The Utility of the Population Approach Applied to Bioequivalence in Patients: Comparison of 2 Formulations of Cyclosporine

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.

[1]  M. Reynaud‐Gaubert,et al.  Improved absorption and bioavailability of cyclosporine A from a microemulsion formulation in lung transplant recipients affected with cystic fibrosis. , 1997, Transplantation proceedings.

[2]  U. Frei.  Overview of the clinical experience with Neoral in transplantation. , 1999, Transplantation proceedings.

[3]  N. Idkaidek,et al.  Comparison of two cyclosporine formulations in healthy Middle Eastern volunteers: bioequivalence of the new Sigmasporin Microoral and Sandimmun Neoral. , 2003, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[4]  A. Pesce,et al.  Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants. , 1988, Clinical chemistry.

[5]  D. Niese.  A double-blind randomized study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients: results after 12 months. The International Sandimmun Neoral Study Group. , 1995, Transplantation proceedings.

[6]  J. Parameshwar,et al.  Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients. , 1999, Therapeutic drug monitoring.

[7]  A. Fahr.  Cyclosporin Clinical Pharmacokinetics , 1993, Clinical pharmacokinetics.

[8]  C. Chaparro,et al.  Pharmacokinetic Profile and Variability of Cyclosporine versus Neoral in Patients with Cystic Fibrosis after Lung Transplantation , 1998, Pharmacotherapy.

[9]  R W Jelliffe,et al.  A population pharmacokinetic model of cyclosporine in the early postoperative phase in patients with liver transplants, and its predictive performance with Bayesian fitting. , 1998, Therapeutic drug monitoring.

[10]  C. Shim,et al.  Bioequivalence of Neoplanta capsule to Sandimmune Neoral, microemulsion formulations of cyclosporin A in human subjects. , 1998, International journal of clinical pharmacology and therapeutics.

[11]  M. Pescovitz,et al.  Safety and tolerability of neoral vs sandimmune: 1-year data in primary renal allograft recipients , 1996 .

[12]  B. Buchholz,et al.  Long-term experience with sandimmun neoral: Results in de novo and stable renal transplant patients after 24-month treatment , 1997 .

[13]  A. Pesce,et al.  Cyclosporine pharmacokinetics in pancreas transplant recipients. , 1988, Transplantation proceedings.

[14]  M. Rowland,et al.  Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients. , 1987, British journal of clinical pharmacology.

[15]  M. Pescovitz,et al.  Safety and tolerability of Neoral vs Sandimmune: 1-year data in primary renal allograft recipients. Neoral Study Group. , 1996, Transplantation proceedings.

[16]  P. Keown,et al.  Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. , 1998, Kidney international.

[17]  D. Holt,et al.  Simple bioequivalence criteria: are they relevant to critical dose drugs? Experience gained from cyclosporine. , 1997, Therapeutic drug monitoring.

[18]  B D Kahan,et al.  INDIVIDUALIZATION OF CYCLOSPORINE THERAPY USING PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS , 1985, Transplantation.

[19]  N Aoyagi,et al.  Application of the NONMEM method to evaluation of the bioavailability of drug products. , 1990, Journal of pharmaceutical sciences.

[20]  J. Lodge,et al.  Neoral vs Sandimmun: interim results of a randomized trial of efficacy and safety in preventing acute rejection in new renal transplant recipients. The U. K. Neoral Study Group. , 1997, Transplantation proceedings.

[21]  Thomas M. Ludden,et al.  Bioequivalence: Individual and Population Compartmental Modeling Compared to the Noncompartmental Approach , 1996, Pharmaceutical Research.

[22]  R. Miller,et al.  A Comparison of the Standard Approach and the NONMEM Approach in the Estimation of Bioavailability in Man , 1997, The Journal of pharmacy and pharmacology.