DRUG LEVEL MONITORING AND ADJUSTMENTSilvio Sandrini, Brescia, Italy

Chairs: Ryszard Grenda, Warsaw, PolandJulio Pascual, Barcelona, Spain

Prof. Silvio SandriniDivision 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 patientmanagement.

Slide 2

I would like to start with four key points that I consider important. I know that anachievement of a reasonable balance between the efficacy and the toxicity ofimmunosuppression has always been the challenge of renal transplant patient care. Due tothe narrow therapeutic index of most immunosuppressive drugs, a close therapeutic drugmonitoring has become an important part in the transplant patient management. Routinemonitoring of drug levels is now common practice and often even 'handled' with less attentionthan in the past. I think that nowadays the relevance of drug monitoring must be updatedmainly in the light of a worsening of the clinical and immunological condition of patientsundergoing kidney transplantation.

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When we discuss the problem of drug monitoring, the first question is, today what is the roleof drug monitoring in the prevention of acute rejection? To answer this question I've reportedthe 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 bloodlevels collected from 1300 patients at different times. The main results of this study were thatin spite of drug monitoring, the range of BTLs was very wide and this confirms the need of amonitoring and the presence of important interpatient variability of an immunosuppressivedrug. During the first months, the authors observed that 50% of the samples were between8-12 ng/mL independently from a target suggested by the studies and this suggests thatmost physicians were confident with this interval of Tacrolimus speaking of Tacrolimusindependently from the target proposed by the protocols. In fact, the lowest target proposedby the Symphony study, 3-7 ng/mL, was also the lowest respected. This means that the

physicians were not confident to keep the blood levels too low. The overall incidence of BPARwas low 10% and important no relationship was observed between BTLs value and acuterejection. The main conclusion of the authors was that today drug monitoring is more likely tobe used in preventing extreme BTLs, too high or too low, than in preventing acute rejection.

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Another problem when we discuss drug monitoring is, what is the best time point forcyclosporine monitoring? Is it C0 or is it C2? This issue you know, was under discussion 10years ago but then it lost relevance. We know that at first pre-dose level was C0 and waswidely adopted as an indicator of cyclosporine exposure. After Neoral introduction, the secondhour of blood concentration, C2 was proposed because it resulted as a good surrogate of theabbreviated 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 levelscontinue to be used routinely, mainly because they are simple to collect.

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In this period, we are using generic Tacrolimus. Generic tacrolimus has become available. Sosome patients have to change from generic to reference Tacrolimus. The question is, what isthe role of drug monitoring in this change? Is it of worth? In this graph, we can see that thecomparison of the pharmacokinetic profile of the reference Tacrolimus and generic Tacrolimusis the same. So according to this graph the change is safe and no particular monitoring isneeded. However, in the clinical setting some authors have observed that the conversionphase was associated with the need of dose adjustment in 21% of patients. So it'spreferable if the change is made to use a close monitoring in this occasion.

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Another conversion suggested in this period is a conversion from short-acting Tacrolimus, atwice daily Tacrolimus dose to a long-acting once daily dose and also in this case the questionis, is drug monitoring important for this phase of change? If you consider the pharmacokineticprofile of long-acting and short-acting, you can see that the first phase of exposure is similarfor the two formulations. But in the second phase from 12 hours to 24 hours you can see thatthe short-acting increases the exposure of 40% and the AUC0-24 is 25% smaller when usinga once daily dose. So after the conversion from short-acting to long-acting dose adjustmentby C0 monitoring is highly recommended to prevent underexposure to a drug.

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Another question is, is the drug monitoring of mycophenolate ACE still of worth? I rememberthat the therapeutic drug monitoring is only required for drugs with a narrow therapeuticindex dependent from two points. One is the presence of intra/individual pharmacokineticvariability and this aspect has been clearly documented also for MPA. The second point is thatthere must be a close relationship between drug concentration and clinical efficacy andtoxicity. This point has been only partially documented for MPA. So MPA blood monitoring hasnot been recommended in the clinical practice and the dose of 2 g/day has been standardisedfor all patients.

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However, I think that MPA monitoring may still be useful in specific clinical settings. Two keypoints to remember. About 25-40% of patients were found underexposed to MPA in spite ofstandard doses. The second point is that there's a strong relationship between MPAexposure and the lower risk of rejection has been documented. So, I think that MPAmonitoring could be proposed especially in most clinical settings and high risk of acuterejection. I mean patients on cyclosporine and calcineurin inhibitor minimisation, patients withhigh immunological risk and patients suffering from antibody-mediated acute rejection.

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Our patients are getting older so, the question is can age modify the pharmacokinetic profileof a drug? In this graph you can see that the pharmacokinetic profile of cyclosporine isincreased 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% lowerin the elderly patients than in young people. So elderly patients are more prone to side

effects due to steroids. So drug monitoring is recommended for elderly patients as foryounger people without significant difference.

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Now another problem that you meet in the management of transplant patients is theinteraction between immunosuppressive drugs and I would like to quickly consider thisaspect. 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 dosecan impact on the pharmacokinetic profile of MMF. So, close monitoring of MMF or MPA shouldbe 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

You know that there is an important pharmacokinetic interaction between cyclosporine andmTOR 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 thecyclosporine 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, thepharmacokinetic profile of the dose the blood levels of Tacrolimus can increase up to 55%. Sodrug monitoring is advisable in patients undergoing an early or late steroid withdrawalprogramme. The interaction between Tacrolimus and mTOR inhibitors is still underinvestigation due to the contradictory findings so far available.

Slide 14

Finally, I consider the drug-drug interaction. I remember that pharmacokinetic drug interactionbetween two drugs can occur through mechanisms interfering with different phases in theprofile: absorption, distribution, metabolism and elimination. Drugs interfering with the activityof CYP-450 cause the most important changes to immunosuppressive drug exposure. Some

antibiotics, antifungal and anti-seizure drugs are well known agents able to interfere stronglywith the pharmacokinetics of immunosuppressive drugs. In this setting immunosuppressivedrug 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 youuse antifungal drugs: Voriconazole, ketoconazole, you see that the dose of cyclosporine orTacrolimus is 80%, 66%, 50% so only if you make a close monitoring of level, can you reachthis reduction. In other cases, the drug can be increased 3- or 4-fold if you use someantibiotics like Rifampicin.

Slide 16

When you consider the drug-drug interaction today, the latest problem that has been raisedin our area is the use of immunosuppressive therapy in HIV+ patients on anti-retroviraltherapy. This slide shows the problem. In this article the authors used one single dose ofTacrolimus in 6 patients on the waiting list, HIV+ and on anti-retroviral based therapy.

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We can see that one patient was treated with only one dose of 7 mg, one 6.5 mg, 1 mg and1 mg you see that the patients that used 7 mg, a single dose after a single dose you can seethat the level of Tacrolimus was 80 ng/mL and the reduction of the level was very low, after350 hours it was again 20 ng/mL. So patients treated with 1 mg you can see that the cMAX islower, about 20 ng/mL but the disappearance of a drug usually is very low. So, in this casedrug monitoring is recommended, essential to prevent toxicity.

Slide 18

So, in conclusion drug monitoring, although in use for many years, always has relevant role inpatient management. Although the prevention of acute rejection is no longer too relevant asin the past, drug monitoring is still essential to avoid over or under drug exposure in manyclinical frames. Drug minimization, transplantation in sensitised patients, BKV nephropathies,drug interactions in HIV+ patients are some of the latest areas requiring close drugmonitoring. In these decades, physicians have become confident with specific therapeuticwindows 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 entirelydefined thank you very much for your attention.

Slide 19

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 sometimesit's very unpredictable what the interaction is. Do you think it's a good idea to just test itbefore he's put on the waiting list giving for 1-2 weeks immunosuppressants to his hearttherapy 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 bloodtests before. I don't think it's so important. It's important to know the problem and to monitorthe patient with attention and to use very, very low doses of immunosuppression at thebeginning 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 areaunder the curve?

Prof. Sandrini: If you use the trough levels or other parameters? No, I prefer to use C2 tomonitor the patients. Area is too difficult to use. I usually use C2 for monitoring, not the areaunder the curve.

Chairman: Are there any other questions? We have time for one question. I have onequestion for you. What is in your opinion now the standard target for trough and Tacrolimuslevels for standard patients and what do you think are the most important clinicalcharacteristics 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 thetarget 8-12 ng/mL during the first months is the most accepted target by the authors. After 1year, 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.