Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin

Natalia Riva, Paulo Caceres Guido, Juan Ibañez, Nieves Licciardone, Marcela Rousseau, Gabriel Mato, Marta Monteverde, Paula Schaiquevich

Background Cyclosporin is a calcineurin inhibitor widely used in renal transplant patients to prevent organ rejection. Several position papers have been published but no reports on the practical experience in pediatric patients undergoing conversion between cyclosporin innovator and generic products are available. Objective To evaluate the pharmacokinetics and safety as part of therapeutic monitoring of cyclosporin in renal transplant pediatric patients who switch from the innovator to the generic formulation in Argentina. Setting Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina. Methods Stable pediatric renal transplant patients (6 months post-transplant) switched from the innovator to the generic formulation of cyclosporin microemulsion capsule. Cyclosporin pharmacokinetic parameters were obtained while taking the innovator and after starting with the generic formulation. Blood samples were drawn before and 1, 2, and 3 h after drug administration and subsequently quantified. Pharmacokinetic parameters were obtained by means of a Bayesian approach. Main outcomes measure Cyclosporin pharmacokinetic parameters (area under the curve, AUC; Blood concentration after 2 h, C2), adverse events and graft rejection. Results A total of 12 patients were included. Median (range) age and time post-transplant were 10.7 years (6.5-17.7) and 8.3 years (3.4-14.0), respectively. Two patients or their parents did not consent to the switch. Median (range) dose normalized cyclosporin AUC and C2 were 1.15 (mg*h/L)/mg/kg (0.72-3.0) and 265.5 (ng/ml)/mg/kg (120.8-725.7), respectively, on the innovator therapy and 1.05 (mg*h/L)/mg/kg (0.54-2.22) and 317.1 (ng/ml)/mg/kg (116.7-564.7) for the generic drug after the switch. The median (range) percentage of change in the AUC and C2 when switching between formulations were 16.7 % (0.7-56.7) and 13.1 % (3.7-68.6), respectively. No significant changes in serum creatinine levels were registered when comparing before and after substitution of products. Adverse events (number of events) recorded 5 months before and after the switch included hirsutism (2), hypertension (2), and gingival hyperplasia (1). Conclusion Conversion of cyclosporin from innovator brand to generic in pediatric renal transplant patients needs to be closely monitored.