Int J Clin Pharm DOI 10.1007/s11096-014-9959-0
RESEARCH ARTICLE
Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin Natalia Riva • Paulo Caceres Guido • Juan Iban˜ez • Nieves Licciardone • Marcela Rousseau • Gabriel Mato • Marta Monteverde • Paula Schaiquevich
Received: 30 December 2013 / Accepted: 10 May 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract 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 Pediatrı´a 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.
N. Riva P. C. Guido P. Schaiquevich (&) Unit of Clinical Pharmacokinetics, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina e-mail: [email protected]
Keywords Cyclosporin Generics Pediatrics Pharmacokinetics Renal transplant
J. Iban˜ez M. Monteverde Nephrology Department, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina
Impact of findings on practice
N. Licciardone Laboratory, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina M. Rousseau G. Mato Pharmacy, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina
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Pediatric renal transplant patients can be switched from innovator brand cyclosporin to generic, without major problems. When generic products for transplant patients are introduced on the local market, pharmacists need to monitor the effects of the switching process.
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Pharmacists are encouraged to perform therapeutic drug monitoring of immunosuppressants together with the transplant physician and other health care professionals in order to optimize clinical outcome in special populations including children.
Introduction Immunosuppressive drugs are used to reduce the immune response in solid organ transplant recipients in order to prevent graft rejection. Cyclosporin is a calcineurin inhibitor frequently used as part of the maintenance immunosuppressive therapy in pediatric kidney and liver transplant patients. This drug is characterized by high interand intra-individual variability in the pharmacokinetic parameters, a narrow therapeutic range, and a documented relationship between blood concentration, safety, and efficacy. Calcineurin inhibitors are subjected to therapeutic drug monitoring (TDM) so as to help clinicians guide the dosage in order to increase the probability of attaining the therapeutic goal of preventing graft rejection while minimizing the probability of adverse events [1–3]. In spite of strict control of the transplant patient, adverse events to calcineurin inhibitors are frequent and lack of efficacy is sometimes observed in clinical practice [4–6]. The pattern of adverse events has been well described for the adult population but very few reports exist in pediatrics [6– 8]. The occurrence of adverse events in spite of the patient having attained cyclosporin blood concentration within the therapeutic window may be a consequence of inter-individual variability in the pharmacodynamic response [9]. Recently, a generic product of cyclosporin has been introduced on the local market giving rise to controversy regarding the efficacy, pattern of adverse events, and even the pharmacokinetics in the pediatric transplant population [10, 11]. Canadian and European consensuses have been published to establish recommendations on the use of generic drugs in transplant patients. Moreover, several societies have published position papers on different aspects of generic immunosuppressant substitution [12– 14]. Aspects these documents and publications have in common are the recommendation of close clinical and therapeutic drug monitoring in patients subjected to conversion to bioequivalent drug products while reinforcing all attitudes and actions that should be taken into account by the health care team for patient wellbeing. Specifically, pharmacokinetic studies for routine clinical control are strongly recommended in this setting [12, 13, 15]. Most transplant centers currently measure a single cyclosporin concentration as either a trough dose (predose, C0) or 2 h after cyclosporin administration (C2). Nevertheless, the
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pharmacokinetic parameter that best identifies patients at risk of graft loss or acute rejection is the area under the concentration versus time curve (AUC) of cyclosporin in blood [15–18]. A feasible approach for estimating the AUC should be available to guarantee the required systemic exposure of the immunosuppressant in the individual patient not only when substitution between marketed drug products takes place but also whenever there are clinical signs of rejection, incidence of adverse events, or lack of compliance. Thus, therapeutic drug monitoring of cyclosporin is highly recommended in the pediatric population and specifically, in those patients undergoing a switch from an innovator to a generic formulation.
Aim of the study The aim of the present study was to implement a therapeutic drug monitoring program for pediatric renal transplant patients subject to conversion from an innovator to a generic product of cyclosporin currently marketed in Argentina and to evaluate adverse events to both formulations of cyclosporin.
Methods The development and implementation of the present program was approved by the Institutional Review Board while pharmacokinetic parameters were evaluated in the routine monitoring for systemic exposure assessment (General instructions for parents whose relatives are hospitalized in Hospital de Pediatria JP Garrahan, Form 1418F62). Patients transplanted between 2005 and 2010 with more than 6 months of post-transplant time were included and subjected to a switch from innovator cyclosporin (Neoral, Novartis) to the generic product on the Argentinean market (Sigmasporin, Bioprofarma). Additionally, patients were only enrolled if they were not undergoing an acute graft rejection. Both study formulations were capsules and contained cyclosporin microemulsion as described in the data base of the Food and Drug Administration, US and the drug product information certified by the Argentinean National Health Institute (ANMAT) [19, 20]. The decision to change the drug product was based on the provision of the social insurance of each patient. The study was conducted in cooperation with the Department of Pharmacy, the Unit of Clinical Pharmacokinetics, the Laboratory of Drug Monitoring, and the Unit of Renal Transplantation at the Hospital de Pediatria J.P. Garrahan, Argentina.
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Pharmacokinetic assessment was carried out in ambulatory patients as performed in routine clinical practice. While taking the innovator drug, blood samples were obtained from a peripheral catheter (Abbocath # 22) before and at 1, 2, and 3 h after cyclosporin administration in the fasted state. Blood concentration after 2 h (C2) was obtained as part of the routine clinical monitoring of all patients who undergo a renal transplant at the hospital. In addition, C0, C1, and C3 were obtained to calculate the area under the curve concentration versus time (AUC) as a better surrogate measure to define systemic exposure for the close monitoring of cyclosporin blood concentrations during the switch. Thereafter, patients were switched to the generic product starting with the afternoon dose. After 3 days, patients returned to the hospital for routine clinical evaluation and for a blood sample 2 h after cyclosporin dosing. Between 7 and 10 days after conversion, the patients underwent a second pharmacokinetic study. All blood samples were quantified for cyclosporin by chemiluminescent microparticle immunoassay (CMIA) on the day of sample collection (Architect, Abbott, Chicago, USA). External specimens were routinely assessed as part of an international proficiency testing program for quality control of the analytical technique (http://www.bioanalytics.co. uk). The estimated pharmacokinetic parameters included AUC and maximum blood concentration (Cmax). These parameters were obtained by submitting the blood concentrations (C0, C1, and C3) of each patient to the service provided by Marquet et al. University of Limoges, France. (https://pharmaco.chu-limoges.fr/). Clinical outcome (absence/presence of acute rejection and graft loss), serum creatinine as a surrogate of renal function, and adverse events were recorded while taking each drug product. An exploratory statistical analysis with the Wilcoxon matched paired test (p \ 0.05) was used to evaluate differences in the parameters of the innovator and the generic product. Finally, dose normalized C2 levels and serum creatinine at 5, 4, 3, 2, 1, 0.5 and 0.25 months before conversion were compared with the corresponding values after starting with the generic product by means of the Wilcoxon matched paired test. A database was developed to register the most frequent adverse events of cyclosporin previously described in literature. Causality assessment for adverse events to cyclosporin and their severity was based on the Naranjo Algorithm and medical consensus. Adverse events were recorded and when they were confirmed to have a causal relationship with cyclosporin treatment, a report was elaborated to notify the national health authorities (ANMAT, Administracio´n Nacional de Medicamentos, Alimentos y Tecnologı´a Me´dica).
Results A total of 12 stable renal transplant patients, seven girls and five boys, were included in the present report of pharmacokinetic and pharmacodynamic monitoring. Nevertheless, the parents or legal tutors of two of the patients declined to generic substitution. In addition, samples from one patient were not appropriately identified in one pharmacokinetic assessment and those results could not be included because of inconsistency. Thus, pharmacokinetic parameters of nine patients were available for the present report while safety data were available for all patients. The median (range) age at transplant and the median (range) post-transplant time until at least one pharmacokinetic assessment were 8.3 years (3.4–14.0) and 10.7 years (6.5–17.7), respectively. Further patient characteristics and demographics are summarized in Table 1. Additionally, concomitant immunosuppressant medication and other drugs for specific concurrent pathological states are described in Table 1. Of all nine patients that were evaluated before and after switch, eight (88.9 %) received cyclosporin in combination with sodium mycophenolate or mophetyl mycophenolate (one patient) and methylprednisone while the remaining patient (11.1 %) received cyclosporin together with azathioprine and steroids (Table 1). Despite well-documented drug–drug interactions between cyclosporin and concomitant immunosuppressants, cyclosporin C2 levels before the switch were targeted according to the therapeutic window proposed by others and stated by the internal consensus of the Department of Nephrology at our Hospital. In this sense, C2 values are targeted and dose-adjustments are carried out based on the international therapeutic window, the patient´s health status, concomitant medications, comorbidities, and performance of renal graft including renal function [31, 32]. Individual pharmacokinetic parameters obtained under both cyclosporin formulations were detailed in Table 2. The individual AUC was reported without dose normalization as patients received the same dose of the innovator and the generic product. In addition, a summary of the pharmacokinetic parameters calculated for both study products and serum creatinine as a surrogate marker of renal function are shown in Table 3. No patient required dose adjustment after conversion. Despite considerable intra-individual variations in AUC, C2, and Cmax, no significant statistical difference was observed when comparing the pharmacokinetic parameters between formulations (p [ 0.05). We observed considerable variation in C2 levels among patients. This variation may be attributed to specific pathological conditions (one patient had a urinary tract infection, two patients had a previous history of acute rejection and one patient
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Int J Clin Pharm Table 1 Patient characteristics and demographics at the start of therapy (n = 12) Characteristic
Median (range)
Age at transplantation (years)
8.3 (3.4–14.0)
Age at formulation substitution (years)
10.7 (6.5–17.7)
Weight (kg)
26 (17–70)
Height (cm)
122 (101–155)
Dose (mg/kg)
1.9 (1.2–4.4)
Number of patients Sex
Female: 8 Male: 4
Type of donor
Cadaveric (n = 12)
Patients enrolled in the pharmacokinetic study (n = 9) Concomitant immunosuppressant medicationsa (number of patients under treatment)
Mycophenolic acid/ mycophenolate mofetil (n = 8) Steroidsb (n = 9) Azathioprine (n = 1)
Concomitant medications for other pathologiesa (number of patients under treatment)
Enalapril (n = 6); Folic acid (n = 9) Vitamine D (n = 1); Iron supplement (n = 7) Carvedilol (n = 1); Losartan (n = 1) Ceftriaxone (n = 1)c; Valganciclovir (n = 1)d Clobazam (n = 1)e
a None of the detailed drugs were found to present drug–drug interactions with cyclosporin b c
Steroids include methylprednisolone and meprednisone For treatment of urinary infection
d
For cytomegalovirus treatment
e
For epilepsy treatment
was non-adherent) and thus, the treating physician outweighed the specific pathological condition against the international consensus based on post-transplant period for dose adjustment. In most patients, the percentage of variation in AUC or C2 when switching formulations was between 0.7 and 35.5 %; however, one patient showed great variability in the parameters (patient # 9). As detailed in Table 3, the median (range) percentage change of AUC and Cmax for each patient when substitution took place was 17.3 % (4.9–56.7) and 11.9 % (5.4–68.6), respectively. No statistical difference was observed at different time intervals when comparing dose normalized C2 blood levels before and after conversion between cyclosporin products (p [ 0.05). Furthermore, serum creatinine as a biomarker of renal function did not change before and after 1 week of switching to the generic formulation as the median (range) values were 0.85 mg/dl (0.55–1.34) and 0.85 mg/dl (0.58–1.2), respectively. In addition, 4 months after switching median (range) serum creatinine was 0.79 mg/dl (0.58–1.37) showing no statistical change over time (p [ 0.05). According to the Renal Transplantation Unit at the Department of Nephrology no acute rejection or graft loss was registered in patients under either trademark within a 5-month interval before and after substitution. Despite a short median follow-up of 3 months (0.25–24) the adverse events (number of cases) recorded for those patients that were available at 5 months after conversion to the generic formulation were hypertension (1), hirsutism (1), and gingival hyperplasia (1). The adverse events (number of cases) during the 5 months previous to substitution and under the innovator drug were hirsutism (1) and hypertension (1).
Table 2 Individual pharmacokinetic parameters calculated for the innovator and generic formulation Patient ID
Pharmacokinetic parameters AUC innovator (mg*h/L)
AUC generic (mg*h/L)
Individual % change in AUC
1
1.87
1.26
31.5
535
590
12.2
542
556
4.4
2
3.49
3.66
0.7
602
612
3.7
1,168
1,251
1.4
3
2.17
1.4
35.5
429
304
29.1
455
371
18.5
4
3.8
4.47
16.0
922
1,152
23.2
1,099
1,458
30.8
5
3.47
3.18
6.6
737
810
12.0
1,160
822
27.8
6
2.11
2.89
37.4
354
926
162.5
396
902
128.5
7
2.93
2.6
10.6
773
835
8.8
798
814
2.8
8
2.24
1.86
17.5
423
366
14.0
1,075
935
13.5
9
3.42
1.48
56.7
831
261
68.6
1,137
629
44.7
C2 innovator (ng/ml)
C2 generic (ng/ml)
Individual % change in C2
Cmax innovator (ng/ml)
Cmax generic (ng/ml)
Individual % change in Cmax
ID identification number, AUC area under the concentration versus time profile, C2 cyclosporin blood concentration 2 h after drug administration
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Int J Clin Pharm Table 3 Cyclosporin pharmacokinetic parameters in pediatric patients with renal transplant converting from an innovator to a generic formulation (n = 9) Phamacokinetic parameter AUC (mg*h/L) AUC/D (mg*h/L)/(mg/kg)
Innovator formulation
Generic formulation 2.6 (1.3–4.5)a
2.9 (1.9–3.8) 1.15 (0.72–2.99)
1.05 (0.54–2.22)
17.4 (0.7–56.7) a
C2 (mg/L)
602.0 (354.0–922.0)
612.0 (261.0–1,152.0)a
C2/D (mg/L)/(mg/kg)
265.5 (120.8–725.7)
317.1 (116.7–564.6)a
1,075.0 (396.0–1,168.0)
822.0 (371.0–1,458.0)
Cmax (mg/L) Cmax/D (mg/L)/(mg/kg)
332.4 (135.2–992.9)
% change
14.0 (3.7–162.5) 18.5 (1.4–128.5)
414.1 (142.5–572.9)
Data are expressed as median (range) AUC area under the curve between 0 and 12 h calculated by Bayesian analysis, D dose corrected by weight, C2 cyclosporin concentration 2 h after dosing, Cmax maximum blood concentration calculated by Bayesian analysis a
p [ 0.05 when comparing the pharmacokinetic parameter between formulations
Discussion To the best of our knowledge, this is the first report on therapeutic cyclosporin monitoring in pediatric stable renal transplant patients that undergo substitution from the innovator to the locally marketed generic product. We observed no significant differences in the pharmacokinetic parameters of cyclosporin exposure and no patient required dose adjustment after conversion, in addition to having had a safe and well-tolerated conversion. The use of generic drug products is widespread and has great impact in lower- and middle-income countries because of cost-saving and affordability of medicines in a setting where health-care and patient budgets are substantially limited [21–23]. Nevertheless, the use of generic drug products and conversion from innovator to generic formulations is still under debate worldwide among scientist and members of transplant societies and there is a clear paucity of pharmacokinetic, safety, and efficacy data mainly in the pediatric population with solid organ transplants [24–29]. Thus, the aim of the present report was to provide scientific data of therapeutic drug monitoring from pediatric renal transplant patients undergoing a switch between two cyclosporin products currently marketed in Argentina. Specifically, clinical pharmacists play an important role in monitoring the safety and efficacy of immunosuppressant drugs and should be actively involved in therapeutic drug monitoring participating in dose adjustment and the recording of adverse events or lack of efficacy and other drug-related problems when generic products are introduced on the local market. Effective immunosuppression therapy within the target range and control of fluctuations in drug blood levels have been reported to directly reduce the incidence of acute rejection and the probability of adverse events in renal transplant patients. The advantages of close therapeutic monitoring of immunosuppressants to warrant optimal systemic exposure within the therapeutic range have been
extensively discussed. Therapeutic drug monitoring of cyclosporin is carried out in most transplant centers worldwide using only one blood level measured before drug administration (C0) or 2 h after oral intake (C2). Currently, the Department of Nephrology at Hospital JP Garrahan follows an institutional consensus (unpublished) to target a therapeutic window for cyclosporin mainly based on the post-transplant period of the individual patient as previously described for adult renal transplants [31, 32]. However, other parameters are currently considered for dose individualization of cyclosporin including clinical and biochemical parameters and potential drug–drug interactions. For example, concurrent use of azathioprine or prednisone and cyclosporin may result in decreased cyclosporin blood levels and increased renal toxicity, respectively [19, 38]. Thus, cyclosporin C2 blood levels are closely monitored to avoid toxicity and lack of efficacy [38]. Nonetheless, the AUC profile is still the best parameter as a surrogate of systemic exposure and a good safety predictor [15, 16]. A valid approximation is the Bayesian forecasting method for AUC calculation along with a limited sampling strategy in order to reduce the required number of samples per patient specifically in pediatric patients based on ethical concerns. The Limoges University Hospital provides a web-based service for Bayesian dose adjustment of cyclosporin in pediatric patients who have undergone renal transplantation including the calculation of the AUC and Cmax based on a limited number of samples obtained at pre-defined times. This online service was used for the pharmacokinetic characterization of our patients. Clinical pharmacists play a special role in routine TDM in order to individualize and optimize therapeutic regimens in a variety of clinical settings based on their knowledge of pharmacology and specifically about pharmacokinetics. In the present study, we assessed cyclosporin TDM in a pediatric population subjected to conversion between commercial forms of cyclosporin on the local market. The
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initiative was conceived at the Department of Pharmacy of Hospital de Pediatria JP Garrahan and carried out by a multidisciplinary team including clinical pharmacists, transplant physicians, pharmacologists, and biochemists. Thus, cyclosporin TDM was successfully implemented in the Hospital in pediatric patients with a renal transplant undergoing conversion between commercial formulations in line with international recommendations for these drugs [12, 13]. The present report sets the basis for future studies in clinical centers in Argentina or elsewhere after generic cyclosporin is introduced onto the market and close monitoring is recommended. We analyzed the percentage of change in AUC and C2 when switching from one study formulation to the other. No statistical difference was observed when comparing the pharmacokinetic parameters of cyclosporin exposure obtained for the innovator and for the generic product. For most of the evaluated patients, the percentage change in the pharmacokinetic parameters of cyclosporin exposure was within 30 %, similar to the variability of the pharmacokinetics of the drug previously reported by other authors [30, 31]. Interestingly, in four patients a difference of more than 40 % between Cmax and C2 was observed. Additionally, one patient in the study group showed a remarkable difference between C2 and Cmax when switching from one formulation to the other, as shown in Table 1 (patient # 6). We hypothesized that this difference may be attributed to a sampling or processing error as blood concentrations of cyclosporin after 1 and 2 h are almost the same when considering the innovator product. Approximately ten years ago, an international consensus statement (CONCERT) was published pursuing recommendations on cyclosporin blood monitoring in renal and liver transplant patients [32]. C2 blood level monitoring was proposed as the best single time point related to systemic cyclosporin exposure up to 4 h after dosing (AUC0-4) and the best surrogate for Cmax coinciding with the time of maximum calcineurin inhibition [15, 31]. Thereafter, different authors recommended therapeutic ranges of cyclosporin C2 based on the post-transplant period, type of graft, and other factors. Nevertheless, the CONCERT group also pointed out that there could be slow or low absorbers with a different time and value of Cmax compared to the rest of the population and these patients may not be detected with a single point blood concentration. This observation is in line with our findings showing that for some patients C2 monitoring may not reflect the maximum concentration and calcineurin inhibition and thus, a potential overexposure to cyclosporin may be recommended by the treating physician based on C2 instead of Cmax or AUC. It is important to emphasize that more than three decades after the introduction of cyclosporin on the Argentinean market, there is still a paucity of information on the
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safety, efficacy, and pharmacokinetic characteristics of calcineurin inhibitors used in the pediatric transplant population. Not only was information lacking on generic products but data available on the pharmacokinetic and pharmacodynamic parameters for the innovator product of cyclosporin were limited and incomplete in the pediatric population [33]. Therefore, we implemented the first intensive vigilance program of immunosuppressants in pediatric renal and hepatic transplant patients in Latin America [7]. The incidence of the most common adverse events to calcineurin inhibitors are under evaluation and a preliminary report showed consistency in the incidence of adverse events with that previously reported in the literature [33, 34]. Although follow-up of the patients in this study was short, no significant differences regarding the incidence and type of adverse events were registered in the immediate-to-4-month period before and after generic conversion. In Argentina, the health system includes private and public coverage. Around 20 % of the solid-organ-transplant patients receive immunosuppressant drugs from their private insurance while 80 % is covered by the national government (National Disposition 1071/07) [35, 36]. Thus, the immunosuppressant drug product that most of the Argentinean patients receive depends on the winning bid established by the government. Drug products containing immunosuppressants need to have previously demonstrated bioequivalence against the innovator or gold standard established by the national health agency (ANMAT) in order to participate in the tendering as well as compliance of production under Good Manufacturing Production and in vitro testing for quality purposes (National Disposition 2446/07;5040/06). These requirements are of substantial importance and may explain the results previously found by Petan and colleagues regarding performance of Mexican products of tacrolimus, another calcineurin inhibitor [37]. Nevertheless, we acknowledge that drug–drug and drug– food interactions may occur when the generic drug product is introduced onto the market without previous evidence from pharmacokinetic and in vitro studies submitted for regulatory and commercial purposes [38]. Several position papers state that the information provided by bioequivalence studies is limited as it was obtained from adult healthy volunteers and more information in transplant patients should be provided for the generic formulations [12, 13]. In addition, despite of being limited to the adult and healthy population, this information is not publicly available but treated as confidential in Argentina. On the contrary, no previous reports on generic cyclosporin pharmacokinetics in pediatric recipients have been published perhaps due to difficulties to carry out those studies. The present study is the first report that provides solid data on cyclosporin therapeutic monitoring in pediatric renal
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transplant patients undergoing conversion between commercial formulations. Therefore, we emphasize the need for therapeutic monitoring, including that of pharmacokinetic and pharmacodynamic parameters (efficacy and safety), after the release of new drug products or generics on the market. This would be particularly important in special populations including children with solid organ transplants who undergo continuous physiological changes. The main limitation of the present analysis is the low number of patients converted to the generic cyclosporin products. Additionally, the time of follow-up of the patients converted to the generic product was brief. Hence, further studies with a long-term follow-up are necessary to support the present data.
Conclusion We conclude that therapeutic drug monitoring of cyclosporin in pediatric patients under conversion from the innovator to the generic product was feasible in our setting and showed no difference in systemic exposure between formulations. Conversion of cyclosporin was safe in our stable pediatric renal transplant population, allowing for the maintenance of systemic exposure without acuterejection episodes or the need for dose adjustment during the study period. Nonetheless, we recommend close therapeutic monitoring of patients undergoing generic immunosuppressant conversion, concomitant pathological conditions to renal transplant, potential drug–drug interactions, specifically in vulnerable populations such as pediatric patients with solid organ transplants. The present experience could be transferred to other clinical settings in order to perform therapeutic drug monitoring when switching between commercial calcineurin inhibitor drug products in transplant patients. Acknowledgments The authors would like to thank Dr. Pierre Marquet for the web service offered by the University of Limoges for pharmacokinetic assessment of immunosuppressants and head nurse Victoria Barroca, for technical assistance. Funding This work was supported by Hospital de Pediatrı´a Prof. Dr. Juan P. Garrahan. Conflicts of interest
None of the authors present conflict of interest.
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editors. World Health Organization. Regional Office for Europe by IOS Press; 2003. pp. 137–149. ISBN 1 58603 334 4. Kaplan WA, Wirtz VJ, Stephens P. The market dynamics of generic medicines in the private sector of 19 low and middle income countries between 2001 and 2011: a descriptive time series analysis. PLoS ONE. 2013;8(9):e74399. Spence M, Nguyen L, Hui R, Chan J. Evaluation of clinical and safety outcomes associated with conversion from brand name to generic tacrolimus in transplant recipients enrolled in an integrated health care system. Pharmacotherapy. 2012;32(11):981–7. Alloway RR, Sadaka B, Trofe-Clark J, Wiland A, Bloom RD. A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients. Am J Transplant. 2012;12(10):2825–31. Kraeuter M, Helmschrott M, Erbel C, Gleissner CA, Frankenstein L, Schmack B, et al. Conversion to generic cyclosporine A in stable chronic patients after heart transplantation. Drug Des Devel Ther. 2013;7:1421–6. Vı´tko S, Ferkl M. Interchangeability of ciclosporin formulations in stable adult renal transplant recipients: comparison of Equoral and Neoral capsules in an international, multicenter, randomized, open-label trial. Kidney Int Suppl. 2010;115:S12–6. Niemczyk M, Paczek L. Generic formulation of Cyclosporine A, Equoral, in de novo kidney transplant recipients: five-year follow-up. Ann Transplant. 2011;16(2):59–62. Al Wakeel J, Shaheen FA, Al Alfi A, Abbas Fagir EH, Iman A, Nampoory MR, et al. Cyclosporine microemulsion formulation (sigmasporin microral) effect as first-line immunosuppressant on renal functions at 3 years. Transplant Proc. 2012;44(1):94–100. Johnston A, Belitsky P, Frei U, Horvath J, Hoyer P, Helderman JH, et al. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients. Eur J Clin Pharmacol. 2004;60(6): 389–95.
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30. Dunn J, Golden D, Van Buren CT, Lewis RM, Lawen J, Kahan BD. Causes of graft loss beyond two years in the cyclosporine era. Transplantation. 1990;49(2):349–53. 31. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol. 2007;2(2):374–84. 32. Levy G, Thervet E, Lake J, Uchida K. On behalf of the CONCERT group: patient management by Neoral C2 monitoring—an international consensus statement. Transplantation. 2002;73:S12–8. 33. Ng VL, Alonso EM, Bucuvalas JC, Cohen G, Limbers CA, Varni JW, et al. Health status of children alive 10 years after pediatric liver transplantation performed in the US and Canada: report of the studies of pediatric liver transplantation experience. J Pediatr. 2012;160(5):820–6. 34. Filler G. Calcineurin inhibitors in pediatric renal transplant recipients. Paediatr Drugs. 2007;9(3):165–74. 35. Miranda I, Cherato M, Onofri A. Cobertura social para trasplantados subsidados por CUCAIBA en la red estatal. Available from: http://www.cucaiba.gba.gov.ar/019.htm. Accessed 12 Feb 2014. 36. Calabria A. Analyzing the market for organs donation: evaluation of the introduction of incentives in Argentina. MPRA Paper No. 36044. 2011. Available from: http://mpra.ub.uni-muenchen.de/ 36044/1/MPRA_paper_36044.pdf. Accessed 12 Feb 2014. 37. Petan JA, Undre N, First MR, Saito K, Ohara T, Iwabe O, et al. Physiochemical properties of generic formulations of tacrolimus in Mexico. Transplant Proc. 2008;40(5):1439–42. 38. Drug interactions. Micromedex Solutions. Available from: http:// www.micromedexsolutions.com/micromedex2/librarian/PFDe faultActionId/evidencexpert.ShowDrugInteractionsResults. Accessed 14 Feb 2014.
RESEARCH ARTICLE
Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin Natalia Riva • Paulo Caceres Guido • Juan Iban˜ez • Nieves Licciardone • Marcela Rousseau • Gabriel Mato • Marta Monteverde • Paula Schaiquevich
Received: 30 December 2013 / Accepted: 10 May 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract 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 Pediatrı´a 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.
N. Riva P. C. Guido P. Schaiquevich (&) Unit of Clinical Pharmacokinetics, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina e-mail: [email protected]
Keywords Cyclosporin Generics Pediatrics Pharmacokinetics Renal transplant
J. Iban˜ez M. Monteverde Nephrology Department, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina
Impact of findings on practice
N. Licciardone Laboratory, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina M. Rousseau G. Mato Pharmacy, Hospital de Pediatrı´a JP Garrahan, Buenos Aires, Argentina
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Pediatric renal transplant patients can be switched from innovator brand cyclosporin to generic, without major problems. When generic products for transplant patients are introduced on the local market, pharmacists need to monitor the effects of the switching process.
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Pharmacists are encouraged to perform therapeutic drug monitoring of immunosuppressants together with the transplant physician and other health care professionals in order to optimize clinical outcome in special populations including children.
Introduction Immunosuppressive drugs are used to reduce the immune response in solid organ transplant recipients in order to prevent graft rejection. Cyclosporin is a calcineurin inhibitor frequently used as part of the maintenance immunosuppressive therapy in pediatric kidney and liver transplant patients. This drug is characterized by high interand intra-individual variability in the pharmacokinetic parameters, a narrow therapeutic range, and a documented relationship between blood concentration, safety, and efficacy. Calcineurin inhibitors are subjected to therapeutic drug monitoring (TDM) so as to help clinicians guide the dosage in order to increase the probability of attaining the therapeutic goal of preventing graft rejection while minimizing the probability of adverse events [1–3]. In spite of strict control of the transplant patient, adverse events to calcineurin inhibitors are frequent and lack of efficacy is sometimes observed in clinical practice [4–6]. The pattern of adverse events has been well described for the adult population but very few reports exist in pediatrics [6– 8]. The occurrence of adverse events in spite of the patient having attained cyclosporin blood concentration within the therapeutic window may be a consequence of inter-individual variability in the pharmacodynamic response [9]. Recently, a generic product of cyclosporin has been introduced on the local market giving rise to controversy regarding the efficacy, pattern of adverse events, and even the pharmacokinetics in the pediatric transplant population [10, 11]. Canadian and European consensuses have been published to establish recommendations on the use of generic drugs in transplant patients. Moreover, several societies have published position papers on different aspects of generic immunosuppressant substitution [12– 14]. Aspects these documents and publications have in common are the recommendation of close clinical and therapeutic drug monitoring in patients subjected to conversion to bioequivalent drug products while reinforcing all attitudes and actions that should be taken into account by the health care team for patient wellbeing. Specifically, pharmacokinetic studies for routine clinical control are strongly recommended in this setting [12, 13, 15]. Most transplant centers currently measure a single cyclosporin concentration as either a trough dose (predose, C0) or 2 h after cyclosporin administration (C2). Nevertheless, the
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pharmacokinetic parameter that best identifies patients at risk of graft loss or acute rejection is the area under the concentration versus time curve (AUC) of cyclosporin in blood [15–18]. A feasible approach for estimating the AUC should be available to guarantee the required systemic exposure of the immunosuppressant in the individual patient not only when substitution between marketed drug products takes place but also whenever there are clinical signs of rejection, incidence of adverse events, or lack of compliance. Thus, therapeutic drug monitoring of cyclosporin is highly recommended in the pediatric population and specifically, in those patients undergoing a switch from an innovator to a generic formulation.
Aim of the study The aim of the present study was to implement a therapeutic drug monitoring program for pediatric renal transplant patients subject to conversion from an innovator to a generic product of cyclosporin currently marketed in Argentina and to evaluate adverse events to both formulations of cyclosporin.
Methods The development and implementation of the present program was approved by the Institutional Review Board while pharmacokinetic parameters were evaluated in the routine monitoring for systemic exposure assessment (General instructions for parents whose relatives are hospitalized in Hospital de Pediatria JP Garrahan, Form 1418F62). Patients transplanted between 2005 and 2010 with more than 6 months of post-transplant time were included and subjected to a switch from innovator cyclosporin (Neoral, Novartis) to the generic product on the Argentinean market (Sigmasporin, Bioprofarma). Additionally, patients were only enrolled if they were not undergoing an acute graft rejection. Both study formulations were capsules and contained cyclosporin microemulsion as described in the data base of the Food and Drug Administration, US and the drug product information certified by the Argentinean National Health Institute (ANMAT) [19, 20]. The decision to change the drug product was based on the provision of the social insurance of each patient. The study was conducted in cooperation with the Department of Pharmacy, the Unit of Clinical Pharmacokinetics, the Laboratory of Drug Monitoring, and the Unit of Renal Transplantation at the Hospital de Pediatria J.P. Garrahan, Argentina.
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Pharmacokinetic assessment was carried out in ambulatory patients as performed in routine clinical practice. While taking the innovator drug, blood samples were obtained from a peripheral catheter (Abbocath # 22) before and at 1, 2, and 3 h after cyclosporin administration in the fasted state. Blood concentration after 2 h (C2) was obtained as part of the routine clinical monitoring of all patients who undergo a renal transplant at the hospital. In addition, C0, C1, and C3 were obtained to calculate the area under the curve concentration versus time (AUC) as a better surrogate measure to define systemic exposure for the close monitoring of cyclosporin blood concentrations during the switch. Thereafter, patients were switched to the generic product starting with the afternoon dose. After 3 days, patients returned to the hospital for routine clinical evaluation and for a blood sample 2 h after cyclosporin dosing. Between 7 and 10 days after conversion, the patients underwent a second pharmacokinetic study. All blood samples were quantified for cyclosporin by chemiluminescent microparticle immunoassay (CMIA) on the day of sample collection (Architect, Abbott, Chicago, USA). External specimens were routinely assessed as part of an international proficiency testing program for quality control of the analytical technique (http://www.bioanalytics.co. uk). The estimated pharmacokinetic parameters included AUC and maximum blood concentration (Cmax). These parameters were obtained by submitting the blood concentrations (C0, C1, and C3) of each patient to the service provided by Marquet et al. University of Limoges, France. (https://pharmaco.chu-limoges.fr/). Clinical outcome (absence/presence of acute rejection and graft loss), serum creatinine as a surrogate of renal function, and adverse events were recorded while taking each drug product. An exploratory statistical analysis with the Wilcoxon matched paired test (p \ 0.05) was used to evaluate differences in the parameters of the innovator and the generic product. Finally, dose normalized C2 levels and serum creatinine at 5, 4, 3, 2, 1, 0.5 and 0.25 months before conversion were compared with the corresponding values after starting with the generic product by means of the Wilcoxon matched paired test. A database was developed to register the most frequent adverse events of cyclosporin previously described in literature. Causality assessment for adverse events to cyclosporin and their severity was based on the Naranjo Algorithm and medical consensus. Adverse events were recorded and when they were confirmed to have a causal relationship with cyclosporin treatment, a report was elaborated to notify the national health authorities (ANMAT, Administracio´n Nacional de Medicamentos, Alimentos y Tecnologı´a Me´dica).
Results A total of 12 stable renal transplant patients, seven girls and five boys, were included in the present report of pharmacokinetic and pharmacodynamic monitoring. Nevertheless, the parents or legal tutors of two of the patients declined to generic substitution. In addition, samples from one patient were not appropriately identified in one pharmacokinetic assessment and those results could not be included because of inconsistency. Thus, pharmacokinetic parameters of nine patients were available for the present report while safety data were available for all patients. The median (range) age at transplant and the median (range) post-transplant time until at least one pharmacokinetic assessment were 8.3 years (3.4–14.0) and 10.7 years (6.5–17.7), respectively. Further patient characteristics and demographics are summarized in Table 1. Additionally, concomitant immunosuppressant medication and other drugs for specific concurrent pathological states are described in Table 1. Of all nine patients that were evaluated before and after switch, eight (88.9 %) received cyclosporin in combination with sodium mycophenolate or mophetyl mycophenolate (one patient) and methylprednisone while the remaining patient (11.1 %) received cyclosporin together with azathioprine and steroids (Table 1). Despite well-documented drug–drug interactions between cyclosporin and concomitant immunosuppressants, cyclosporin C2 levels before the switch were targeted according to the therapeutic window proposed by others and stated by the internal consensus of the Department of Nephrology at our Hospital. In this sense, C2 values are targeted and dose-adjustments are carried out based on the international therapeutic window, the patient´s health status, concomitant medications, comorbidities, and performance of renal graft including renal function [31, 32]. Individual pharmacokinetic parameters obtained under both cyclosporin formulations were detailed in Table 2. The individual AUC was reported without dose normalization as patients received the same dose of the innovator and the generic product. In addition, a summary of the pharmacokinetic parameters calculated for both study products and serum creatinine as a surrogate marker of renal function are shown in Table 3. No patient required dose adjustment after conversion. Despite considerable intra-individual variations in AUC, C2, and Cmax, no significant statistical difference was observed when comparing the pharmacokinetic parameters between formulations (p [ 0.05). We observed considerable variation in C2 levels among patients. This variation may be attributed to specific pathological conditions (one patient had a urinary tract infection, two patients had a previous history of acute rejection and one patient
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Int J Clin Pharm Table 1 Patient characteristics and demographics at the start of therapy (n = 12) Characteristic
Median (range)
Age at transplantation (years)
8.3 (3.4–14.0)
Age at formulation substitution (years)
10.7 (6.5–17.7)
Weight (kg)
26 (17–70)
Height (cm)
122 (101–155)
Dose (mg/kg)
1.9 (1.2–4.4)
Number of patients Sex
Female: 8 Male: 4
Type of donor
Cadaveric (n = 12)
Patients enrolled in the pharmacokinetic study (n = 9) Concomitant immunosuppressant medicationsa (number of patients under treatment)
Mycophenolic acid/ mycophenolate mofetil (n = 8) Steroidsb (n = 9) Azathioprine (n = 1)
Concomitant medications for other pathologiesa (number of patients under treatment)
Enalapril (n = 6); Folic acid (n = 9) Vitamine D (n = 1); Iron supplement (n = 7) Carvedilol (n = 1); Losartan (n = 1) Ceftriaxone (n = 1)c; Valganciclovir (n = 1)d Clobazam (n = 1)e
a None of the detailed drugs were found to present drug–drug interactions with cyclosporin b c
Steroids include methylprednisolone and meprednisone For treatment of urinary infection
d
For cytomegalovirus treatment
e
For epilepsy treatment
was non-adherent) and thus, the treating physician outweighed the specific pathological condition against the international consensus based on post-transplant period for dose adjustment. In most patients, the percentage of variation in AUC or C2 when switching formulations was between 0.7 and 35.5 %; however, one patient showed great variability in the parameters (patient # 9). As detailed in Table 3, the median (range) percentage change of AUC and Cmax for each patient when substitution took place was 17.3 % (4.9–56.7) and 11.9 % (5.4–68.6), respectively. No statistical difference was observed at different time intervals when comparing dose normalized C2 blood levels before and after conversion between cyclosporin products (p [ 0.05). Furthermore, serum creatinine as a biomarker of renal function did not change before and after 1 week of switching to the generic formulation as the median (range) values were 0.85 mg/dl (0.55–1.34) and 0.85 mg/dl (0.58–1.2), respectively. In addition, 4 months after switching median (range) serum creatinine was 0.79 mg/dl (0.58–1.37) showing no statistical change over time (p [ 0.05). According to the Renal Transplantation Unit at the Department of Nephrology no acute rejection or graft loss was registered in patients under either trademark within a 5-month interval before and after substitution. Despite a short median follow-up of 3 months (0.25–24) the adverse events (number of cases) recorded for those patients that were available at 5 months after conversion to the generic formulation were hypertension (1), hirsutism (1), and gingival hyperplasia (1). The adverse events (number of cases) during the 5 months previous to substitution and under the innovator drug were hirsutism (1) and hypertension (1).
Table 2 Individual pharmacokinetic parameters calculated for the innovator and generic formulation Patient ID
Pharmacokinetic parameters AUC innovator (mg*h/L)
AUC generic (mg*h/L)
Individual % change in AUC
1
1.87
1.26
31.5
535
590
12.2
542
556
4.4
2
3.49
3.66
0.7
602
612
3.7
1,168
1,251
1.4
3
2.17
1.4
35.5
429
304
29.1
455
371
18.5
4
3.8
4.47
16.0
922
1,152
23.2
1,099
1,458
30.8
5
3.47
3.18
6.6
737
810
12.0
1,160
822
27.8
6
2.11
2.89
37.4
354
926
162.5
396
902
128.5
7
2.93
2.6
10.6
773
835
8.8
798
814
2.8
8
2.24
1.86
17.5
423
366
14.0
1,075
935
13.5
9
3.42
1.48
56.7
831
261
68.6
1,137
629
44.7
C2 innovator (ng/ml)
C2 generic (ng/ml)
Individual % change in C2
Cmax innovator (ng/ml)
Cmax generic (ng/ml)
Individual % change in Cmax
ID identification number, AUC area under the concentration versus time profile, C2 cyclosporin blood concentration 2 h after drug administration
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Int J Clin Pharm Table 3 Cyclosporin pharmacokinetic parameters in pediatric patients with renal transplant converting from an innovator to a generic formulation (n = 9) Phamacokinetic parameter AUC (mg*h/L) AUC/D (mg*h/L)/(mg/kg)
Innovator formulation
Generic formulation 2.6 (1.3–4.5)a
2.9 (1.9–3.8) 1.15 (0.72–2.99)
1.05 (0.54–2.22)
17.4 (0.7–56.7) a
C2 (mg/L)
602.0 (354.0–922.0)
612.0 (261.0–1,152.0)a
C2/D (mg/L)/(mg/kg)
265.5 (120.8–725.7)
317.1 (116.7–564.6)a
1,075.0 (396.0–1,168.0)
822.0 (371.0–1,458.0)
Cmax (mg/L) Cmax/D (mg/L)/(mg/kg)
332.4 (135.2–992.9)
% change
14.0 (3.7–162.5) 18.5 (1.4–128.5)
414.1 (142.5–572.9)
Data are expressed as median (range) AUC area under the curve between 0 and 12 h calculated by Bayesian analysis, D dose corrected by weight, C2 cyclosporin concentration 2 h after dosing, Cmax maximum blood concentration calculated by Bayesian analysis a
p [ 0.05 when comparing the pharmacokinetic parameter between formulations
Discussion To the best of our knowledge, this is the first report on therapeutic cyclosporin monitoring in pediatric stable renal transplant patients that undergo substitution from the innovator to the locally marketed generic product. We observed no significant differences in the pharmacokinetic parameters of cyclosporin exposure and no patient required dose adjustment after conversion, in addition to having had a safe and well-tolerated conversion. The use of generic drug products is widespread and has great impact in lower- and middle-income countries because of cost-saving and affordability of medicines in a setting where health-care and patient budgets are substantially limited [21–23]. Nevertheless, the use of generic drug products and conversion from innovator to generic formulations is still under debate worldwide among scientist and members of transplant societies and there is a clear paucity of pharmacokinetic, safety, and efficacy data mainly in the pediatric population with solid organ transplants [24–29]. Thus, the aim of the present report was to provide scientific data of therapeutic drug monitoring from pediatric renal transplant patients undergoing a switch between two cyclosporin products currently marketed in Argentina. Specifically, clinical pharmacists play an important role in monitoring the safety and efficacy of immunosuppressant drugs and should be actively involved in therapeutic drug monitoring participating in dose adjustment and the recording of adverse events or lack of efficacy and other drug-related problems when generic products are introduced on the local market. Effective immunosuppression therapy within the target range and control of fluctuations in drug blood levels have been reported to directly reduce the incidence of acute rejection and the probability of adverse events in renal transplant patients. The advantages of close therapeutic monitoring of immunosuppressants to warrant optimal systemic exposure within the therapeutic range have been
extensively discussed. Therapeutic drug monitoring of cyclosporin is carried out in most transplant centers worldwide using only one blood level measured before drug administration (C0) or 2 h after oral intake (C2). Currently, the Department of Nephrology at Hospital JP Garrahan follows an institutional consensus (unpublished) to target a therapeutic window for cyclosporin mainly based on the post-transplant period of the individual patient as previously described for adult renal transplants [31, 32]. However, other parameters are currently considered for dose individualization of cyclosporin including clinical and biochemical parameters and potential drug–drug interactions. For example, concurrent use of azathioprine or prednisone and cyclosporin may result in decreased cyclosporin blood levels and increased renal toxicity, respectively [19, 38]. Thus, cyclosporin C2 blood levels are closely monitored to avoid toxicity and lack of efficacy [38]. Nonetheless, the AUC profile is still the best parameter as a surrogate of systemic exposure and a good safety predictor [15, 16]. A valid approximation is the Bayesian forecasting method for AUC calculation along with a limited sampling strategy in order to reduce the required number of samples per patient specifically in pediatric patients based on ethical concerns. The Limoges University Hospital provides a web-based service for Bayesian dose adjustment of cyclosporin in pediatric patients who have undergone renal transplantation including the calculation of the AUC and Cmax based on a limited number of samples obtained at pre-defined times. This online service was used for the pharmacokinetic characterization of our patients. Clinical pharmacists play a special role in routine TDM in order to individualize and optimize therapeutic regimens in a variety of clinical settings based on their knowledge of pharmacology and specifically about pharmacokinetics. In the present study, we assessed cyclosporin TDM in a pediatric population subjected to conversion between commercial forms of cyclosporin on the local market. The
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initiative was conceived at the Department of Pharmacy of Hospital de Pediatria JP Garrahan and carried out by a multidisciplinary team including clinical pharmacists, transplant physicians, pharmacologists, and biochemists. Thus, cyclosporin TDM was successfully implemented in the Hospital in pediatric patients with a renal transplant undergoing conversion between commercial formulations in line with international recommendations for these drugs [12, 13]. The present report sets the basis for future studies in clinical centers in Argentina or elsewhere after generic cyclosporin is introduced onto the market and close monitoring is recommended. We analyzed the percentage of change in AUC and C2 when switching from one study formulation to the other. No statistical difference was observed when comparing the pharmacokinetic parameters of cyclosporin exposure obtained for the innovator and for the generic product. For most of the evaluated patients, the percentage change in the pharmacokinetic parameters of cyclosporin exposure was within 30 %, similar to the variability of the pharmacokinetics of the drug previously reported by other authors [30, 31]. Interestingly, in four patients a difference of more than 40 % between Cmax and C2 was observed. Additionally, one patient in the study group showed a remarkable difference between C2 and Cmax when switching from one formulation to the other, as shown in Table 1 (patient # 6). We hypothesized that this difference may be attributed to a sampling or processing error as blood concentrations of cyclosporin after 1 and 2 h are almost the same when considering the innovator product. Approximately ten years ago, an international consensus statement (CONCERT) was published pursuing recommendations on cyclosporin blood monitoring in renal and liver transplant patients [32]. C2 blood level monitoring was proposed as the best single time point related to systemic cyclosporin exposure up to 4 h after dosing (AUC0-4) and the best surrogate for Cmax coinciding with the time of maximum calcineurin inhibition [15, 31]. Thereafter, different authors recommended therapeutic ranges of cyclosporin C2 based on the post-transplant period, type of graft, and other factors. Nevertheless, the CONCERT group also pointed out that there could be slow or low absorbers with a different time and value of Cmax compared to the rest of the population and these patients may not be detected with a single point blood concentration. This observation is in line with our findings showing that for some patients C2 monitoring may not reflect the maximum concentration and calcineurin inhibition and thus, a potential overexposure to cyclosporin may be recommended by the treating physician based on C2 instead of Cmax or AUC. It is important to emphasize that more than three decades after the introduction of cyclosporin on the Argentinean market, there is still a paucity of information on the
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safety, efficacy, and pharmacokinetic characteristics of calcineurin inhibitors used in the pediatric transplant population. Not only was information lacking on generic products but data available on the pharmacokinetic and pharmacodynamic parameters for the innovator product of cyclosporin were limited and incomplete in the pediatric population [33]. Therefore, we implemented the first intensive vigilance program of immunosuppressants in pediatric renal and hepatic transplant patients in Latin America [7]. The incidence of the most common adverse events to calcineurin inhibitors are under evaluation and a preliminary report showed consistency in the incidence of adverse events with that previously reported in the literature [33, 34]. Although follow-up of the patients in this study was short, no significant differences regarding the incidence and type of adverse events were registered in the immediate-to-4-month period before and after generic conversion. In Argentina, the health system includes private and public coverage. Around 20 % of the solid-organ-transplant patients receive immunosuppressant drugs from their private insurance while 80 % is covered by the national government (National Disposition 1071/07) [35, 36]. Thus, the immunosuppressant drug product that most of the Argentinean patients receive depends on the winning bid established by the government. Drug products containing immunosuppressants need to have previously demonstrated bioequivalence against the innovator or gold standard established by the national health agency (ANMAT) in order to participate in the tendering as well as compliance of production under Good Manufacturing Production and in vitro testing for quality purposes (National Disposition 2446/07;5040/06). These requirements are of substantial importance and may explain the results previously found by Petan and colleagues regarding performance of Mexican products of tacrolimus, another calcineurin inhibitor [37]. Nevertheless, we acknowledge that drug–drug and drug– food interactions may occur when the generic drug product is introduced onto the market without previous evidence from pharmacokinetic and in vitro studies submitted for regulatory and commercial purposes [38]. Several position papers state that the information provided by bioequivalence studies is limited as it was obtained from adult healthy volunteers and more information in transplant patients should be provided for the generic formulations [12, 13]. In addition, despite of being limited to the adult and healthy population, this information is not publicly available but treated as confidential in Argentina. On the contrary, no previous reports on generic cyclosporin pharmacokinetics in pediatric recipients have been published perhaps due to difficulties to carry out those studies. The present study is the first report that provides solid data on cyclosporin therapeutic monitoring in pediatric renal
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transplant patients undergoing conversion between commercial formulations. Therefore, we emphasize the need for therapeutic monitoring, including that of pharmacokinetic and pharmacodynamic parameters (efficacy and safety), after the release of new drug products or generics on the market. This would be particularly important in special populations including children with solid organ transplants who undergo continuous physiological changes. The main limitation of the present analysis is the low number of patients converted to the generic cyclosporin products. Additionally, the time of follow-up of the patients converted to the generic product was brief. Hence, further studies with a long-term follow-up are necessary to support the present data.
Conclusion We conclude that therapeutic drug monitoring of cyclosporin in pediatric patients under conversion from the innovator to the generic product was feasible in our setting and showed no difference in systemic exposure between formulations. Conversion of cyclosporin was safe in our stable pediatric renal transplant population, allowing for the maintenance of systemic exposure without acuterejection episodes or the need for dose adjustment during the study period. Nonetheless, we recommend close therapeutic monitoring of patients undergoing generic immunosuppressant conversion, concomitant pathological conditions to renal transplant, potential drug–drug interactions, specifically in vulnerable populations such as pediatric patients with solid organ transplants. The present experience could be transferred to other clinical settings in order to perform therapeutic drug monitoring when switching between commercial calcineurin inhibitor drug products in transplant patients. Acknowledgments The authors would like to thank Dr. Pierre Marquet for the web service offered by the University of Limoges for pharmacokinetic assessment of immunosuppressants and head nurse Victoria Barroca, for technical assistance. Funding This work was supported by Hospital de Pediatrı´a Prof. Dr. Juan P. Garrahan. Conflicts of interest
None of the authors present conflict of interest.
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