as the Sandimmune formulation. Peppermint oil (100 mg/kg) tripled the mean cyclosporine maximum concentration (C(max)) from 0.60 to 1.6 microg/mL and increased the area under the concentration versus time curve (AUC(0-infinity)) from 8.3 to 24.3 microg x h/mL. The median time to reach C(max) (t(max)) was increased from 2 to 6 h. Terminal half-life (10 h) and mean residence time (MRT; 15 h) were unaffected. Coadministration of TPGS (50 mg/kg) with cyclosporine in a saline vehicle doubled cyclosporine C(max) from 1.3 to 2.9 microg/mL and increased AUC(0-infinity) from 28.5 to 59.7 microg x h/mL. The t(max) was unchanged (3 h). Terminal half-life and MRT were increased by 44% (15.4 versus 10.7 h) and 24% (19.9 versus 16.0 h), respectively. Cyclosporine pharmacokinetics were not altered when corn oil was used instead of saline as a gavage vehicle, however the TPGS effect was abolished. Ketoconazole (10 and 20 mg/kg) had no effect on cyclosporine absorption. The lack of a significant ketoconazole effect may reflect poor metabolism of cyclosporine in rat intestinal tissue and suggests that inhibition of cytochrome P450 3A is not the only means by which peppermint oil enhances cyclosporine oral bioavailability.     

Pharmacokinetics of two oral cyclosporin a formulations in clinically stable heart-transplant patients

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 +/- 0.4 mgkg(-1)body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in C(max)(ss)( 732 +/- 178 vs 935 +/- 250 ng ml(-1), P< 0.001) and t(max)( 2.63 +/- 1.21 vs 1.36 +/- 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 +/- 19 vs 66 +/- 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations.     

Oral administration of liposomes containing cyclosporine: a pharmacokinetic study

Liposomal formulation containing cyclosporine A (CSA) were prepared. The most stable liposomes with the composition of CSA, dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) in molar ratio 1:0.2:1, respectively were administered orally to New Zealand rabbits. The pharmacokinetic of the administered CSA was compared with that of the commercially available oily oral formulation of CSA (Sandimmune) at dose of 15 mg/kg. Cyclosporine concentration in blood was monitored using a radioimmunoassay method (RIA). A change in the pharmacokinetic parameters of CSA due to liposomal encapsulation was observed. A peak concentration was reached in 50 min in case of liposomes compared with 225 min in case of Sandimmune. The rate of absorption (C_max/AUC_0–∞) was significantly faster following the liposome administration. A significant difference in the area under the concentration curve (AUC_0–∞) was found and this was attributed to the difference in the terminal half-lives (t_1/2β) which were 8.88±1.94 and 19.3±8.48 h for liposomes and Sandimmune preparations, respectively. The mean residence time (MRT) and the mean absorption time (MAT) were dramatically decreased following the administration of liposomal formulation. Generally, there was less inter-individual variation in the values of rate of absorption, t_1/2β and MRT when CSA liposomes were orally administered compared to the administration of Sandimmune. Thus, an oral liposomal formulation for CSA can be developed to offer the advantages of low variability and fast onset of action.     

Bioequivalence of Soft Gelatin Capsules and Oral Solution of a New Cyclosporine Formulation

Study Objective . To compare the bioavailability of cyclosporine from two oral dosage forms of a new microemulsion formulation. Design . Open, randomized, three-treatment, three-period crossover investigation. Setting . University-affiliated clinical pharmacology research unit. Patients . Twenty-four healthy male volunteers. Interventions . Single oral administrations of cyclosporine 180 mg given as a soft gelatin capsule (reference), an oral solution under fasting conditions, and the oral solution mixed with orange juice. Measurements and Main Results . Serial venous blood samples were obtained over 48 hours after each administration to measure cyclosporine in whole blood by a specific monoclonal radioimmunoassay. For all three treatments, the mean maximum blood concentration (C_max) of approximately 1100 ng/ml was reached at about 1.3 hours (t_max) after administration; the area under the blood concentration-time curve (AUC) was, on average, 4700 ng·hr/ml. Bioequivalence was conclusively demonstrated for both the absorption rate (C_max and t_max) and extent (AUC) of cyclosporine among the treatments inasmuch as the point estimates and 90% confidence intervals were within the respective equivalence ranges. Conclusions . When administered in conjunction with routine concentration monitoring, the two oral dosage forms of the new microemulsion formulation of cyclosporine can be interchanged without need for dosage adjustments. In addition, the oral solution can be mixed with fruit juice without affecting the rate or extent of cyclosporine absorption.     

环孢素A聚乳酸纳米粒胶体的制备与大鼠生物利用度的测定环孢素A聚乳酸纳米粒胶体的制备与大鼠生物利用度的测定

目的研究环孢素A聚乳酸纳米粒胶体(CyA-NP)的制备处方与工艺,并以新山地明(Neoral)为参比制剂,进行相对生物利用度考察。方法以溶剂-非溶剂法制备CyA-NP,用HPLC法测定全血中的药物浓度,计算胶体的生物利用度。结果胶体中的纳米粒均匀圆整,粒径为57.5 nm,药物回收率大于90%。CyA-NP的AUC0-72为29.06 mg·h·L^-1,Neoral的AUC0-72为28.59 mg·h·L^-1,与Neoral相比,CyA-NP的相对生物利用度为101.6%,峰浓度较小(P<0.05),吸收较慢(P<0.05),消除亦较慢(P<0.1)。结论以溶剂-非溶剂法可以简便制得CyA-NP,其大鼠相对生物利用度与Neoral相比无显著性差异,有望成为Neoral的代用品。     

环孢素A-羟丙甲纤维素酞酸酯纳米粒的大鼠相对生物利用度

目的制备环孢素A-HPMCP(两种型号HP50与HP55)纳米粒，并与新山地明(Neoral)进行大鼠相对生物利用度与药物动力学行为的比较。方法以溶剂-非溶剂法制备CyA-HP50 NP与CyA-HP55 NP，用HPLC法测定其相对生物利用度，并用3P97程序计算药代动力学参数。结果3种制剂的血药浓度-时间数据均以2室模型拟合最佳。与Neoral相比，CyA-HP50 NP与CyA-HP55 NP的相对生物利用度分别为82.3%和119.6%，均无显著性差异；CyA-HP50 NP与CyA-HP55 NP的K₁₀均较小(P<0.05)，说明药物消除较慢。与CyA-HP50 NP相比，CyA-HP55 NP的相对生物利用度为145.3%，有显著性差异(P<0.01)。结论CyA-HPMCP NP 制备方法简便，生物利用度高，可望开发为一种新的制剂。     

Recommendations for bioequivalence testing of cyclosporine generics revisited

The immunosuppressant cyclosporine is generally considered a critical-dose drug. The validity of standard criteria to establish bioequivalence between cyclosporine formulations has recently been challenged. Recommendations included establishment of individual bioequivalence rather than average bioequivalence, establishment of bioequivalence in transplant patients and in subgroups known to be poor absorbers, as well as long-term efficacy and safety studies in transplant patients. However, at the moment individual bioequivalence is a theoretical concept, the practical benefits of which have not statistically been proven. The proposed patient pharmacodynamic studies can be expected to require an unrealistically high number of subjects to achieve sufficient statistical power. It is well established that the common practice of blood-concentration-guided dosing of cyclosporine efficiently compensates for interindividual and intraindividual variability and allows for safely switching cyclosporine formulations as bioinequivalent as Sandimmune and Neoral. Recent studies comparing the generic cyclosporine formulation SangCya with Neoral, including individual bioequivalence, bioequivalence in transplant patients, and long-term safety after switching from Sandimmune to SangCya, confirmed that it was valid to conclude bioequivalence of both cyclosporine formulations based on standard average bioequivalence criteria. Present FDA guidelines for approving bioequivalence can be considered adequate and sufficient for generic cyclosporine formulations.