Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn's disease or ulcerative colitis who had failed conventional therapy.

BACKGROUND: Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). AIM: To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/adalimumab therapy, compared with adalimumab monotherapy in patients with inadequate disease control on conventional therapy. METHODS: Patients with moderate to severe CD or UC from randomised, double-blind, placebo-controlled trials were analysed. Adalimumab was added to background therapy; patients were categorised as receiving adalimumab monotherapy (CD induction, n = 245, maintenance, n = 185; UC induction, n = 213, maintenance, n = 157) or combination therapy (CD induction, n = 139, maintenance, n = 139; UC induction, n = 140, maintenance, n = 100) according to baseline immunomodulator use. Efficacy was reported for the intent-to-treat populations from each study, with remission defined as CD activity index <150 for CD and Mayo score ≤2 with no subscore >1 for UC. Safety was assessed via adverse events. RESULTS: The proportions of patients achieving remission were similar for adalimumab monotherapy and immunomodulator combination therapy in all studies. Median adalimumab concentrations at week 4 or 8 were numerically but not significantly higher with adalimumab combination therapy vs. monotherapy in the CD and UC studies respectively. Incidence and rate of adverse events was similar for adalimumab monotherapy and combination therapy. CONCLUSIONS: Post hoc analysis of six randomised, controlled trials demonstrated no efficacy benefits with immunomodulator/adalimumab combination therapy, compared with adalimumab monotherapy in CD and UC patients with inadequate disease control on conventional therapy; the safety of the two treatment approaches was comparable.

Randomised clinical study: discrepancies between patient-reported outcomes and endoscopic appearance in moderate to severe ulcerative colitis.

BACKGROUND: Associations between patient-reported outcomes and mucosal healing have not been established in ulcerative colitis (UC). AIM: To evaluate relationships of rectal bleeding and stool frequency with mucosal healing and quality of life (QoL) in patients with UC in two Phase 3 studies (ULTRA 1 and 2). METHODS: Associations of patient-reported rectal bleeding and stool frequency subscores with mucosal healing (Mayo endoscopy subscore = 0 or 0/1) and QoL [inflammatory bowel disease questionnaire (IBDQ)] were assessed in adalimumab-randomised patients (160/80 mg at Weeks 0/2 followed by 40 mg biweekly or weekly) at Weeks 8 (n = 433) and 52 (n = 299), and in patients with mucosal healing [endoscopy subscore = 0 (n = 17); 0/1 (n = 52)] at Weeks 8 and 52. RESULTS: At Week 8, the positive predictive values (PPVs) of rectal bleeding subscore = 0, stool frequency subscore = 0 or both scores = 0 for endoscopy subscore = 0/1 were 69%, 84% and 90% respectively; all proportions increased at Week 52. Equivalent PPVs for these subscores in patients with endoscopy subscore = 0 were 26%, 37% and 46% respectively. Among patients with endoscopy subscore = 0 at Week 8, 87% reported no rectal bleeding, while only 29% reported normal stool frequency; these proportions had increased to 94% and 41% respectively, at Week 52. Among patients with mucosal healing, IBDQ scores trended highest for patients with both rectal bleeding and stool frequency subscores = 0. CONCLUSIONS: Absence of rectal bleeding and normal stool frequency are often predictive of mucosal healing and QoL, but complete normalisation of stool frequency is encountered rarely in patients with mucosal healing.

Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long-term development outcome of children exposed to maternal thiopurine therapy are very limited. AIM: To assess the long-term effects of in utero exposure to thiopurines during pregnancy on infant health status. METHODS: A prospective multicentre follow-up study was performed in children exposed intrauterine to maternal thiopurine therapy. Physical, cognitive and social aspects of infant health status were assessed with the 43-item TNO-AZL Preschool Children Quality of Life Questionnaire (TAPQOL). Furthermore, information on visits to general practitioner and medical specialists, and physician's advice regarding lactation was evaluated. Data were compared with normative data from a control group consisting of 340 children. RESULTS: Thirty children were included in this study [median 3.8 years (IQR 2.9-4.7)]. No differences on global medical and psychosocial health status were found between children exposed to intrauterine thiopurines and the reference group. Exposure to intrauterine thiopurines was not associated with increased susceptibility to infection or immunodeficiency in childhood. Twenty-one of 30 children were exclusively formula-fed based on a negative advice of medical specialists directed at thiopurine use during lactation. CONCLUSIONS: Thiopurine use during pregnancy did not affect long-term development or immune function of children up to 6 years of age. Our results underscore the present notion that mothers, even those using thiopurines, should be encouraged to breastfeed their infants.

Biotransformation of 6-thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6-thioguanine.

BACKGROUND AND PURPOSE: Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients. EXPERIMENTAL APPROACH: In 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg(-1) 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. KEY RESULTS: The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 × 10(8) RBC)(-1) . Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r= 0.7, P= 0.02 and r= 0.6, P= 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r=-0.8, P= 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r=-0.7, P= 0.02). CONCLUSIONS AND IMPLICATIONS: The great variability of the AUC per mg for 6-TG observed after p.o. and i.v. administration of 6-TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6-TGN was low in all patients.

Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy.

BACKGROUND AND PURPOSE: 5-aminosalicylate (5-ASA) raises levels of 6-thioguanine nucleotides (6-TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN - 6-thioguanosine mono-, di- and triphosphate (6-TGMP, 6-TGDP, 6-TGTP) - and of 6-methylmercaptopurine ribonucleotides (6-MMPR) after 5-ASA are not known. EXPERIMENTAL APPROACH: Effects of increasing 5-ASA doses on AZA metabolites were investigated prospectively in 22 patients with inflammatory bowel disease in 4-week study periods. Patients started with 2 g 5-ASA daily, and then were increased to 4 g daily and followed by a washout period. Thiopurine doses remained unchanged throughout the entire study. Levels of 6-TGMP, 6-TGDP, 6-TGTP and 6-MMPR as well as of 5-ASA and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) were determined each study period. KEY RESULTS: Median baseline levels in 17 patients of 6-TGDP, 6-TGTP and 6-MMPR were 52, 319 and 1676 pmol per 8 x 10(8) red blood cells respectively. After co-administration of 2 g 5-ASA daily, median 6-TGDP and 6-TGTP levels increased but median 6-MMPR levels were unchanged. Increasing 5-ASA to 4 g daily did not affect median 6-TGDP and 6-TGTP levels, but median 6-MMPR levels decreased. After discontinuation of 5-ASA, both 6-TGDP and 6-TGTP levels decreased and median 6-MMPR levels increased. The 6-TGTP/(6-TGDP+6-TGTP)-ratio did not change during the study, but 6-MMPR/6-TGN ratios decreased. CONCLUSIONS AND IMPLICATIONS: Individual 6-TGN metabolites increased after addition of 5-ASA, but 6-MMPR-levels and the 6-MMPR/6-TGN ratios decreased. Further studies are needed to decide whether this pharmacokinetic interaction would result in improvement of efficacy and/or increased risk of toxicity of AZA.

Limited stability of thiopurine metabolites in blood samples: relevant in research and clinical practise.

BACKGROUND: Monitoring of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) is used to assess compliance and explain adverse reactions in IBD-patients. Correlations between dosage, metabolite concentrations and therapeutic efficacy or toxicity are contradictive. Research is complicated by analytical problems as matrices analyzed and analytical procedures vary widely. Moreover, stability of thiopurine metabolites is not well documented, yet pivotal for interpretation of analytical outcomes. Therefore, we prospectively investigated metabolite stability in blood samples under standard storage conditions. METHODS: Stability at room temperature and refrigeration (22 degrees C, 4 degrees C) was investigated during 1 week and frozen samples (-20 degrees C, -80 degrees C) were analyzed during 6 months storage. Ten patient samples were analyzed for each study period. RESULTS: Median 6-TGN concentrations on day 7 decreased significantly to 53% and 90% during storage at ambient temperature or refrigeration. Median 6-MMP concentrations on day 7 decreased significantly to 55% and 86%, respectively. Samples stored at -20 degrees C also showed significant decreases in both 6-TGN and 6-MMP in comparison with baseline values. At -80 degrees C, only 6-MMP showed a significant decrease in values compared to baseline. CONCLUSION: The stability of thiopurine metabolites is clearly a limiting factor in studies investigating utilisation of TDM and correlations with therapeutic outcome in IBD-patients. This has to be accounted for in clinical practice and (multi-center) trials investigating thiopurine drugs.

Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts.

BACKGROUND: Thiopurines have proven efficacy in long-term maintenance therapy of inflammatory bowel disease (IBD). Limited data are available with regard to factors predicting effectiveness and failure of long-term thiopurine use in IBD patients. METHODS: The data in this retrospective study are based on an 8-year intercept cohort of previous or present thiopurine-using IBD patients. Both cohorts are assessed by descriptive and statistical analysis aimed at determining thiopurine effectiveness and the variables that are predictive for failure of thiopurine therapy. RESULTS: In all, 363 IBD patients were included (60% female), 63% with Crohn's disease and 33% with ulcerative colitis. Overall, thiopurines were continued in 145/363 (40%) and discontinued in 208/363 (57%) patients. The proportion of patients still using thiopurines at 3, 6, 12, 24, and 60 months was 73%, 69%, 63%, 51%, and 42%, respectively. Patients discontinued thiopurines due to adverse events (39%), refractoriness (16%), and ongoing remission / patient's request (4%). 6-methylmercaptopurine (6-MMP) concentration and 6-MMP/6-thioguanine nucleotides (6-TGN) ratio were significant higher in the failure group. Prolonged continuation of thiopurines was associated with a decreased risk of discontinuation. CONCLUSIONS: Azathioprine and 6-mercaptopurine were considered effective in approximately 40% of IBD patients after 5 years of treatment. A quarter of the patients discontinued thiopurines within 3 months, mostly due to adverse events. A high 6-MMP concentration or 6-MMP/6-TGN ratio was associated with therapeutic failure. If thiopurine use was successfully initiated in the first months, its use was usually extended over many years, as long-term use was associated with continuation of therapy.