Mixed-effect modeling was used to compare the population pharmacokinetics of 2 formulations of cyclosporine in patients. An open-label, multicenter, conversion study in stable, 6-month post-renal allograft recipients was conducted to compare the safety and pharmacokinetics of oral Pliva Cyclosporine Soft Gelatin Capsules (USP Modified) with Neoral (cyclosporine soft gelatin capsules, USP Modified) in stable post-renal transplant patients. Blood samples were collected predose and for 12 hours postdose on days 1, 14, 15, 28, and 29. Whole-blood samples were analyzed for cyclosporine using high-performance liquid chromatography and mass spectroscopy. Estimates of pharmacokinetic parameters were generated using noncompartmental and population compartmental pharmacokinetic analysis. Moreover, the effects of demographic factors on the pharmacokinetics of cyclosporine were evaluated using the nonlinear mixed-effects modeling program NONMEM. The rate and extent of bioavailability of cyclosporine did not differ between Pliva Cyclosporine Soft Gelatin Capsules and Neoral. In the final model, gender and actual body weight significantly affected the central and peripheral volumes of distribution. In addition, the pharmacokinetics of cyclosporine was defined robustly in this patient population using population pharmacokinetic approaches. Results indicate that the Pliva Cyclosporine Soft Gelatin Capsules and Neoral are bioequivalent when administered to renal transplant patients. Pliva Cyclosporine Soft Gelatin Capsules can then be substituted for Neoral in stabilized patients without anticipating dose adjustments.

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Renal dysfunction can have substantial effects on the pharmacokinetics and pharmacodynamics of drugs. A wide variety of animal models have been developed in an attempt to mimic conditions seen in human renal failure. In reality, no single animal model would be completely satisfactory because the etiology and development of renal failure are diverse. During recent years injection of uranyl nitrate has been found to be the most effective and easiest method to produce renal dysfunction in laboratory animals. Changes over the last 10 years in government regulations on the production and use of radioactive substances make the compound less available. There is, therefore, a need for a more accessible compound comparable to uranyl nitrate as an inducer of renal failure. The present study compares the effects of another known nephrotoxin, cisplatin, with uranyl nitrate in the rat. Cisplatin was chosen because of its ability to produce kidney damage and its identical site and mechanism of action on the kidneys as uranyl nitrate. In the present study, rats were given different i.v. doses of uranyl nitrate or cisplatin dissolved in 0.9% of saline solution. The effects of nephrotoxins were evaluated on the basis of changes in body weight, creatinine and blood urea nitrogen (BUN) concentrations. It was found that the degree of renal damage produced by uranyl nitrate and cisplatin is a function of the administered dose. With increasing dose there is evidence of more severe kidney damage, as measured by substantially increased plasma concentrations of creatinine and BUN. The time required to return to normal creatinine and BUN concentrations was also a function of dose. Furthermore, plasma alanine aminotransferase (ALT) activity was measured as an index of hepatocellular damage. The ALT test showed that a single dose does not affect the liver function. From dose-response curves a dose of 4 mg/kg body weight of uranyl nitrate or cisplatin was chosen to produce acute renal failure in animals for pharmacokinetic study of barbital. Barbital (100 mg/kg) was administered on the fifth day (the day of maximum renal dysfunction) to uranyl nitrate, cisplatin-treated and control rats. The elimination rate constant (k), elimination half life (t1/2), volume of distribution at steady state (Vss), total (CLt) and renal clearance (CLr) were significantly different in treated groups of rats from control, however no such difference was detected between uranyl nitrate and cisplatin-treated group of rats. In short, cisplatin is comparable to uranyl nitrate in producing renal failure in the rat and can be considered a suitable alternative.

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