DRUG LEVEL MONITORING AND ADJUSTMENT Silvio Sandrini, Brescia, Italy Chairs: Ryszard Grenda, Warsaw, Poland Julio Pascual, Barcelona, Spain

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1 DRUG LEVEL MONITORING AND ADJUSTMENT Silvio Sandrini, Brescia, Italy Chairs: Ryszard Grenda, Warsaw, Poland Julio Pascual, Barcelona, Spain Prof. Silvio Sandrini Division and Chair of Nephrology University Hospital Spedali Civili Brescia, Italy Slide 1 my topic is drug level monitoring and adjustment, a very important problem in patient management. Slide 2

2 I would like to start with four key points that I consider important. I know that an achievement of a reasonable balance between the efficacy and the toxicity of immunosuppression has always been the challenge of renal transplant patient care. Due to the narrow therapeutic index of most immunosuppressive drugs, a close therapeutic drug monitoring has become an important part in the transplant patient management. Routine monitoring of drug levels is now common practice and often even 'handled' with less attention than in the past. I think that nowadays the relevance of drug monitoring must be updated mainly in the light of a worsening of the clinical and immunological condition of patients undergoing kidney transplantation. Slide 3 When we discuss the problem of drug monitoring, the first question is, today what is the role of drug monitoring in the prevention of acute rejection? To answer this question I've reported the results of a study that is a polled analysis from three randomized controlled clinical trials: FDCC, Symphony and OptiCept. In these studies the authors considered about 5000 blood levels collected from 1300 patients at different times. The main results of this study were that in spite of drug monitoring, the range of BTLs was very wide and this confirms the need of a monitoring and the presence of important interpatient variability of an immunosuppressive drug. During the first months, the authors observed that 50% of the samples were between 8-12 ng/ml independently from a target suggested by the studies and this suggests that most physicians were confident with this interval of Tacrolimus speaking of Tacrolimus independently from the target proposed by the protocols. In fact, the lowest target proposed by the Symphony study, 3-7 ng/ml, was also the lowest respected. This means that the

3 physicians were not confident to keep the blood levels too low. The overall incidence of BPAR was low 10% and important no relationship was observed between BTLs value and acute rejection. The main conclusion of the authors was that today drug monitoring is more likely to be used in preventing extreme BTLs, too high or too low, than in preventing acute rejection. Slide 4 Another problem when we discuss drug monitoring is, what is the best time point for cyclosporine monitoring? Is it C0 or is it C2? This issue you know, was under discussion 10 years ago but then it lost relevance. We know that at first pre-dose level was C0 and was widely adopted as an indicator of cyclosporine exposure. After Neoral introduction, the second hour of blood concentration, C2 was proposed because it resulted as a good surrogate of the abbreviated AUC thus more reliable than C0 to know the exposure to cyclosporine. However, this point has never been determined definitively and today in clinical practice C0 blood levels continue to be used routinely, mainly because they are simple to collect. Slide 5

4 In this period, we are using generic Tacrolimus. Generic tacrolimus has become available. So some patients have to change from generic to reference Tacrolimus. The question is, what is the role of drug monitoring in this change? Is it of worth? In this graph, we can see that the comparison of the pharmacokinetic profile of the reference Tacrolimus and generic Tacrolimus is the same. So according to this graph the change is safe and no particular monitoring is needed. However, in the clinical setting some authors have observed that the conversion phase was associated with the need of dose adjustment in 21% of patients. So it's preferable if the change is made to use a close monitoring in this occasion. Slide 6 Another conversion suggested in this period is a conversion from short-acting Tacrolimus, a twice daily Tacrolimus dose to a long-acting once daily dose and also in this case the question is, is drug monitoring important for this phase of change? If you consider the pharmacokinetic profile of long-acting and short-acting, you can see that the first phase of exposure is similar for the two formulations. But in the second phase from 12 hours to 24 hours you can see that the short-acting increases the exposure of 40% and the AUC0-24 is 25% smaller when using a once daily dose. So after the conversion from short-acting to long-acting dose adjustment by C0 monitoring is highly recommended to prevent underexposure to a drug. Slide 7

5 Another question is, is the drug monitoring of mycophenolate ACE still of worth? I remember that the therapeutic drug monitoring is only required for drugs with a narrow therapeutic index dependent from two points. One is the presence of intra/individual pharmacokinetic variability and this aspect has been clearly documented also for MPA. The second point is that there must be a close relationship between drug concentration and clinical efficacy and toxicity. This point has been only partially documented for MPA. So MPA blood monitoring has not been recommended in the clinical practice and the dose of 2 g/day has been standardised for all patients. Slide 8 However, I think that MPA monitoring may still be useful in specific clinical settings. Two key points to remember. About 25-40% of patients were found underexposed to MPA in spite of standard doses. The second point is that there's a strong relationship between MPA exposure and the lower risk of rejection has been documented. So, I think that MPA monitoring could be proposed especially in most clinical settings and high risk of acute rejection. I mean patients on cyclosporine and calcineurin inhibitor minimisation, patients with high immunological risk and patients suffering from antibody-mediated acute rejection.

6 Slide 9 Our patients are getting older so, the question is can age modify the pharmacokinetic profile of a drug? In this graph you can see that the pharmacokinetic profile of cyclosporine is increased in the elderly more than in the younger people and the difference is about 30%. You know that usually in older people you use a less dose of immunosuppressive therapy. Slide 10 In the elderly however, age has no impact on the pharmacokinetic profile of Tacrolimus, MPA, Everolimus and Sirolimus. I remember that methylprednisolone clearance is about 30% lower in the elderly patients than in young people. So elderly patients are more prone to side

7 effects due to steroids. So drug monitoring is recommended for elderly patients as for younger people without significant difference. Slide 11 Now another problem that you meet in the management of transplant patients is the interaction between immunosuppressive drugs and I would like to quickly consider this aspect. You know that when you use MMF and cyclosporine, cyclosporine reduces up to 50% the exposure of MMF and this effect is dose-dependent. So, any change in cyclosporine dose can impact on the pharmacokinetic profile of MMF. So, close monitoring of MMF or MPA should be recommended in the case of cyclosporine minimisation, withdrawal or a new introduction. Tacrolimus, Sirolimus, Everolimus and steroids don't modify the profile of MPA. Slide 12

8 You know that there is an important pharmacokinetic interaction between cyclosporine and mtor inhibitors and both drugs increase blood and tissue concentration one with the other. Cyclosporine dose reduction is required to prevent cyclosporine toxicity. You know that the cyclosporine dose has been used up to 60% when used with mtor inhibitors. Slide 13 I remember for Tacrolimus the interaction with steroids, when steroids are stopped, the pharmacokinetic profile of the dose the blood levels of Tacrolimus can increase up to 55%. So drug monitoring is advisable in patients undergoing an early or late steroid withdrawal programme. The interaction between Tacrolimus and mtor inhibitors is still under investigation due to the contradictory findings so far available. Slide 14 Finally, I consider the drug-drug interaction. I remember that pharmacokinetic drug interaction between two drugs can occur through mechanisms interfering with different phases in the profile: absorption, distribution, metabolism and elimination. Drugs interfering with the activity of CYP-450 cause the most important changes to immunosuppressive drug exposure. Some

9 antibiotics, antifungal and anti-seizure drugs are well known agents able to interfere strongly with the pharmacokinetics of immunosuppressive drugs. In this setting immunosuppressive drug monitoring is again essential to prevent the over or under drug exposure. Slide 15 This slide is just to remember how important the dose reduction is in some conditions. If you use antifungal drugs: Voriconazole, ketoconazole, you see that the dose of cyclosporine or Tacrolimus is 80%, 66%, 50% so only if you make a close monitoring of level, can you reach this reduction. In other cases, the drug can be increased 3- or 4-fold if you use some antibiotics like Rifampicin. Slide 16 When you consider the drug-drug interaction today, the latest problem that has been raised in our area is the use of immunosuppressive therapy in HIV+ patients on anti-retroviral therapy. This slide shows the problem. In this article the authors used one single dose of Tacrolimus in 6 patients on the waiting list, HIV+ and on anti-retroviral based therapy. Slide 17

10 We can see that one patient was treated with only one dose of 7 mg, one 6.5 mg, 1 mg and 1 mg you see that the patients that used 7 mg, a single dose after a single dose you can see that the level of Tacrolimus was 80 ng/ml and the reduction of the level was very low, after 350 hours it was again 20 ng/ml. So patients treated with 1 mg you can see that the cmax is lower, about 20 ng/ml but the disappearance of a drug usually is very low. So, in this case drug monitoring is recommended, essential to prevent toxicity. Slide 18 So, in conclusion drug monitoring, although in use for many years, always has relevant role in patient management. Although the prevention of acute rejection is no longer too relevant as in the past, drug monitoring is still essential to avoid over or under drug exposure in many clinical frames. Drug minimization, transplantation in sensitised patients, BKV nephropathies, drug interactions in HIV+ patients are some of the latest areas requiring close drug monitoring. In these decades, physicians have become confident with specific therapeutic windows and any effort to update this issue can be considered no longer worth of interest. Unfortunately, this is not true since the best immunosuppression is still far from being entirely defined thank you very much for your attention. Slide 19

11 Chairman: Thank you very much for this wonderful presentation, which is open for discussion. Are there any questions from the audience? Question: The question regarding HIV, we have a patient on the waiting list but sometimes it's very unpredictable what the interaction is. Do you think it's a good idea to just test it before he's put on the waiting list giving for 1-2 weeks immunosuppressants to his heart therapy to try to get an idea of what the appropriate dose will be? Prof. Sandrini: Well in my centre, I have treated 15 HIV+ patients without making any blood tests before. I don't think it's so important. It's important to know the problem and to monitor the patient with attention and to use very, very low doses of immunosuppression at the beginning of a transplant. Question: By drug monitoring, do you mean just C2 concentration measurements? Prof. Sandrini: Can you speak louder, sorry? Question: The question was should we monitor more with C2 concentrations or with area under the curve? Prof. Sandrini: If you use the trough levels or other parameters? No, I prefer to use C2 to monitor the patients. Area is too difficult to use. I usually use C2 for monitoring, not the area under the curve. Chairman: Are there any other questions? We have time for one question. I have one question for you. What is in your opinion now the standard target for trough and Tacrolimus levels for standard patients and what do you think are the most important clinical characteristics to change this target? In mean in association with MMF. Prof. Sandrini: I think that any centre now has his own target with Tacrolimus. I think that the target 8-12 ng/ml during the first months is the most accepted target by the authors. After 1 year, with time, the target is about 5-8 ng /ml and this is the most accepted in the literature. Question: Thank you, thank you very much. Chairman: Ok thank you very much we're moving on.