Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation.

BACKGROUND: Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The purpose of this pharmacokinetic study performed in stable renal transplant recipients was to evaluate interchangeability of Gengraf and Neoral. METHODS: Using an open-label, three-period design, 50 renal transplant recipients taking stable doses of Neoral completed a multicenter study. Subjects continued their Neoral regimen during period I (days 1-14). Subjects then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28), followed by conversion to the same milligram-for-milligram dosing regimen of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic evaluations (maximum observed blood concentration [C(max) ], concentration before dosing [C(trough) ], time to maximum observed concentration [T(max) ], and area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Additional predose samples (C (trough)) were evaluated on days 7, 21, and 35. Laboratory and safety parameters were also evaluated. RESULTS: The pharmacokinetics of Gengraf (C(max), T(max), C(trough), and AUC) were indistinguishable from the Neoral values in stable renal allograft recipients. The bioequivalent capsules were interchangeable with respect to C(max), C(trough), and AUC at steady state and also on conversion from one capsule formulation to the other. The 90% confidence intervals (CI) for the Gengraf versus Neoral comparison at steady state (day 28 vs. day 14) were 0.95 to 1.03 for AUC and 0.92 to 1.04 for C(max). Trough concentrations remained consistent throughout the study, with no need for dosage adjustment in any of the subjects. Gengraf is well tolerated, with an excellent safety profile, comparable to the safety profile of Neoral. CONCLUSIONS The pharmacokinetics of Gengraf are equivalent and indistinguishable from those of Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable renal transplant recipients.

Randomized, open-label preference study of two cyclosporine capsule formulations (usp modified) in stable solid-organ transplant recipients.

BACKGROUND: Prior research has indicated patient dissatisfaction with the odor, size, and taste of cyclosporine capsules, as well as the halitosis and body odor the capsules can cause. OBJECTIVES: The purposes of this investigation were to (1) compare the overall cyclosporine capsule preference (Gengraf vs Neoral) in stable, solid-organ transplant recipients, (2) assess patient preference based on specific capsule attributes, and (3) determine the reliability of the Cyclosporine Capsule SatiSfaCtion Survey (original to this study). METHODS: In this multicenter, randomized, open-label, parallel-group, preference study, patients were recruited from 144 centers in North America with established transplant programs. Solid-organ transplant recipients who had taken stable doses of cyclosporine (Neoral) for >/=2 consecutive months were randomized in a 9:1 ratio to receive another cyclosporine formulation (Gengraf) or to remain on Neoral therapy. Patients completed the Cyclosporine Capsule Satisfaction Survey prior to randomization (baseline survey) and after taking the study drug for 4 weeks (final survey). The survey consisted of multiple attribute items with high face validity in assessing patients' perceptions and preferences with regard to their overall experience, as well as specific attributes of cyclosporine capsules known to affect patient acceptance. RESULTS: The intent-to-treat population included 1906 patients (1211 men, 693 women [sex unknown in 2 patients]; mean [SD] age, 50.2 [12.4] years). A total of 1708 patients were switched to Gengraf; 198 continued on Neoral. Based on their overall experience with both capsule formulations, the majority of patients switched to Gengraf (61.9%) responded that they preferred the Gengraf capsule, compared with 13.7% who preferred the Neoral capsule and 24.4% who indicated no preference (P < 0.001). A similar preference for Gengraf was observed based on capsule odor (66.3%), ease of swallowing (51.5%), taste (57.1%), and impact on breath odor (52.5%) and body odor (48.4%) (P < 0.001 for each test). The results of internal consistency and reproducibility calculations were high for the Cyclosporine Capsule Satisfaction Survey. Internal consistency ranged from alpha = 0.84 to 0.95 for the subscales and was alpha = 0.95 for the overall score. Ranges for reproducibility in the subscales were r = 0.75 to 0.79, with an overall reproducibility of r = 0.85. Guyatt's responsiveness statistics for the subscale and overall scores were moderately high to very high, indicating that the survey is capable of measuring change in response to treatment. CONCLUSIONS: Of the transplant recipients receiving Gengraf in this study, most preferred Gengraf to Neoral based on overall experience, capsule odor, difficulty swallowing, taste, breath odor, and body odor. Among all study patients, fewer patients receiving Gengraf were bothered by capsule odor, difficulty in swallowing, taste, or the impact on breath or body odor compared with patients who continued to receive Neoral. Internal consistency, reproducibility, and responsiveness results show that the Cyclosporine Capsule Satisfaction Survey is a psychometrically valid instrument that is appropriate for use in clinical trials.