Eur J Clin Pharmacol DOI 10.1007/s00228-015-1862-7
REVIEW ARTICLE
Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment E. G. Quetglas 1 & A. Armuzzi 2 & S. Wigge 3 & G. Fiorino 4 & L. Barnscheid 3 & M. Froelich 1 & Silvio Danese 4
Received: 2 February 2015 / Accepted: 4 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. Results It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics. Keywords Inflammatory bowel disease . Crohn’s disease . Ulcerative colitis . Immunomodulators . Biologics
Introduction Ulcerative colitis (UC) and Crohn’s disease (CD) are the most common types of chronic inflammatory bowel diseases (IBDs). Extensive studies in the past decades have suggested that the aetiology of IBD involves environmental and genetic factors that lead to dysfunction of the epithelial barrier with consequent deregulation of the mucosal immune system and responses to gut microbiota. Clinical presentation usually starts gradually, although its beginning can be also abrupt * Silvio Danese [email protected] 1
Project Strategy & Science, Grünenthal GmbH, Aachen, Germany
2
Medicina Interna e Gastroenterologia, Complesso Integrato Columbus-Universitá Cattolica, Rome, Italy
3
Translational Science, Grünenthal GmbH, Aachen, Germany
4
Centro per la Ricerca e la Cura delle Malattie Inflammatorie Croniche Intestinali, IRCCS Humanitas, Milan, Italy
and sometimes can even appear as a fulminant disease. The clinical evolution typically involves exacerbations or spontaneous and drug-induced remissions. Microscopically, UC is restricted to the mucosa of the large bowel, while CD can affect the whole thickness of the bowel wall and can be present at any part of the gastrointestinal tract. The inflammatory origin is sustained by the cellular infiltrate in the lamina propria in combination with alterations of the composition and changes in mucosal architecture. Structural changes and several other features like mucosal lesions, mucin depletion, Paneth cell metaplasia and the fact that the muscularis mucosae may be thickened may help to establish a diagnosis of IBD or to evaluate the severity of the condition, but some other factors, over-manifested on this situation, can contribute to physician’s decision-making. These factors include hyperemia, increased vessel permeability, alterations in the production of numerous liver-derived proteins and the expression of various enzymatic polymorphisms. The advent of anti-tumour necrosis factor alpha (anti-TNF) antibodies dramatically changed the way IBD, refractory to standard medications [corticosteroids, thiopurines (azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate (MTX))], is treated by achieving steroid-free remission, improving quality of life and reducing hospitalizations and surgeries. However, primary nonresponse, intolerance and loss of response are frequent for all available anti-TNF agents. In the near future, possibly one of the trends to impact IBD therapy will be the increasing use of pharmacokinetics (PKs) to customize drug dosing for individual patients, even more when considering the multiple factors impacting on the PKs of monoclonal antibodies including the presence of antidrug antibodies, concomitant immunosuppression and low serum albumin and high C-reactive protein (CRP) concentrations [1]. The aim of this article is, by following the recommendations of the European Crohn’s and Colitis Organization
Eur J Clin Pharmacol
(ECCO) review, the most adequate drug doses and administration intervals to offer the most accurate therapeutic strategy for each individual patient. Nevertheless, the fact is that this is not always easy as most common treatments have been used in this disease for more than 20 years; on the one hand, information comes mainly from independent clinical trials with an inadequate design (retrospective, open-label, non-randomized, etc.) in most of the cases, and on the other hand, some of the assumptions made are extrapolated from other autoimmune diseases and transplantation proceedings. Also, drugs which became only recently available suffer from similar lack of adequate information as registration trials, including outcomes and efficacy data, and do not reflect day-by-day practice or provide enough information about effectiveness.
General approach to intersubject variability The regulation of metabolizing enzymes and transporters can be importantly affected, leading to an increase of the free fraction in plasma and, logically, to the amount capable for distribution to many other tissues [2, 3]. Also, during inflammatory processes, changes in the expression of transport proteins can occur, contributing to an altered availability of the different compounds. The most representative family of drug transporters is the ATP-binding cassette (ABC) transporters, which behave as exporters or effluxers, functioning as pumps that extrude toxins and drugs out of the cell [4]. Different ABC transporters, ABCB1, ABCC1–3 and ABCG2, are of particular interest: ABCB1 protein (P-glycoprotein), a prototype of ABC transporters and also the most extensively studied gene (MDR1), functions in pumping tumour suppression drugs out of the cell. ABCC1–3 family members, also known as MRP, have also been demonstrated to confer MDR to organic anion compounds. ABCG2, also known as breast cancer resistance protein (BCRP), confers resistance to most of topoisomerase I or II inhibitors such as topotecan, irinotecan and doxorubicin [5, 6]. The solute carrier (SLC) family of transporters comprehends facilitative transporters, primary and secondary active transporters, ion channels and aquaporins. These are mainly expressed on the basolateral membrane, in contraposition to ABC, mediating the uptake of substrates into cells such as hepatocytes [7, 8]. Inflammatory conditions are associated with downregulation in the expression of several of these drug-metabolizing enzymes and transporters [8–11]. At least, theoretically, when the patient improves from the condition secondary to an established treatment, the expression of the transporter and drug-metabolizing enzyme genes should be normalized; for patients who do not respond to treatment, the maintenance of an inflammatory state would not let the expression of transporters and drug-metabolizing enzymes recover, remaining
low [12, 13]. Yacyshyn et al. demonstrated differences in Pglycoprotein (Pgp)-170 expression and activity between UC and CD, but also, lack of efficacy of cyclosporine A (CsA) in CD is based in these assumptions. The authors found in UC fewer CD8+ cells in between intraepithelial lymphocytes and relatively more CD4+ cells that expressed less Pgp-170, but those in a normal basis are more sensitive to CsA; furthermore, in non-IBD controls, Pgp-170 expression was downregulated due to cytokine production coincident with inflammation [14].
Pharmacokinetic parameters and drug monitoring in IBD Because of their efficacy, safety profile and comparatively low cost, conventional therapies remain the foundation of IBD management. In recent years, besides the influence of behavioural and environmental factors, genetic differences have been estimated to account for 20–95 % variability (there are now numerous examples of cases in which interindividual differences in drug response are due to sequence variants in genes encoding drug-metabolizing enzymes, drug transporters or drug targets) in the therapeutic effects of medications [15]. To optimize therapeutic efforts and to minimize side effects, pharmacogenetic studies currently examine the relationship between single-gene polymorphisms and associated effects on the PKs and, to a much lesser extent, pharmacodynamics (PDs) of medications [15]. Aminosalicylates: mesalazine Sulfasalazine is a prodrug of the 5-aminosalicylic acid (5ASA) or mesalazine (bound through an azo group to sulfapyridine). Mesalazine itself has been administered either orally in controlled-release formulations, pH dependent and composite (pH dependent combined with controlled release) and, more recently, in a delayed-release multi-matrix system or rectally in the form of suppositories, enemas and foam. Also, other azo prodrugs (olsalazine, balsalazide) have been developed for the treatment of UC [16–18]. As stated by the last ECCO consensus, extensive ulcerative colitis of mild– moderate severity should initially be treated with oral 5ASA >2 g/day (one daily dose or divided doses), in combination with topical mesalazine [19]. Pharmacokinetics and pharmacodynamics The most relevant PK parameters of mesalazine and N-acetylmesalazine in these patients are summarized in Table 1. After oral or rectal administration, mesalazine is taken up by the epithelial cells in the small and large intestine, respectively. During absorption, after oral administration, presystemic acetylation occurs [23, 24] being both mesalazine and N-acetyl-mesalazine excreted back into
Eur J Clin Pharmacol Table 1 PK parameters of mesalazine and N-acetyl mesalazine after administration of sulfasalazine by I.V. route
Mesalazine N-Acetyl mesalazine
f (%)
tmax (h)
FP (%)
Vd (L/kg)
Cl (mL/min/kg)
t1/2β (h)
– –
– –
43 78
0.3–0.5 –
4.3–9.9a 2.9b
0.5–1 5–11
a
Systemic clearance (Cl) is dose dependent, indicating nonlinear PK [20, 21]. This is due to the fact that metabolism by acetylation in the liver and in the intestinal wall (following oral administration) to N-acetylmesalazine is saturable [22]. Similarly, t1/2β increases to 2.4 h if higher doses are given [23, 24]
b
ClR, glomerular filtration and active tubular secretion [25, 26]
the intestinal lumen [27, 28]. Transport of both compounds from the basolateral to the apical site is accomplished by Pgp [29, 30]. As previously mentioned with CsA, the disease itself might affect the topical levels of mesalazine. The relationship between the ingested dose of mesalazine and the rectal tissue drug concentration does not appear to be proportional, since oral doses from 2.4 to 4.8 g/day do not result in a twofold increase of the rectal tissue concentration [31]. When patients with recurrence after surgical resection CD were submitted to colon-ileoscopy, all postoperative patients with mucosal mesalazine concentration lower than 20 ng/mg showed recurrence at the neo-ileal site, whereas no patient had a recurrence when the concentrations of mesalazine were >100 ng/mg of tissue of the juxta-anastomotic area [32]. Similar results were found in patients with UC, in which a significant (r=−0.85) inverse correlation was observed between the mucosal concentrations of mesalazine and inflammatory signs [33]. Mesalazine is believed to act topically in the apical side of the intestine. Pharmacokinetic differences concerning different slow-release tablet formulations are explained due to quite different drug delivery characteristics, and it is obviously the reason why they are not interchangeable. In some particular formulations (acrylic resin coating), there is a delay (3–4 h) in the presence of mesalazine and Nacetyl-mesalazine in the small bowel. In contrast, after ingestion of another formulation (ethyl cellulose coated), mesalazine can be found in the duodenum and jejunum rapidly (1 h postprandially) and the intraluminal concentrations are similar at three different sampling sites and constant for about 4 h [27, 28]. If only the colon or the rectosigmoid areas are involved in IBD, rectal mesalazine (enemas or suppositories) should be the preferred formulation. Enemas distribute mesalazine within 0.5 to 2 h from the rectum and sigma up to the transverse colon and partly even to the ascending colon, as monitored through scintigraphy [34–36]. Once a steady state is reached, urinary excretion of mesalazine (0 to 11 % of dose) and that of N-acetyl-mesalazine (7 to 35 % of dose) indicate that around 15 % of the administered mesalazine is absorbed [37, 38]. The intestinal N-acetyltransferase 1 (NAT1) metabolizes mesalazine, while sulfapyridine (when administered as
sulfasalazine) is absorbed and hepatic N-acetyltransferase 2 (NAT2) transforms it into N-acetyl-sulfapyridine. While polymorphism with NAT2 enzymes has been claimed responsible of side effects, in the case of sulfapyridine [39–42], the association of the NAT1/NAT2 genotypes with efficacy or toxicity of mesalazine or sulfasalazine has not been found [43]. Clinical indications Oral 5-ASA-containing compounds are the first-line maintenance treatment in UC patients having previously responded to 5-ASA or steroids [oral (1.2 g/day) or rectal (3 g/week, in divided doses)] [19]. Rectal 5-ASA is the first-line maintenance treatment in proctitis and an alternative in left-sided colitis. A combination of oral and rectal 5-ASA can be used as a second-line maintenance treatment [19]. Although sulfasalazine is equally or slightly more effective, other oral 5-ASA preparations are preferred for toxicity reasons. There is no robust evidence to support the choice of any specific 5ASA preparation for maintenance [19]. Also, active colonic CD may be treated with sulfasalazine if only mildly active [44]. Corticosteroids Corticosteroids are used in different formulations: oral (prednisolone, prednisone and budesonide), intravenous (hydrocortisone and methylprednisolone), topical and in the form of suppositories, foam or liquid enemas (hydrocortisone, prednisolone metasulfobenzoate, betamethasone and budesonide). The main strategy in the use of corticosteroids attempts to maximize the topical effect while limiting its systemic side effects. As an example, budesonide presents a poor bioavailability due to its low absorption and extensive first-pass metabolism that provides it with a therapeutic benefit and reduced systemic toxicity in ileocaecal CD or UC [45]. In another extreme, beclometasone dipropionate has been studied in oral and enema forms in UC and is no better than 5-ASA [46, 47]. PK parameters of glucocorticoids in IBD patients are presented in Table 2.
Eur J Clin Pharmacol Table 2
PK parameters of glucocorticoids used in IBD treatment
Prednisolone (after prednisone) Prednisolone Methylprednisolone [48] Hydrocortisone Budesonide [49, 50]
f (%)
tmax (h)
FP (%)
Vd (L/kg)
Cl (mL/min/kg)
t1/2β (h)
80 78–85 – 96 10–21
1–3 1–3 0.5–1 1 –
70 60–95 62 90 88
0.4–0.7a 1.5–2.2a 1.3 0.3–0.6b 5.9 (22R) 3.4 (22S)
2.5–3.5a 2.5–3.5a 4–4.9 1.2–4.2b 27.9 (22R) 15.9 (22S)
1–3 2–4 2.5–3.5 1.8 2.7
a
Prednisolone is bound in a nonlinear fashion to plasma proteins over the therapeutic dose range, and consequently, distribution and clearance of prednisolone are dependent on its dose and plasma concentrations [51–58]
b
Indicates some nonlinearity in the disposition of hydrocortisone at higher doses [59, 60]
Pharmacokinetics and pharmacodynamics IBD patients with normal and low absorption for prednisone and prednisolone have been described. There seems to be no major difference in the PKs between active disease and remission, and most patients with IBD probably present a normal disposition of corticosteroids [61]. Both compounds are metabolically interconvertible, representing prednisolone as the pharmacologically active compound. With independency of the dose, a constant proportion of orally administered prednisolone is metabolized to prednisone. Conversion is about 26 %, although this can vary with time and dose [51, 62]. In the urine, C). Although the functional significance of metabolites produced by AO is unknown, SNP AOX1 c.3404A>G in AO was associated with lack of response to thiopurines [121].
Eur J Clin Pharmacol
Inosine triphosphatase (ITPase) catalyzes the conversion of inosine triphosphate (ITP) to inosine monophosphate (IMP). ITPase deficiency is present in 5–7 % of Caucasians, and the mutation ITPA94C>A was initially associated with allergytype adverse events of flu-like illness, rash and pancreatitis in a cohort of 62 IBD patients suffering from adverse events to AZA [122]. Because decreased TPMT enzyme activity correlates with elevated 6-TGN levels and 6-TGN is considered to be the immunosuppressant metabolite, it appears very likely that 6TGN concentration may predict drug efficacy. However, many studies failed to prove an association between clinical activity scores and 6-TGN concentration [123–125]. Dubinsky et al. were the first to define the therapeutic range of 6-TGN and to demonstrate a significantly higher response in thiopurine-treated children with 6-TGN levels above 235 pmol per 8×108 RBC [126]. A meta-analysis of 12 studies demonstrated a positive correlation between clinical response and high 6-TGN levels (threshold 230–260 pmol/8×108 RBC) with an odds ratio of 3.3 (sensitivity 62 %; specificity 72 %) [127]. Whereas low 6-TGN levels correlate with increased disease activity, 6-TGN levels above 450 seem to correlate with an increased risk for myelotoxicity [128]. Nevertheless, 6-TGN levels and thiopurine dosage correlate very poorly [129]. Furthermore, in 37 of 51 patients with thiopurine failure, AZA/6-MP dose escalation resulted in minor 6-TGN level changes, but in a significant increase of 6-MMP levels [130]. Thiopurine therapy that is solitarily 6-TGN controlled may therefore lead to severe hepatotoxicity due to a ‘hidden’ disproportionate increase in exposure to the 6-MMP (>5700 pmol/8×108 RBC) [131]. Also, in another study, 6-TGN levels above 400 pmol/8 × 108 RBC in patients lacking steroid-free clinical remission were a 100 % predictive factor of thiopurine refractoriness [132]. Based on currently available data monitoring of the 6-MP metabolites, 6-TGN and 6MMP can be recommended in the absence of clinical response after 3–4 months of therapy to differentiate the following: (1) poor adherence and under-dosing (low 6-TGN levels and low 6-MMP levels) in about 10 % of outpatients with CD; however, most CD patients (74.3 %) in long-standing remission had low self-reported adherence to AZA [133]. Hence, metabolite measurement may be useful when drug non-adherence is suspected but denied by the patient. Another subgroup would be those underdosed patients with subtherapeutic levels of both metabolites that may benefit from dosage escalation; (2) pharmocogenetic thiopurine resistance and increased likelihood for hepatotoxicity (low 6-TGN levels and high 6-MMP levels); and (3) thiopurine-refractory disease (high 6-TGN levels and high 6-MMP levels) [134]. Although this algorithm has not been completely confirmed it can be considered beneficial. In any case, the predictive value of 230–260 pmol/8× 108 RBC must be evaluated with caution due to its poor sensitivity. This has been observed by comparing corticosteroid-
free clinical remission patients with patients who did not respond favourably (steroid dependency, additional medical or surgical treatment) or experience adverse events during thiopurine treatment [135]. IBD is characterized by a relapsing and remitting course, contributing to high placebo response rates in clinical trials. Distinguishing a therapeutic beneficial response due to therapy or due to a natural course is difficult, whatever the metabolite levels may be. As pharmacodynamics and pharmacokinetics are not directly associated, it is unsurprising that the clinical assessment of outcome is not necessarily related to 6-TGN concentrations. On the other hand, other methodological issues have to be highlighted like low specificity of 6TGN metabolite measurement, chemical stability of 6-TGN that is limited and influenced by storage temperature and 6TGN measured in red blood cells, which are a surrogate for the actual target cells—the leukocytes. In conclusion, thiopurine metabolites have a limited value in predicting response when determined routinely in all thiopurine-using patients but remain valuable in case of refractory disease or in counteracting adverse events [136]. In the clinical setting, the most established routine practice is the biweekly measurement of full blood count and liver function tests within the first 3 months of therapy and a measurement every 3 months thereafter is a common monitoring scheme, although liver function tests may not be required that frequently [137]. Although weekly measurements of serum amylase within the first 8 weeks of treatment have been proposed as useful in preventing the clinical development of drug-induced pancreatitis (suggested by a retrospective study), there is no agreement in the scientific community [138]. Along with the better understanding of the pharmacogenomics of thiopurines has come the opportunity for deliberate manipulation of metabolism by the addition of concomitant medications that optimize metabolic profiles in individual patients. In a small prospective study of 26 patients on stable thiopurine doses, metabolites were monitored as first 2 g and then 4 g daily of mesalamine. 6-TGN levels rose in a dose-dependent manner in both groups, before dropping again after aminosalicylates were stopped [139]. Up to one fifth of patients with wild-type TPMT activity prescribed with AZA or 6-MP demonstrate a skewed drug metabolism in which 6MP is preferentially methylated to yield 6-MMP. Coprescription of allopurinol with low-dose AZA/6-MP (25– 33 %) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites, thereby reducing drug toxicity and recapturing treatment response; however, the biochemical mechanism remains unclear. Inhibition of TPMT by allopurinol would explain these results; however, both in vitro and in vivo studies have shown lack of inhibition of erythrocyte and human liver cytosolic TPMT activity following the addition of both allopurinol and its active metabolite
Eur J Clin Pharmacol
oxypurinol (alloxanthine). A recent prospective study in patients with IBD has demonstrated a decrease in XO activity, an increase in HGPRT and a rise in plasma 6-TGN levels, but there is a reduction in 6-MMP ribonucleotides following treatment with AZA/6-MP and allopurinol [140–143]. The increase of HGPRT and the decrease of XO activities may explain at least, in part, the observed changes in thiopurine metabolite concentrations. Clinical indications The ECCO recommendations for thiopurines use in UC and CD patients are highlighted in Tables 3 and 4. MTX The folic acid antagonist MTX is an immunomodulator used in IBD patients, mainly CD, who have failed treatment or are intolerant to thiopurines. Since folic acid is an essential component in the synthesis of DNA precursors such as purines and thymidylate, the inhibition of dihydrofolate reductase (DHFR) by MTX results in an immunosuppressive effect. Pharmacokinetics and pharmacodynamics After intramuscular or subcutaneous administration, MTX undergoes hepatic and intracellular metabolism, first by hepatic aldehyde oxidase, producing the major metabolite 7-hydroxyMTX (7-OH-MTX). Not as potent as MTX, 7-OH-MTX is less soluble than MTX and its concentrations exceed that of MTX, penetrating into the cells where it can be polyglutamated, making the metabolite less toxic than the parent compound [144, 145]. Intracellular MTX polyglutamate is Table 3 ECCO recommendations on the use of thiopurines in UC [19]
synthesized by folylpolyglutamate synthase and is an inhibitor of DHFR as potent as MTX [146]. These derivatives remain in tissues for extended periods of time, allowing administration of the drug once weekly [147]. The intracellular accumulation reaches a steady-state level after approximately 6 weeks, whereas MTX starts to become clinically effective 2–3 months after initiating the once-weekly administration [148]. Intramuscular MTX 25 mg once a week has been proven to be effective in patients with corticosteroid-refractory CD, and lower doses of up to 15 mg have shown to be well tolerated for maintenance of remission [149, 150]. Controlled trials of oral MTX 12.5 and 15 mg/week have been negative, and this is the reason why it is usually administered subcutaneously or intramuscularly to patients with IBD [151]. After a low dose of oral MTX, the drug is rapidly absorbed and Cmax values are similar in patients with CD, UC and RA [152]. MTX absorption is apparently dose dependent, since low doses of MTX (
REVIEW ARTICLE
Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment E. G. Quetglas 1 & A. Armuzzi 2 & S. Wigge 3 & G. Fiorino 4 & L. Barnscheid 3 & M. Froelich 1 & Silvio Danese 4
Received: 2 February 2015 / Accepted: 4 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Background The following review is a compilation of the recent advances and knowledge on the behaviour of the most frequently used compounds to treat inflammatory bowel disease in an organism. Results It considers clinical aspects of each entity and the pharmacokinetic/pharmacodynamic relationship supported by the use of plasma monitoring, tissue concentrations, and certain aspects derived from pharmacogenetics. Keywords Inflammatory bowel disease . Crohn’s disease . Ulcerative colitis . Immunomodulators . Biologics
Introduction Ulcerative colitis (UC) and Crohn’s disease (CD) are the most common types of chronic inflammatory bowel diseases (IBDs). Extensive studies in the past decades have suggested that the aetiology of IBD involves environmental and genetic factors that lead to dysfunction of the epithelial barrier with consequent deregulation of the mucosal immune system and responses to gut microbiota. Clinical presentation usually starts gradually, although its beginning can be also abrupt * Silvio Danese [email protected] 1
Project Strategy & Science, Grünenthal GmbH, Aachen, Germany
2
Medicina Interna e Gastroenterologia, Complesso Integrato Columbus-Universitá Cattolica, Rome, Italy
3
Translational Science, Grünenthal GmbH, Aachen, Germany
4
Centro per la Ricerca e la Cura delle Malattie Inflammatorie Croniche Intestinali, IRCCS Humanitas, Milan, Italy
and sometimes can even appear as a fulminant disease. The clinical evolution typically involves exacerbations or spontaneous and drug-induced remissions. Microscopically, UC is restricted to the mucosa of the large bowel, while CD can affect the whole thickness of the bowel wall and can be present at any part of the gastrointestinal tract. The inflammatory origin is sustained by the cellular infiltrate in the lamina propria in combination with alterations of the composition and changes in mucosal architecture. Structural changes and several other features like mucosal lesions, mucin depletion, Paneth cell metaplasia and the fact that the muscularis mucosae may be thickened may help to establish a diagnosis of IBD or to evaluate the severity of the condition, but some other factors, over-manifested on this situation, can contribute to physician’s decision-making. These factors include hyperemia, increased vessel permeability, alterations in the production of numerous liver-derived proteins and the expression of various enzymatic polymorphisms. The advent of anti-tumour necrosis factor alpha (anti-TNF) antibodies dramatically changed the way IBD, refractory to standard medications [corticosteroids, thiopurines (azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate (MTX))], is treated by achieving steroid-free remission, improving quality of life and reducing hospitalizations and surgeries. However, primary nonresponse, intolerance and loss of response are frequent for all available anti-TNF agents. In the near future, possibly one of the trends to impact IBD therapy will be the increasing use of pharmacokinetics (PKs) to customize drug dosing for individual patients, even more when considering the multiple factors impacting on the PKs of monoclonal antibodies including the presence of antidrug antibodies, concomitant immunosuppression and low serum albumin and high C-reactive protein (CRP) concentrations [1]. The aim of this article is, by following the recommendations of the European Crohn’s and Colitis Organization
Eur J Clin Pharmacol
(ECCO) review, the most adequate drug doses and administration intervals to offer the most accurate therapeutic strategy for each individual patient. Nevertheless, the fact is that this is not always easy as most common treatments have been used in this disease for more than 20 years; on the one hand, information comes mainly from independent clinical trials with an inadequate design (retrospective, open-label, non-randomized, etc.) in most of the cases, and on the other hand, some of the assumptions made are extrapolated from other autoimmune diseases and transplantation proceedings. Also, drugs which became only recently available suffer from similar lack of adequate information as registration trials, including outcomes and efficacy data, and do not reflect day-by-day practice or provide enough information about effectiveness.
General approach to intersubject variability The regulation of metabolizing enzymes and transporters can be importantly affected, leading to an increase of the free fraction in plasma and, logically, to the amount capable for distribution to many other tissues [2, 3]. Also, during inflammatory processes, changes in the expression of transport proteins can occur, contributing to an altered availability of the different compounds. The most representative family of drug transporters is the ATP-binding cassette (ABC) transporters, which behave as exporters or effluxers, functioning as pumps that extrude toxins and drugs out of the cell [4]. Different ABC transporters, ABCB1, ABCC1–3 and ABCG2, are of particular interest: ABCB1 protein (P-glycoprotein), a prototype of ABC transporters and also the most extensively studied gene (MDR1), functions in pumping tumour suppression drugs out of the cell. ABCC1–3 family members, also known as MRP, have also been demonstrated to confer MDR to organic anion compounds. ABCG2, also known as breast cancer resistance protein (BCRP), confers resistance to most of topoisomerase I or II inhibitors such as topotecan, irinotecan and doxorubicin [5, 6]. The solute carrier (SLC) family of transporters comprehends facilitative transporters, primary and secondary active transporters, ion channels and aquaporins. These are mainly expressed on the basolateral membrane, in contraposition to ABC, mediating the uptake of substrates into cells such as hepatocytes [7, 8]. Inflammatory conditions are associated with downregulation in the expression of several of these drug-metabolizing enzymes and transporters [8–11]. At least, theoretically, when the patient improves from the condition secondary to an established treatment, the expression of the transporter and drug-metabolizing enzyme genes should be normalized; for patients who do not respond to treatment, the maintenance of an inflammatory state would not let the expression of transporters and drug-metabolizing enzymes recover, remaining
low [12, 13]. Yacyshyn et al. demonstrated differences in Pglycoprotein (Pgp)-170 expression and activity between UC and CD, but also, lack of efficacy of cyclosporine A (CsA) in CD is based in these assumptions. The authors found in UC fewer CD8+ cells in between intraepithelial lymphocytes and relatively more CD4+ cells that expressed less Pgp-170, but those in a normal basis are more sensitive to CsA; furthermore, in non-IBD controls, Pgp-170 expression was downregulated due to cytokine production coincident with inflammation [14].
Pharmacokinetic parameters and drug monitoring in IBD Because of their efficacy, safety profile and comparatively low cost, conventional therapies remain the foundation of IBD management. In recent years, besides the influence of behavioural and environmental factors, genetic differences have been estimated to account for 20–95 % variability (there are now numerous examples of cases in which interindividual differences in drug response are due to sequence variants in genes encoding drug-metabolizing enzymes, drug transporters or drug targets) in the therapeutic effects of medications [15]. To optimize therapeutic efforts and to minimize side effects, pharmacogenetic studies currently examine the relationship between single-gene polymorphisms and associated effects on the PKs and, to a much lesser extent, pharmacodynamics (PDs) of medications [15]. Aminosalicylates: mesalazine Sulfasalazine is a prodrug of the 5-aminosalicylic acid (5ASA) or mesalazine (bound through an azo group to sulfapyridine). Mesalazine itself has been administered either orally in controlled-release formulations, pH dependent and composite (pH dependent combined with controlled release) and, more recently, in a delayed-release multi-matrix system or rectally in the form of suppositories, enemas and foam. Also, other azo prodrugs (olsalazine, balsalazide) have been developed for the treatment of UC [16–18]. As stated by the last ECCO consensus, extensive ulcerative colitis of mild– moderate severity should initially be treated with oral 5ASA >2 g/day (one daily dose or divided doses), in combination with topical mesalazine [19]. Pharmacokinetics and pharmacodynamics The most relevant PK parameters of mesalazine and N-acetylmesalazine in these patients are summarized in Table 1. After oral or rectal administration, mesalazine is taken up by the epithelial cells in the small and large intestine, respectively. During absorption, after oral administration, presystemic acetylation occurs [23, 24] being both mesalazine and N-acetyl-mesalazine excreted back into
Eur J Clin Pharmacol Table 1 PK parameters of mesalazine and N-acetyl mesalazine after administration of sulfasalazine by I.V. route
Mesalazine N-Acetyl mesalazine
f (%)
tmax (h)
FP (%)
Vd (L/kg)
Cl (mL/min/kg)
t1/2β (h)
– –
– –
43 78
0.3–0.5 –
4.3–9.9a 2.9b
0.5–1 5–11
a
Systemic clearance (Cl) is dose dependent, indicating nonlinear PK [20, 21]. This is due to the fact that metabolism by acetylation in the liver and in the intestinal wall (following oral administration) to N-acetylmesalazine is saturable [22]. Similarly, t1/2β increases to 2.4 h if higher doses are given [23, 24]
b
ClR, glomerular filtration and active tubular secretion [25, 26]
the intestinal lumen [27, 28]. Transport of both compounds from the basolateral to the apical site is accomplished by Pgp [29, 30]. As previously mentioned with CsA, the disease itself might affect the topical levels of mesalazine. The relationship between the ingested dose of mesalazine and the rectal tissue drug concentration does not appear to be proportional, since oral doses from 2.4 to 4.8 g/day do not result in a twofold increase of the rectal tissue concentration [31]. When patients with recurrence after surgical resection CD were submitted to colon-ileoscopy, all postoperative patients with mucosal mesalazine concentration lower than 20 ng/mg showed recurrence at the neo-ileal site, whereas no patient had a recurrence when the concentrations of mesalazine were >100 ng/mg of tissue of the juxta-anastomotic area [32]. Similar results were found in patients with UC, in which a significant (r=−0.85) inverse correlation was observed between the mucosal concentrations of mesalazine and inflammatory signs [33]. Mesalazine is believed to act topically in the apical side of the intestine. Pharmacokinetic differences concerning different slow-release tablet formulations are explained due to quite different drug delivery characteristics, and it is obviously the reason why they are not interchangeable. In some particular formulations (acrylic resin coating), there is a delay (3–4 h) in the presence of mesalazine and Nacetyl-mesalazine in the small bowel. In contrast, after ingestion of another formulation (ethyl cellulose coated), mesalazine can be found in the duodenum and jejunum rapidly (1 h postprandially) and the intraluminal concentrations are similar at three different sampling sites and constant for about 4 h [27, 28]. If only the colon or the rectosigmoid areas are involved in IBD, rectal mesalazine (enemas or suppositories) should be the preferred formulation. Enemas distribute mesalazine within 0.5 to 2 h from the rectum and sigma up to the transverse colon and partly even to the ascending colon, as monitored through scintigraphy [34–36]. Once a steady state is reached, urinary excretion of mesalazine (0 to 11 % of dose) and that of N-acetyl-mesalazine (7 to 35 % of dose) indicate that around 15 % of the administered mesalazine is absorbed [37, 38]. The intestinal N-acetyltransferase 1 (NAT1) metabolizes mesalazine, while sulfapyridine (when administered as
sulfasalazine) is absorbed and hepatic N-acetyltransferase 2 (NAT2) transforms it into N-acetyl-sulfapyridine. While polymorphism with NAT2 enzymes has been claimed responsible of side effects, in the case of sulfapyridine [39–42], the association of the NAT1/NAT2 genotypes with efficacy or toxicity of mesalazine or sulfasalazine has not been found [43]. Clinical indications Oral 5-ASA-containing compounds are the first-line maintenance treatment in UC patients having previously responded to 5-ASA or steroids [oral (1.2 g/day) or rectal (3 g/week, in divided doses)] [19]. Rectal 5-ASA is the first-line maintenance treatment in proctitis and an alternative in left-sided colitis. A combination of oral and rectal 5-ASA can be used as a second-line maintenance treatment [19]. Although sulfasalazine is equally or slightly more effective, other oral 5-ASA preparations are preferred for toxicity reasons. There is no robust evidence to support the choice of any specific 5ASA preparation for maintenance [19]. Also, active colonic CD may be treated with sulfasalazine if only mildly active [44]. Corticosteroids Corticosteroids are used in different formulations: oral (prednisolone, prednisone and budesonide), intravenous (hydrocortisone and methylprednisolone), topical and in the form of suppositories, foam or liquid enemas (hydrocortisone, prednisolone metasulfobenzoate, betamethasone and budesonide). The main strategy in the use of corticosteroids attempts to maximize the topical effect while limiting its systemic side effects. As an example, budesonide presents a poor bioavailability due to its low absorption and extensive first-pass metabolism that provides it with a therapeutic benefit and reduced systemic toxicity in ileocaecal CD or UC [45]. In another extreme, beclometasone dipropionate has been studied in oral and enema forms in UC and is no better than 5-ASA [46, 47]. PK parameters of glucocorticoids in IBD patients are presented in Table 2.
Eur J Clin Pharmacol Table 2
PK parameters of glucocorticoids used in IBD treatment
Prednisolone (after prednisone) Prednisolone Methylprednisolone [48] Hydrocortisone Budesonide [49, 50]
f (%)
tmax (h)
FP (%)
Vd (L/kg)
Cl (mL/min/kg)
t1/2β (h)
80 78–85 – 96 10–21
1–3 1–3 0.5–1 1 –
70 60–95 62 90 88
0.4–0.7a 1.5–2.2a 1.3 0.3–0.6b 5.9 (22R) 3.4 (22S)
2.5–3.5a 2.5–3.5a 4–4.9 1.2–4.2b 27.9 (22R) 15.9 (22S)
1–3 2–4 2.5–3.5 1.8 2.7
a
Prednisolone is bound in a nonlinear fashion to plasma proteins over the therapeutic dose range, and consequently, distribution and clearance of prednisolone are dependent on its dose and plasma concentrations [51–58]
b
Indicates some nonlinearity in the disposition of hydrocortisone at higher doses [59, 60]
Pharmacokinetics and pharmacodynamics IBD patients with normal and low absorption for prednisone and prednisolone have been described. There seems to be no major difference in the PKs between active disease and remission, and most patients with IBD probably present a normal disposition of corticosteroids [61]. Both compounds are metabolically interconvertible, representing prednisolone as the pharmacologically active compound. With independency of the dose, a constant proportion of orally administered prednisolone is metabolized to prednisone. Conversion is about 26 %, although this can vary with time and dose [51, 62]. In the urine, C). Although the functional significance of metabolites produced by AO is unknown, SNP AOX1 c.3404A>G in AO was associated with lack of response to thiopurines [121].
Eur J Clin Pharmacol
Inosine triphosphatase (ITPase) catalyzes the conversion of inosine triphosphate (ITP) to inosine monophosphate (IMP). ITPase deficiency is present in 5–7 % of Caucasians, and the mutation ITPA94C>A was initially associated with allergytype adverse events of flu-like illness, rash and pancreatitis in a cohort of 62 IBD patients suffering from adverse events to AZA [122]. Because decreased TPMT enzyme activity correlates with elevated 6-TGN levels and 6-TGN is considered to be the immunosuppressant metabolite, it appears very likely that 6TGN concentration may predict drug efficacy. However, many studies failed to prove an association between clinical activity scores and 6-TGN concentration [123–125]. Dubinsky et al. were the first to define the therapeutic range of 6-TGN and to demonstrate a significantly higher response in thiopurine-treated children with 6-TGN levels above 235 pmol per 8×108 RBC [126]. A meta-analysis of 12 studies demonstrated a positive correlation between clinical response and high 6-TGN levels (threshold 230–260 pmol/8×108 RBC) with an odds ratio of 3.3 (sensitivity 62 %; specificity 72 %) [127]. Whereas low 6-TGN levels correlate with increased disease activity, 6-TGN levels above 450 seem to correlate with an increased risk for myelotoxicity [128]. Nevertheless, 6-TGN levels and thiopurine dosage correlate very poorly [129]. Furthermore, in 37 of 51 patients with thiopurine failure, AZA/6-MP dose escalation resulted in minor 6-TGN level changes, but in a significant increase of 6-MMP levels [130]. Thiopurine therapy that is solitarily 6-TGN controlled may therefore lead to severe hepatotoxicity due to a ‘hidden’ disproportionate increase in exposure to the 6-MMP (>5700 pmol/8×108 RBC) [131]. Also, in another study, 6-TGN levels above 400 pmol/8 × 108 RBC in patients lacking steroid-free clinical remission were a 100 % predictive factor of thiopurine refractoriness [132]. Based on currently available data monitoring of the 6-MP metabolites, 6-TGN and 6MMP can be recommended in the absence of clinical response after 3–4 months of therapy to differentiate the following: (1) poor adherence and under-dosing (low 6-TGN levels and low 6-MMP levels) in about 10 % of outpatients with CD; however, most CD patients (74.3 %) in long-standing remission had low self-reported adherence to AZA [133]. Hence, metabolite measurement may be useful when drug non-adherence is suspected but denied by the patient. Another subgroup would be those underdosed patients with subtherapeutic levels of both metabolites that may benefit from dosage escalation; (2) pharmocogenetic thiopurine resistance and increased likelihood for hepatotoxicity (low 6-TGN levels and high 6-MMP levels); and (3) thiopurine-refractory disease (high 6-TGN levels and high 6-MMP levels) [134]. Although this algorithm has not been completely confirmed it can be considered beneficial. In any case, the predictive value of 230–260 pmol/8× 108 RBC must be evaluated with caution due to its poor sensitivity. This has been observed by comparing corticosteroid-
free clinical remission patients with patients who did not respond favourably (steroid dependency, additional medical or surgical treatment) or experience adverse events during thiopurine treatment [135]. IBD is characterized by a relapsing and remitting course, contributing to high placebo response rates in clinical trials. Distinguishing a therapeutic beneficial response due to therapy or due to a natural course is difficult, whatever the metabolite levels may be. As pharmacodynamics and pharmacokinetics are not directly associated, it is unsurprising that the clinical assessment of outcome is not necessarily related to 6-TGN concentrations. On the other hand, other methodological issues have to be highlighted like low specificity of 6TGN metabolite measurement, chemical stability of 6-TGN that is limited and influenced by storage temperature and 6TGN measured in red blood cells, which are a surrogate for the actual target cells—the leukocytes. In conclusion, thiopurine metabolites have a limited value in predicting response when determined routinely in all thiopurine-using patients but remain valuable in case of refractory disease or in counteracting adverse events [136]. In the clinical setting, the most established routine practice is the biweekly measurement of full blood count and liver function tests within the first 3 months of therapy and a measurement every 3 months thereafter is a common monitoring scheme, although liver function tests may not be required that frequently [137]. Although weekly measurements of serum amylase within the first 8 weeks of treatment have been proposed as useful in preventing the clinical development of drug-induced pancreatitis (suggested by a retrospective study), there is no agreement in the scientific community [138]. Along with the better understanding of the pharmacogenomics of thiopurines has come the opportunity for deliberate manipulation of metabolism by the addition of concomitant medications that optimize metabolic profiles in individual patients. In a small prospective study of 26 patients on stable thiopurine doses, metabolites were monitored as first 2 g and then 4 g daily of mesalamine. 6-TGN levels rose in a dose-dependent manner in both groups, before dropping again after aminosalicylates were stopped [139]. Up to one fifth of patients with wild-type TPMT activity prescribed with AZA or 6-MP demonstrate a skewed drug metabolism in which 6MP is preferentially methylated to yield 6-MMP. Coprescription of allopurinol with low-dose AZA/6-MP (25– 33 %) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites, thereby reducing drug toxicity and recapturing treatment response; however, the biochemical mechanism remains unclear. Inhibition of TPMT by allopurinol would explain these results; however, both in vitro and in vivo studies have shown lack of inhibition of erythrocyte and human liver cytosolic TPMT activity following the addition of both allopurinol and its active metabolite
Eur J Clin Pharmacol
oxypurinol (alloxanthine). A recent prospective study in patients with IBD has demonstrated a decrease in XO activity, an increase in HGPRT and a rise in plasma 6-TGN levels, but there is a reduction in 6-MMP ribonucleotides following treatment with AZA/6-MP and allopurinol [140–143]. The increase of HGPRT and the decrease of XO activities may explain at least, in part, the observed changes in thiopurine metabolite concentrations. Clinical indications The ECCO recommendations for thiopurines use in UC and CD patients are highlighted in Tables 3 and 4. MTX The folic acid antagonist MTX is an immunomodulator used in IBD patients, mainly CD, who have failed treatment or are intolerant to thiopurines. Since folic acid is an essential component in the synthesis of DNA precursors such as purines and thymidylate, the inhibition of dihydrofolate reductase (DHFR) by MTX results in an immunosuppressive effect. Pharmacokinetics and pharmacodynamics After intramuscular or subcutaneous administration, MTX undergoes hepatic and intracellular metabolism, first by hepatic aldehyde oxidase, producing the major metabolite 7-hydroxyMTX (7-OH-MTX). Not as potent as MTX, 7-OH-MTX is less soluble than MTX and its concentrations exceed that of MTX, penetrating into the cells where it can be polyglutamated, making the metabolite less toxic than the parent compound [144, 145]. Intracellular MTX polyglutamate is Table 3 ECCO recommendations on the use of thiopurines in UC [19]
synthesized by folylpolyglutamate synthase and is an inhibitor of DHFR as potent as MTX [146]. These derivatives remain in tissues for extended periods of time, allowing administration of the drug once weekly [147]. The intracellular accumulation reaches a steady-state level after approximately 6 weeks, whereas MTX starts to become clinically effective 2–3 months after initiating the once-weekly administration [148]. Intramuscular MTX 25 mg once a week has been proven to be effective in patients with corticosteroid-refractory CD, and lower doses of up to 15 mg have shown to be well tolerated for maintenance of remission [149, 150]. Controlled trials of oral MTX 12.5 and 15 mg/week have been negative, and this is the reason why it is usually administered subcutaneously or intramuscularly to patients with IBD [151]. After a low dose of oral MTX, the drug is rapidly absorbed and Cmax values are similar in patients with CD, UC and RA [152]. MTX absorption is apparently dose dependent, since low doses of MTX (
