The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients.
OBJECTIVE
A drug interaction between infliximab and azathioprine has previously been reported in Crohn's 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 Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement.


METHODS
Crohn's 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 Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12.


RESULTS
Twelve Crohn's 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 Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.
Department of Clinical Pharmacy & Toxicology, Orbis Medical Centre, Sittard, The Netherlands. Electronic address: d.wong@orbisconcern.nl.
D R
DR
Wong
Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, The Netherlands.
M
M
Pierik
Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
M L
ML
Seinen
Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
A A
AA
van Bodegraven
Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, The Netherlands.
L P L
LP
Gilissen
Department of Gastroenterology, Laurentius Hospital, Roermond, The Netherlands.
P
P
Bus
Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
J A
JA
Bakker
Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, The Netherlands.
A A M
AA
Masclee
Department of Clinical Pharmacy & Toxicology, University Hospital Maastricht, Maastricht, The Netherlands; Department of Toxicology, Maastricht University, CAPHRI School for Public Health and Primary Care, Maastricht, The Netherlands.
C
C
Neef
Department of Gastroenterology, Orbis Medical Centre, Sittard, The Netherlands.
L G J B
LG
Engels
Department of Clinical Pharmacy & Toxicology, Orbis Medical Centre, Sittard, The Netherlands.
P M
PM
Hooymans
D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D001379:Azathioprine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy / Q000378:metabolism*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000097:blood; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008780:Methyltransferases / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000097:blood; D012720:Severity of Illness Index; D013868:Thioinosine / Q000031:analogs & derivatives / Q000097:blood; D013873:Thionucleotides / Q000097:blood; D055815:Young Adult; D000097630:Inosine Triphosphatase
D000068879:Adalimumab; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D001379:Azathioprine; D002097:C-Reactive Protein; D006150:Guanine Nucleotides; D007041:Hypoxanthine Phosphoribosyltransferase; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D013868:Thioinosine; D013873:Thionucleotides; D000097630:Inosine Triphosphatase; C003964:6-thioguanylic acid; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; C022745:thiopurine methyltransferase
6-MMPR; 6-MP; 6-TGN; 6-TGTP; 6-methylmercaptopurine ribonucleotides; 6-thioguanine nucleotides; 6-thioguanine triphosphate; 95% CI; 95% confidence interval; AZA; Adalimumab; Azathioprine; C-reactive protein; CD; CDAI; CRP; Crohn's disease; Crohn's disease activity index; Drug interaction; HGPRT; HPLC; IBD; IMP; ITPase; MCV; Mercaptopurine; RBC; TDM; TPMT; Therapeutic drug monitoring; UC; azathioprine; high performance liquid chromatography; hypoxanthine-guanine phosphoribosyl transferase; inflammatory bowel disease; inosine monophosphate; inosine triphosphate pyrophosphatase; mean corpuscular volume; mercaptopurine; red blood cells; therapeutic drug monitoring; thiopurine S-methyltransferase; ulcerative colitis