Celebrating Various Anniversaries

This month we highlight an article in the most recent Compass issue (June), celebrating the 10-year anniversary of the ImmunoSuppressants Bayesian dose Adjustment (ISBA) web-site in Limoges, France. Jean-Baptiste Woillard and Franck Saint-Marcoux, on behalf of the Pharmacometrics Scientific Committee, share their experiences working behind the platform. The publication coincides with last month’s interview (Professor Pierre Marquet), and describes in greater detail the history and rationale behind the platform, as well as its successes.

The June 2015 issue of the Compass was particularly full with contributions from various scientific committees, including: the Biomarker Working Group part of the IS Scientific Committee (Mercè Brunet; “Report on the IV symposium on biomarkers of immunosuppression and clinical outcome in transplantation”), Committee on Clinical Toxicology & Drugs of Abuse (Heather Signorelli, Kamisha Johnson-Davis, and Gwendolyn McMillin; “Nicotine metabolite testing”); Young Scientist Committee, which also celebrates a 10-year anniversary (!) (Jennifer Button; “The rise and fall of the phenidates: the UK perspective. Have the phenidates had their date?”). In addition, head-office remembers fondly the last 20 years (!) of service to our association, new members are highlighted and the future of the beloved Compass newsletter is discussed.

ISBA website celebrates 10-year anniversary for dose adjustments of immunosuppressive drugs
Jean-Baptiste Woillard and Franck Saint-Marcoux, Limoges, France (on behalf of the ISBA website team)

Mycophenolate mofetil (MMF), tacrolimus (TAC) and cyclosporine (CsA) are three widely used immunosuppressive drugs for the prevention of allograft rejection in transplantation. For these three molecules, TDM is either mandatory or consensually recommended. Although generally based on the measurement of trough levels (C0), since the “Lake Louise Consensus Conference on cyclosporin monitoring” reported by Prof. Michael Oellerich and other colleagues in 1995, multiple consensus reports have encouraged the use of AUC to monitor transplant patients given either CSA, TAC or MMF (1-3).

However, when considering using the AUC, one faces a tedious issue: how can the AUC be achieved or, more precisely, for practical, ethical, and economic reasons, how can the number of concentration measurements be limited while still maintaining accuracy? Different processes have been proposed for determining sampling times that are needed to produce the most accurate estimation using as few samples as possible. The simplest method of estimating AUC is multiple regression analysis (MRA). However, MRA has major drawbacks: it can only be applied if the dosing schedule is closely respected; errors in timing lead to errors in estimation; and extrapolations can only be used with accuracy in the population for which they were developed. Although useful when rigorously validated and appropriately applied, such a tool does not provide an individualized estimation of pharmacokinetic (PK) parameters. As an alternative, we have developed Bayesian estimators to estimate AUC using limited individual data that allow an individual calculation of the PK parameters and consequently the dose to reach an AUC target value for each patient (4, 5). To do this, we have developed original PK models built on large populations of transplanted patients who were enrolled in PK studies promoted and coordinated by the Limoges University Hospital, other academic institutions or by pharmaceutical companies.

Since 2001-2002, the department has been proposing dose adjustments using these tools. The first models were developed by Dr Jean Debord who has been working in the team for more than 20 years (6). At the very beginning, the activity was limited to the patients within our institution. However, some other French centres soon started sending in requests for difficult cases. Finally, in April 2005, Prof. Pierre Marquet decided to launch an expert system for ImmunoSuppressants Bayesian dose Adjustment (ISBA) and to make it accessible to all transplantation centres worldwide through a secured website (https://pharmaco.chu-limoges.fr/). The objective of this service were to offer dose adjustment of MMF, TAC and CsA by providing: individual patient’s exposure to the drug (inter-dose area under the curve, i.e., AUC0-12h for b.i.d. and AUC0-8h for t.i.d. dosing) estimated using Maximum a Posteriori Bayesian Estimators (MAP-BEs) on the basis of three blood samples collected in the first three hours following drug intake; the modelled concentration- time curve; and one or a range of recommended dose(s) to reach the therapeutic target. However, having developed a strategy to offer such a PK-based dose adjustment service using the AUC, a second tiresome issue occurs: many questioned the feasibility and the interest of clinicians.

Today, celebrating its 10-year anniversary, the ISBA website has received about 75 000 requests. Its current activity is:

• Number of transplantation facilities: No less than 121 different clinical departments, mostly involved in solid organ transplantation, have sent us at least one dose adjustment request. They are located on 6 continents or sub-continents.
• An average of 800 requests per month posted on ISBA
• Multiple Bayesian estimators: In line with our understanding of precision medicine, the ISBA website proposes dose adjustment tools adapted to each patient profile, based on a large panel of Bayesian estimators, for the different immunosuppressive drugs, transplanted organ or other conditions, drug associations, etc.
• Most importantly for patient care, results have all been validated by trained pharmacologists and made available after a median time of 56 minutes

This retrospective analysis of the ISBA expert system activity demonstrates that a “PK-based” dose adjustment service can actually be feasible. Such an activity can become an active and viable part of patient care. It probably has a positive impact on the patient’s outcome. However, this last point still has to be demonstrated.

Seen from the lab, such an activity is obviously rewarding. When handling a dose adjustment request, one is required to contact the patient care areas to obtain information which significantly improves the visibility to the physicians, resulting in better inter-departmental communication. This also increases the interest and knowledge of younger pharmacologists in the overall care of the patient. This prevents from limiting pharmacology and pharmacokinetics to their theoretical aspects which greatly improves job satisfaction!

1. Oellerich M, Armstrong VW, Kahan B et al. Lake Louise Consensus Conference on cyclosporin monitoring in organ transplantation: report of the consensus panel. Ther Drug Monit. 1995 Dec;17(6):642-54.
2. Wallemacq P, Armstrong VW, Brunet M et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009 Apr;31(2):139-52.
3. Tett SE, Saint-Marcoux F, Staatz CE, et al. Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure. Transplant Rev (Orlando). 2011 Apr;25(2):47-57.
4. Saint-Marcoux F, Vandierdonck S, Prémaud A, et al. Large scale analysis of routine dose adjustments of mycophenolate mofetil based on global exposure in renal transplant patients. Ther Drug Monit. 2011 Jun;33(3):285-94.
5. Saint-Marcoux F, Woillard JB, Jurado C, et al. Lessons from routine dose adjustment of tacrolimus in renal transplant patients based on global exposure. Ther Drug Monit. 2013 Jun;35(3):322-7.
6. Leger F, Debord J, Le Meur Y, et al. Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants. Clin Pharmacokinet. 2002;41(1):71-80.