Lennard P. L. Gilissen

Review article: thiopurines in inflammatory bowel disease

In the past 10–20 years, knowledge of both thiopurine pharmacology and ‐pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity.

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (± 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284–452) and 2837 (CI95% 2101–3573) pmol/8 × 108 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7–92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.

6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment.

Objective 6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10–20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG. Methods Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters. Results Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 ± 828 picomol/8 × 108 red blood cells (RBC)) than with 20 mg once daily (937 ± 325 picomol/8 × 108 RBC; P = 0.001). Conclusions 6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients

Background : In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S‐methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6‐methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites.

Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

BACKGROUND AND AIMS Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235 pmol/8×10(8) erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level. METHODS Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity. RESULTS Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8×10(8) erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8×10(8) erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04). CONCLUSIONS Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response.

The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients

BACKGROUND AND AIMS A drug interaction between infliximab and azathioprine has previously been reported in Crohns disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohns disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS Crohns disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohns disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS Twelve Crohns disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS In this study in Crohns disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.

Safe 6-thioguanine therapy of a TPMT deficient Crohn's disease patient by using therapeutic drug monitoring

The immunosuppressive thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), have proven efficacy in steroid-dependant or refractory inflammatory bowel disease (IBD). In case of TPMT deficiency serious myelosuppression may occur. 6-thioguanine (6-TG), has been suggested in case of AZA and 6-MP resistant or intolerant patients. Our case demonstrates that very low dose 6-TG under close clinical surveillance and frequent therapeutic drug monitoring, may be a rescue drug for IBD-patients with low or without functional TPMT activity.

Antibacterial gauzes are effective in preventing infections after percutaneous endoscopic gastrostomy placement: a retrospective analysis.

Objectives The most common complication after percutaneous endoscopic gastrostomy (PEG) placement is peristomal wound infection (up to 40% without antibiotic prophylaxis). Single-dose parenteral prophylactic antibiotics as advised by current guidelines decrease the infection rate to 9–15%. We assume a prolonged effect of local antibiotic treatment with antibacterial gauzes. This study is the first to describe the effect of antibacterial gauzes in preventing infections in PEG without the use of antibiotics. Methods A retrospective data analysis was carried out of all patients with PEG insertion between January 2009 and October 2014 in the Catharina Hospital Eindhoven. Data include placement and the period of the first 2 weeks after PEG placement, and long-term follow-up. All patients received a locally applied antibacterial gauze polyhexamethylene biguanide immediately following PEG insertion for 3 days. No other antibiotics were administered. The main outcomes were wound infection, peritonitis, and necrotizing fasciitis; secondary outcomes included other complications. Results A total of 331 patients with only antibacterial gauzes were analyzed. The total number of infections 2 weeks after PEG insertion was 9.4%, including 8.2% minor and 1.2% major infections (peritonitis). No wound infection-related mortality or bacterial resistance was found. Costs are five times lower than antibiotics, and gauzes are more practical and patient friendly for use. Conclusion Retrospectively, antibacterial gauzes are at least comparable with literature data on parenteral antibiotics in preventing peristomal wound infection after PEG placement, with an infection rate of 9.4%. Rates of other complications found in this study were comparable with current literature data.

Double-Balloon Endoscopy in Overt and Occult Small Bowel Bleeding: Results, Complications, and Correlation with Prior Videocapsule Endoscopy in a Tertiary Referral Center

Background/Aims Videocapsule endoscopy (VCE) and double-balloon endoscopy (DBE) allow deep exploration in patients with suspected small bowel pathology. VCE is often performed as an initial small bowel examination to explore whether an intervention by DBE is indicated and to determine insertion route. The study aim was to evaluate the correlation between DBE and VCE in patients with obscure or overt bleeding or anemia, as well as intervention frequency, and complications. Methods Retrospective observational study. Results DBE procedures (n=205) showed small bowel lesions in 64% cases. Antegrade DBE showed positive results in 79% cases, mostly angiodysplasias (63%). Retrograde DBE showed positive results in 22% cases. An intervention was performed in 64% of DBE procedures. The major complication rate was 0.5%, which was one case of perforation. Pancreatitis did not occur. The overall diagnostic agreement was 66% among the 134 DBEs with preceded VCE. Conclusions In cases of overt or occult bleeding or anemia, DBE was positive in 64%, with only a few complications. Positive correlation was 66% among initially performed VCEs and DBEs. Owing to the time-consuming and invasive character of DBE, performing VCE before DBE might still be clinically relevant.

Double-Balloon Endoscopy after Incomplete Colonoscopy and Its Comparison with Computed Tomography Colonography

Background/Aims Because of the national screening program for colorectal carcinoma in The Netherlands, the number of colonoscopies has increased. In case of incomplete colonoscopy, computed tomography colonography (CTC) and double-balloon colonoscopy (DBc) are alternative options. This study evaluated cecal intubation rate and pathology detection rate in the previously unexplored part of the colon, complication rate of DBc, and CTC results after incomplete colonoscopy. Methods Retrospective observational study in a tertiary referral hospital regarding DBc and CTC reports from cases with incomplete colonoscopy. Results Sixty-three DBcs were performed after incomplete colonoscopy. Cecal intubation rate was 95%. Detection rate was 58% (5% carcinoma and 3% high-grade dysplastic adenoma). CTC preceded 54% of DBcs and 62% of CTC findings were confirmed. In 16%, a biopsy was taken, and in 60%, an intervention (mostly polypectomy) was performed. One major complication (1.5%) occurred, i.e., arterial bleeding due to polypectomy necessitating right hemicolectomy. CTC (n=213) showed a possible lesion in 35%, and could be confirmed by follow-up endoscopy or surgery in 65%. Conclusions DBc is effective and safe for completion of colon inspection in incomplete colonoscopy. In patients with a high likelihood of pathology, DBc is preferred over CTC.