Recommendations for the Implementation of Neoral C2 Monitoring in Clinical Practice

Abstract

INTRODUCTION The weight of published evidence has demonstrated that patient management by Neoral C2 monitoring (i.e. adjusting doses according to drug levels at 2 hours postdose), compared with management by conventional “trough” concentration can improve clinical outcomes for de nouo renal and liver transplant patients (1–9). Initial studies suggest that Neoral C2 monitoring also can detect cyclosporine overexposure in maintenance patients. Evidence to date has demonstrated the benefit of dose reduction in these patients, in terms of improving short-term renal function and reducing hypertension (10–11). The weight of evidence together with the establishment of target C2 levels for both renal and liver transplantation, and the development of a simple dose-adjustment formula (Fig. 1), have stimulated the implementation of Neoral C2 monitoring in clinical practice. Neoral C2 targets have been established for both de novo and maintenance liver transplant patients (Table 1) (12). Target levels for renal transplant patients based on accumulated data to date are outlined in Table 2 (12,13).Figure 1: Neoral C2 dose adjustment formula (13).Table 1: Target Neoral C2 levels for liver transplant patients (12)Table 2: Target Neoral C2 levels for renal transplant patients (12,13)As a result of this progress, Neoral C2 monitoring has now been successfully adopted by transplant centers worldwide, across healthcare systems and patient types. The collective experience of a cross-section of these centers has provided recommendations for the successful implementation of Neoral C2 monitoring in clinical practice. These recommendations focus on a step-wise approach to implementation. Three major objectives of this approach are: to ensure the commitment of all unit staff and patients affected by the change to C2 monitoring; to set up a system that ensures that patients are sampled on time and that C2 and C0 samples can be differentiated at all stages, through to reporting; and to minimize the impact of implementation on workload, and clinic and ward routines. The major steps in the implementation process are outlined in Figure 2.Figure 2: Step-wise process for implementation of Neoral C2 monitoring.A STEP-WISE APPROACH Step 1: Review of Clinical Evidence The first step involves a review of the scientific rationale and clinical evidence by the clinical team, to ensure that everyone is committed to the implementation of this new technique. Step 2: Presentation of the C2 Concept The second—and most critical—step in the process involves the presentation of the scientific rationale for and clinical benefits of Neoral C2 monitoring to all members of the transplant team, the external departments that will be affected by the change from C0 to C2 monitoring (e.g., clinical laboratory staff), and the satellite units that refer patients for transplantation. Without the understanding and agreement of everyone involved, the implementation of Neoral C2 monitoring is likely to be undermined at a later stage with the potential for patient safety to be compromised and effort wasted. Some units have published a short newsletter to sustain communication with all those involved in the change to Neoral C2 monitoring, as a follow up to the initial meeting. At this stage, timelines for implementation and the patient population in which the process will be piloted should also be agreed upon. Centers have found that this is done most easily by focusing first on de novo cases (see Step 5). In addition, contact should be established with referring satellite units to decide what arrangements will be made for sampling patients after discharge. Step 3: Formation of the Transition Team The third step involves the formation of a multidisciplinary transition team consisting of members from key departments whose role it will be to drive implementation by: • Championing Neoral C2 monitoring and acting as an information resource within their own departments • Contributing their expertise to the unit implementation protocol • Training staff within their own departments It is important at this stage to appoint an enthusiastic and experienced team leader who will have responsibility for overseeing the whole implementation process, keeping to agreed timelines, and liaising within and between departments. Step 4: System Development Once the transition team is formed, an implementation protocol should be developed. Ward, clinic, and laboratory systems will need to be set up to ensure that patients take their dose on time, blood samples are taken 2-hours postdose (±15 min) (14), and that C2 and C0 samples can be differentiated at all stages, through to final reporting. Establishing a protocol is particularly important at the outset because staff will be less familiar with Neoral C2 sampling. It is intended that the set up of ward, clinic, and laboratory systems should happen concurrently. Implementation in the Inpatient Setting. The inpatient setting is an ideal starting point for the implementation of Neoral C2 monitoring because it offers a relatively controlled environment compared to the outpatient clinic. Also, by piloting procedures with a small number of patients, a great deal can be learned before full-scale implementation in the maintenance population. Experience from centers that have implemented Neoral C2 monitoring suggests that all nursing staff should be trained in the benefits and procedures involved with Neoral C2 monitoring. It is also advisable that one member of the nursing staff oversee the monitoring of patients on each daytime shift in order to streamline communication with patients, the phlebotomy service, the clinical laboratory, and junior medical staff. The appointed nurse has the responsibility for making sure that the patients take their Neoral at the designated time, that the phlebotomist takes the blood samples by the 2-hour cut off point, and that samples are clearly labeled and dispatched to the laboratory. In some centers it may be necessary for dosing and sampling of Neoral C2 patients to be staggered, depending on the capacity of the phlebotomy service and the needs of individual patients. A documentation system for Neoral C2 patients is essential to the efficiency of this process to minimize the workload of the ward staff and phlebotomists. The documentation system could consist of the following elements, adapted for local use: • Quick identification of Neoral C2 patients by means of a clearly visible list (e.g. a wall chart) and readily available Neoral C2 labels to be adhered to the patients’ notes • Documentation of dosing and sampling times and Neoral C2 levels on specific C2 inserts for the patients’ notes • A checklist of Neoral C2 patients to ensure patients are not overlooked • Readily available Neoral C2 labels to be adhered to the blood samples and to the packaging for dispatch The system for differentiating between C2 and C0 samples on the ward can be further enhanced by separately timing phlebotomy for these two groups. For patients being monitored by C0, all blood work can be scheduled for early morning (e.g. 8:30 am) when Neoral C2 patients are administered their dose of Neoral by the designated nurse. The phlebotomist then returns 2 hours later (e.g. 10:30 am) to perform all the blood work for the Neoral C2 patients, including the C2 sample, and to label the C2 samples for dispatch to the laboratory by the agreed time. Separate timing prevents mixing up C0 and C2 samples and enables both sets of patients to complete all their blood work at once. In the event that a patient’s blood sample is taken late, the time should be noted, the laboratory informed, and sampling rescheduled for the next day. The ideal opportunity to educate patients about this new management technique is while they are on the ward. The designated nurse, or a clinician or pharmacist, should educate patients about the outcome benefits of Neoral C2 monitoring and the need to have their blood sample taken 2 hours (±15 min) postdose. Harnessing the enthusiasm of patients and promoting their understanding of the benefits of tailoring their Neoral therapy is key to successful implementation, especially when they may have samples taken at satellite units where staff are less familiar with the new technique. De novo patients are unlikely to need extensive counseling, however, they should be provided with verbal and written information about C2 monitoring and the procedure that will be adopted for sampling, after they have been discharged to the care of the outpatient clinic (see Implementation in the Outpatient Setting). The exception to this may be re-transplanted patients who were previously monitored by cyclosporine C0 and who will require more extensive counseling at the outset on the difference between the two techniques. Implementation in the Outpatient Setting. A new system will need to be set up for monitoring Neoral C2 patients on an outpatient basis to facilitate their discharge from the ward setting. The principles of educating staff, appointing a Neoral C2 nurse, establishing a documentation and labeling system, and educating patients also can be applied to the outpatient setting. The main difference in the outpatient setting is that the nurse in charge will need to ensure that Neoral C2 monitoring does not disrupt the efficient running of the clinic. This can be achieved by establishing a staggered appointment schedule with the phlebotomist to ensure patients are sampled on time and to avoid a back-log. Staggering the appointment schedule may have other benefits. As the experience of centers where Neoral C2 monitoring has been implemented shows, the efficiency of the clinic can be improved, and patients are very positive about having a specific appointment for their blood work. Additionally, the nurse in charge will need to inform patients about when to take their dose of Neoral. Most patients can be relied on to take their Neoral dose at home (and to note the time) prior to coming to their clinic appointment, so that the length of the clinic visit is not prolonged. Once Neoral C2 monitoring is established as a routine procedure in de novo patients and the outpatient clinic system is running, the unit may decide to transfer maintenance Neoral patients. Because these patients are already established on cyclosporine C0 monitoring, a procedure will need to be put in place for recall and counseling. In order to give the patient time to digest the information—and to save clinic time—transplant units that have transferred maintenance patients from conventional trough to C2 monitoring have used a recall system whereby patients are sent a letter before their next clinic visit that explains the benefits of the new procedure. The letter can be followed up with a telephone call to provide a more in-depth explanation of the benefits of Neoral C2 monitoring, to ensure that the patient understands the arrangements for taking their Neoral dose, and to confirm the time when they are due at the clinic for their C2 sample to be taken. From the outset, it is also important to decide how many patients the transplant unit can transfer at each outpatient clinic and to give these patients appointments at the start of the clinic session, to minimize disruption for both staff and patients. Set up of Clinical Laboratory Procedures. Laboratory staff need to understand the rationale and benefits of Neoral C2 monitoring, especially because they are remote from the patient setting. An understanding of their contribution to improving transplant patient outcomes, is critical to the success of the whole implementation program as they play a pivotal role in ensuring accurate testing and reporting of Neoral C2 levels. In the laboratory, the critical difference between cyclosporine C0 monitoring and C2 monitoring is the extra step involved in the dilution of the Neoral C2 sample. (This may not be necessary if the laboratory is using the CEDIA Plus [Microgenics, Fremont, CA], which can directly measure 0.0–2.0 μg/mL). Dilution of the Neoral C2 sample is necessary because it contains much higher concentrations of cyclosporine than a C0 sample. A dilution protocol needs to be established and validated in the laboratory before patient Neoral C2 samples can be handled on a routine basis. Apart from a simple dilution procedure prior to using the established measurement procedure for cyclosporine, no other assay changes are required (14). Additionally, a separate system for logging and reporting Neoral C2 samples should be established. Owing to the large number of non-transplant indications for cyclosporine (e.g. psoriasis, nephrotic syndrome, uveitis, rheumatoid arthritis) it is likely that cyclosporine C0 samples will continue to be sent to the laboratory from other departments, even if all transplant patients are eventually transferred to Neoral C2 monitoring. Therefore, it may be worth considering the use of different units to report C0 and C2 levels back to the transplant team to ensure that the medical staff, who are using the levels to adjust the dose, are basing their decisions on correct data. If patients have their Neoral C2 blood sample taken at a satellite unit, the unit’s laboratory will need to be informed of the change to C2 monitoring as part of the implementation process and be supplied with Neoral C2 sample labels to be used on their requisition forms. Step 5: Piloting Neoral C2 Monitoring Piloting Neoral C2 monitoring in a small group of patients (e.g., de novo patients) allows sampling and reporting procedures to be reviewed and altered, if necessary, and the unit protocol to be validated. It also enables the transplant team to become familiar with the Neoral C2 target levels (see Tables 1 and 2) and dose adjustments according to C2 level (see Fig. 1). When piloting Neoral C2 monitoring in clinical practice, it should be noted that a small proportion of patients can have markedly delayed absorption of cyclosporine (i.e., extended time to peak cyclosporine concentration [Cmax]). These patients are referred to as “slow” absorbers. Increasing the Neoral dose according to the C2 level in these patients may lead to excessive cyclosporine exposure. Measurement of C2 alone cannot determine whether a low absorber of cyclosporine is a “true low absorber” or a “slow absorber” (a patient can be defined as a low absorber in the early post-transplant phase, if the C2 level (in μg/mL) divided by the preceding dose of Neoral (in mg/kg) is less than 0.2 μg/mL/mg/kg (P Keown, personal communication). If the C2 value recorded on Day 3 or later indicates that the patient is a low absorber, carrying out further sampling at a later time-point (e.g., C6) may help to determine if they are a true low absorber or a slow absorber. In true low absorbers, both C2 and C6 would be low and Neoral dosing should be adjusted according to C2 value. In slow absorbers, C6 is likely to be higher than C2 and caution should be exercised when increasing the dose of Neoral, in order to avoid toxicity. It is also advisable to repeat the C6 level after 2 to 3 weeks to confirm the maintenance status of the patient, owing to the rapid changes in the pharmacokinetic characteristics of cyclosporine in the early posttransplant period. In the maintenance renal transplant recipient, a C2 level higher than 1.0 μg/mL, for example, could be considered excessive exposure to cyclosporine; however, this needs to be confirmed in long-term prospective studies. Step 6: Implementation Once the pilot phase has been evaluated and systems have been adjusted, full-scale implementation can take place. Routine auditing of Neoral C2 monitoring, however, is necessary over time to detect problems at an early stage and to evaluate the impact of higher numbers of patients on the efficiency of sampling and reporting. These audits could also be used to decide when to implement Neoral C2 monitoring in the maintenance patient population. CONCLUSIONS Neoral C2 monitoring provides the optimal strategy for individualizing therapy for de novo and maintenance transplant patients (1–15). The establishment of target C2 levels for renal and liver transplantation (12,13) and the development of a simple dose-adjustment formula (13) have stimulated the adoption of Neoral C2 monitoring in routine clinical practice. Experience from centers that have successfully adopted Neoral C2 monitoring suggests that a step-wise approach is the key to the smooth implementation of this valuable patient management tool. By following the six-step approach, units contemplating the use of Neoral C2 monitoring will be able to maximize both the unit’s support for the transition from trough monitoring and the efficiency of sampling and reporting systems. The step-wise approach will ensure that patients can be sampled on time and managed according to the resulting C2 level, with minimal disruption to ward, clinic, and laboratory routines.