The main goal of treating rheumatic diseases is to achieve rapid and effective suppression of inflammation. More and more drugs have been proven to be able to achieve these goals nowadays. The current practice is to give a recommended dose of drugs to our patients according to the body weight, risk factors and tolerance, etc. However, all our patients are different individuals who have different pharmacokinetics, and this difference in pharmacokinetics can affect the true drug concentration that is working inside them. This may create problems of “over” and “under” treatment. Therefore, monitoring the drug level may help to titrate the drug dosage in each individual in order to achieve an optimal dosage which maximizes the efficacy while minimizing toxicities. In this review article, we will briefly review the role of drug level monitoring in determining drug efficacy and toxicities in Hydroxychloroquine, Mycophenolate Mofetil, Tacrolimus and TNF inhibitors.
Hydroxychloroquine (HCQ) has long been proved to be useful in the treatment of Systemic Lupus Erythematosus (SLE). HCQ has been shown to have not only immunomodulatory effects, but also with antithrombotic, lipid and glucose lowering effects, which is particularly important in SLE patients who are prone to atherosclerotic events secondary to chronic systemic inflammation.1
In the latest recommendations for treatment of lupus nephritis, HCQ has been recommended for the routine use in lupus nephritis.2–4 In a randomized-double-blind, placebo-controlled study of 47 clinically stable SLE patients, it was demonstrated that the risk of SLE flares rose 2.5-folds during a 6-month period after discontinuation of the drug.5
HCQ is an anti-malarial drug that is rapidly absorbed in the gastrointestinal tract. It takes about 4-6 weeks for its onset of action but may take up to 3-6 months to achieve its maximal efficacy. Most of it is excreted through the kidneys and it has a long half-life of about 40-50 days. The current common practice is to give a dosage of 200-400 mg daily as a maintenance dose. Recent publication has suggested that daily consumption of 5.0 mg/kg of real body weight or less is associated with a lower risk of retinopathy for up to 10 years.6 However, it was found that the HCQ blood levels in patients treated with the same daily doses varied and therefore, studies have been conducted to demonstrate whether there is a relationship between the drug level and SLE activity.
A longitudinal cohort study was done in order to determine whether HCQ level was correlated with lower risk of SLE flares in Chinese patients.7 276 Chinese patients, who had been on HCQ for more than 6 months, were recruited and followed up for three years with their baseline HCQ concentration levels checked. It was found that the annual incidence of SLE flares at follow up were not statistically different in patients with different concentration levels at baseline. However, in the subgroup of 73 SLE patients with SLE remission at baseline, trends of lower disease activity and incidence of flares were observed in the group of patients with therapeutic HCQ levels.
A French study was conducted on 143 SLE patients in order to demonstrate the possible relationship between whole-blood HCQ concentration and clinical efficacy of HCQ.8 After 6 months of follow up, the mean whole blood HCQ concentration was significantly lower in patients with active disease at baseline and with disease exacerbations during follow up. Multivariate logistic regression showed that the HCQ concentration was the only predictor of exacerbation. Receiver operative characteristic curve analysis showed that the whole blood HCQ concentration of 1,000 ng/ml had a negative predictive value of 96% for exacerbation during follow up.
In order to validate this proposed target level, a multicenter randomized prospective study was conducted to determine the potential benefits of individualizing HCQ dosing schedules in order to reach this proposed target level.9 Patients were randomized to either stay on the same usual dosage of HCQ or with augmentation of HCQ dosage to achieve a target level of more than 1,000 ng/ml. However, after follow up for 7months, the rates of SLE flares were not statistically different between the two groups. One possible postulation for the negative result was that it was difficult to achieve and maintain the target level throughout the whole follow-up period, as the HCQ dosage was only allowed to be adjusted once at randomization. Possible factors for difficulty in maintaining the drug level include poor drug adherence, pharmacokinetic variations of HCQ, lag time between clinic visits, lack of control of the use of other immunosuppressive agents, etc. Therefore, it was proposed that the design of future studies should allow for more than one adjustment of drug dosage with monitoring of HCQ level in order to determine the optimal target level.
To conclude, there is a trend that higher HCQ levels were associated with fewer flares of SLE. Larger studies are necessary for confirming the relationship between drug level and clinical efficacy and even toxicities. Despite a lack of consensus on the HCQ level that could balance therapeutic efficacy against toxicities, monitoring the HCQ level may be utilized for identifying and correcting non adherence.
3 Mycophenolate Mofetil
Mycophenolate Mofetil (MMF) has been increasingly used as the first line treatment for lupus nephritis. More and more studies have proven that it is not inferior to usual cyclophosphamide (CYC) treatment in lupus nephritis. The Aspreva Lupus Management Study (ALMS), one of the largest randomized trial found that the clinical response rate was not significantly different between MMF and monthly CYC in proliferative lupus nephritis.10 According to the latest EULAR, ACR and Asian Lupus Nephritis Network recommendation,2-4 MMF was recommended as the initial treatment for most cases of lupus nephritis.
MMF is the prodrug of Mycophenolic acid (MPA), which is the active immunosuppressant. MPA is highly bound to serum albumin and 90% of it is excreted in the urine.11 Because of this strong serum albumin binding and renal excretion property, the serum level of MPA varies greatly. Therefore, drug level monitoring and dosage adjustment are necessary in order to maintain efficacy and to reduce toxicities.
To determine the role of drug level monitoring of MPA and its efficacy, it is necessary to find out whether a higher MPA exposure or level is correlated with a lower disease activity. In solid organ transplantations, it was shown than low MPA under curve from 0 to 12 hour post dose (AUC 0-12) is best associated with increased risk of biopsy proven acute rejection.12 However, studies have also shown that the pharmacokinetics of MPA in autoimmune disease patients is different from that in organ transplant patients. Therefore, a French study was conducted on 71 SLE patients who were on MMF for at least 10 weeks with their AUC0-12 calculated from 3 blood samples using a Bayesian estimator.13 The mean MPA AUC0-12 was found to be significantly lower in patients with active SLE than those with inactive SLE. In a multivariate analysis, MPA AUC0-12 was found to be the only parameter that was shown to be associated with SLE activity.
Another trial was done later to determine the correlation between MPA trough level and AUC0-12 as measuring MPA trough level was more convenient than estimating the AUC0-12 value in daily practice.14 38 patients with SLE and ANCA associated vasculitis who were on MMF were recruited, and it was demonstrated that there was a significant association of AUC0-12 with MPA trough levels at 12 hour using the regression analysis. The MPA trough level can thus be a relatively good estimation of MPA exposure. The second part of this study also demonstrated that higher MPA trough levels were associated with lesser disease flares in SLE and ANCA associated vasculitis. Remission can be maintained in patients whose trough levels were 3.5 mg/l or more, whereas having a trough level 4.5 mg/l or more can well discriminate patients with and without MPA related adverse effects. Therefore, it was proposed that most favorable results were obtained with MPA trough levels between 3.5-4.5 mg/l.
The monitoring of MPA trough level or exposure (AUC) is useful in improving response rates in lupus nephritis by preventing the chance of inadequate exposure while at the same time reducing unnecessary toxicities in patients exposed to high drug level. This is particularly important in Asian patients as 3 gram/day is usually not well tolerated and hence, leading to higher infection risk and mortality. The monitoring of drug level can aid physicians to identify patients with unduly high exposure in which dosage reduction can be made earlier.
Calcinuerin inhibitors including Tacrolimus (TAC) and Cyclosporine A (CsA) have been used widely in organ transplantation. TAC binds to FK 506 binding protein 12 and CsA binds to cyclophilin, and both of them in turn inhibit calcineurin and thereby, inhibiting T cell activation. Recent studies have shown that TAC was more favorable than CsA in terms of adverse effects with a lower incidence of hyperlipidemia, hypertension, gingival hyperplasia and hirsutism.15
TAC has been found to be an alternative regime for lupus nephritis. An open pilot study done in 2003 has showed that TAC together with steroid could achieve 67% of complete response and 22% partial response in 9 patients with diffuse proliferative glomerulonephritis after 6 months of therapy.16 A larger randomized controlled trial recently published demonstrated that TAC was non inferior to MMF for the induction therapy for active proliferative lupus nephritis.17 Since TAC is well known to have a narrow therapeutic index, drug level monitoring is, thus, crucial.
In the first open labeled pilot study, the mean whole blood TAC level in complete, partial and no response for lupus nephritis were 5.9+/-2.5, 11.7 +/-4.9 and 7.2ng ng/ml16. Unlike HCQ and MMF, no definite correlation was found between efficacy and trough level of TAC. As this study involved 9 patients only, it was suggested that these observations should be confirmed in a larger cohort of patients. Nevertheless, it was suggested that monitoring of TAC level was essential in order to ensure drug compliance and to reduce incidence of drug related adverse effects. In the subsequent randomized trial, a larger cohort of 150 SLE patients was recruited, however, as with the first pilot study, no relationship could be observed between the TAC level and drug efficacy.17
Therefore, up to now, no correlation between drug level of TAC and efficacy has been demonstrated. The importance of drug level monitoring for TAC is mainly for reducing toxicities and for compliance surveillance.
5 Tumor Necrosis Factor Inhibitors (TNF-inhibitors)
According to the EULAR recommendations for the management of rheumatoid arthritis in 2013 update,18 biologics should be started after the use of conventional synthetic DMARDS if the therapeutic target (that is defined as that clinical remission or at least low disease activity cannot be achieved in 6 months) cannot be reached or in the presence of poor prognostic factors, such as positive rheumatoid factor (RF) or anti-cyclic citrullinated protein (anti-CCP) especially at high levels or with very high disease activity or in the presence of early joint damage. The TNF inhibitors including infliximab, etanercept, adalimumab, golimumab and certolizumab pegol tend to be the first biologic agents used in rheumatoid arthritis (RA). Up to now, there is no evidence and consensus that any TNF inhibitor is more effective than the other one.
TNF inhibitors are bioengineered molecules and they can be in the form of therapeutic antibodies, antibody fragments or protein constructs. As they are bioengineered molecules, they have an ability to provoke immunogenicity which is referred to as the ability of a substance to provoke an immune response. The TNF inhibitors can therefore have the potential to provoke the production of antibodies against themselves, which is known as antidrug antibodies.19 The neutralizing human antibodies produced can bind to the binding site of TNF inhibitors and inhibit them from binding to their targets which are the TNF molecules. The efficacy of TNF inhibitors will hence be reduced in the presence of these antidrug antibodies. The mechanisms involved in immunogenicity against biologics are very complex and many factors, such as patient factors, underlying disease, treatment schedule or assay methods, etc., can influence this process. Therefore, the proportion of patients who develop antidrug antibodies can vary greatly despite being put on the same dosage of TNF inhibitors for the same disease.
Many factors can lead to a low drug level, which reduces the efficacy of TNF inhibitors. These factors include poor drug compliance, inadequate response or poor drug level monitoring tools, etc. In the presence of antidrug antibodies development, would there be a relationship between the drug level and its efficacy in RA patients? The first prospective study was conducted on 272 RA patients who were given adalimumab and followed up for 156 weeks with their adalimumab blood level, adalimumab antibody level and disease activity monitored.20 It was found that patients without these antibodies had significantly higher adalimumab concentration and the presence of antidrug antibodies could substantially influence the serum adalimumab level. Patients with the presence of adalimumab antibodies and hence, a lower adalimumab level had a higher DAS28 score over time and achieved sustained minimal disease activity or sustained remission less often than patients without adalimumab antibodies. Therefore, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission in RA.
Another issue with immunogenicity is cross-reactivity. It is a common practice to switch to another TNF inhibitor if one is not responsive. A cohort study involving more than 200 RA patients treated with adalimumb showed that patients who had switched from previous use of infliximab to adalimumab developed anti-adalimumab antibodies more often than those who were TNF inhibitors naïve, demonstrating the possibility of “cross-reactivity” in the development of antidrug antibodies.21 Another observation was that the improvement in DAS28 score was significantly lower in switchers without anti-infliximab antibodies than those who were TNF inhibitors naïve, indicating that the failure of TNF inhibitors could not be explained entirely by immunogenicity and could be due to refractory to the drug mechanism itself.
There are many unknown factors leading to the failure of TNF inhibitors, the presence of antidrug antibodies is just one of them. When a TNF inhibitor fails, the options would include switching to another TNF inhibitor therapy, switching to another class of drug or intensifying therapy. Currently, there is no solid evidence based recommendations to guide the decision. However, monitoring drug level and immunogenicity testing after failure of TNF inhibitor therapy can help us to make the clinical decision. If drug level is sub-therapeutic and in the absence of antidrug antibodies, better drug compliance may be enhanced; if the level is sub-therapeutic and in the presence of antidrug antibodies, then the lack of efficacy may be due to the antidrug antibodies which can substantially lower the drug level and switching to another TNF inhibitor or another class of biologic may be helpful. On the other hand, if the drug level is in the therapeutic range without the presence of antidrug antibodies, the reason for failure may be due to a failure of mechanism and switching to a non-TNF biologic may be employed. However, in the context of optimal drug level with the presence of antidrug antibodies, the physician may stay on the current TNF inhibitor and monitor the drug level until there is lowering of clinical efficacy with low drug level and thereafter, may consider switching to another TNF inhibitor or to a non TNF biologic.19 Therefore, checking the drug level and the presence of antidrug antibody level can guide one’s decision when one TNF inhibitor fails.
There are limitations regarding the use of therapeutic drug monitoring and therefore, it is still not employed routinely in our daily practice. In Hong Kong, tests for monitoring rheumatic drugs are not available. Furthermore, the therapeutic window of each drug has yet to be confirmed by larger clinical trials in order to define a universally accepted window for each rheumatic drug.
Therapeutic drug monitoring may be helpful in enhancing drug efficacy and in reducing toxicities. It can also allow the detection of drug non-adherence. There is a trend that the drug level of Hydroxychloroquine, Mycophenolate Mofetil and TNF inhibitors correlate with disease activity, whereas no such relationship has been found with Tacrolimus. However, more data is needed to support the use of therapeutic drug monitoring in improving drug efficacy and minimizing toxicities in rheumatic disease. Also, more studies are needed for the establishment of optimal therapeutic target and guidelines on level monitoring together with reliable drug monitoring assays are required.
Tang C. Godfrey T. & Stawell R. (2012). Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects.Intern Med J. 42(9) 968-978.
Bertsias G.K. Tektonidou M. Amoura Z. Aringer M. Bajema I. Berden J.H. et al. (2012). European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. EULAR/ERA-EDTA recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 71 1771-1782.
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Bertsias, G.K., Tektonidou, M., Amoura, Z., Aringer, M., Bajema, I., Berden, J.H., et al. (2012). European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association. EULAR/ERA-EDTA recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis., 71, 1771-1782.)| false 10.1136/annrheumdis-2012-201940
Mok C.C. Yap D.Y. Navarra S.V. Liu Z.H. Zhao M.H. Lu L. et al. (2014). Asian Lupus Nephritis Network (ALNN). Overview of lupus nephritis management guidelines and perspective from Asia. Nephrology (Carlton) 19 11-20.
Hahn B.H. et al. (2016). American College of Rheumatology Guidelines for Screening Case Definition Treatment and Management of Lupus Nephritis. Arthritis care & research 64(6) 797–808. PMC. Web. 1 Mar. 2016.
The Canadian Hydroxychloroquine Study group. (1991). A randomized study of the effect of withdrawing hydroxylchloroquine sulfate in systemic lupus erythematosus. N Engl J Med 324 150-154.
Ronald B. Melles M.D. Michael F. Marmor M.D. (2014). The Risk of Toxic Retinopathy in Patients on long term Hydroxychlorouine Therapy. JAMA Ophthalmol. 132(12) 1453-1460.
Mok C.C. Penn H.J. Chan K.L. Tse S.M. Langman L.J. & Jannetto P.J. (2016). Arthritis Care Res (Hoboken) 68(9) 1295-1302. .
Costedoat-Chalumeau N. Amoura Z. Hulot J.S. Hammoud H.A. Aymard G. Cacoub P. et al. (2006). Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 54 3284-3290.
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Costedoat-Chalumeau, N., Amoura, Z., Hulot, J.S., Hammoud, H.A., Aymard, G., Cacoub, P., et al. (2006). Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum., 54, 3284-3290.)| false 10.1002/art.22156
Costedoat-Chalumeau N. Galicier L. Aumaître O. Francčs C. Le Guern V. Lioté F. et al. (2013). Group PLUS. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicenter controlled trial (PLUS Study). Ann Rheum Dis. 72 1786-1792.
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Costedoat-Chalumeau, N., Galicier, L., Aumaître, O., Francčs, C., Le Guern, V., Lioté, F., et al. (2013). Group PLUS. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicenter controlled trial (PLUS Study). Ann Rheum Dis., 72, 1786-1792.)| false 10.1136/annrheumdis-2012-202322
Appel G.B. Contreras G. Dooley M.A. et al. (2009). Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 20(5) 1103-1112.
Mok C.C. (2015): Mycophenolate Mofetil for lupus nephritis: an update. Expert Review of Clinical Immunology 11(12).
Arns W. Cibrik D.M. Walker R.G. Mourad G. Budde K. Mueller E.A. et al. (2006). Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature. Transplantation 82 1004-1012.
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Arns, W., Cibrik, D.M., Walker, R.G., Mourad, G., Budde, K., Mueller, E.A., et al. (2006). Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature. Transplantation, 82, 1004-1012.)| false 10.1097/01.tp.0000232697.38021.9a
Zahr N. Arnaud L. Marquet P. et al. (2010). Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. 62 2047-2054.
Neumann I. Fuhrmann H. Fang I.F. et al. (2008).Association between mycophenolic acid12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil. Nephrol Dial Transplant. 23 3514-3520.
Penniga L. Moller C.H. Gustafsson F. et al. (2010). Tarolimus versus cyclosporine as primary immunosuppression after heart transplantation: systemic review with meta-analyses and trial sequential analyses of randomized trials. Eur J Clin Pharmacol. 66 1177-1187.
- Export Citation
Penniga, L., Moller, C.H., Gustafsson, F., et al. (2010). Tarolimus versus cyclosporine as primary immunosuppression after heart transplantation: systemic review with meta-analyses and trial sequential analyses of randomized trials. Eur J Clin Pharmacol., 66, 1177-1187.)| false 10.1007/s00228-010-0902-6
Mok C.C. Tong K.H. To C.H. Siu Y.P. & Au T.C. (2005). Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labeled pilot study. Kidney Int. 68(2) 813-817.
Mok C.C. Ying K.Y. Yim C.W. Siu Y.P. Tong K.H. To C.H. & Ng W.L. (2016). Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomized controlled trial and long-term follow-up. Ann Rheum Dis. 75(1) 30-36. . Epub 2014 Dec 30.
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Mok, C.C., Ying, K.Y., Yim, C.W., Siu, Y.P., Tong, K.H., To, C.H. & Ng, W.L. (2016). Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomized controlled trial and long-term follow-up. Ann Rheum Dis., 75(1), 30-36.)| false 10.1136/annrheumdis-2014-206456. Epub 2014 Dec 30.
Smolen J.S. Landewé R. & Breedveld F.C. (2013). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis.
Mok C.C. Tsai W.C. Chen D.Y. Wei J.C.C. (2016). Immunogenicity of anti-TNF biologic agents in the treatment of rheumatoid arthritis. Expert Opinion on Biological Therapy 16(2).
Bartelds G.M. Krieckaert C.M. Nurmohamed M.T. et al. (2011). Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up. JAMA 305(14) 1460-1468.
Bartelds G.M. Wijbrandts C.A. Nurmohamed M.T. et al. (2010). Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumor necrosis factor naďve patients: a cohort study. Ann Rheum Dis. 69 817-821.
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Bartelds, G.M., Wijbrandts, C.A., Nurmohamed, M.T., et al. (2010). Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumor necrosis factor naďve patients: a cohort study. Ann Rheum Dis., 69, 817-821.)| false 10.1136/ard.2009.112847