Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency
Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportuni...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Metabolites |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-1989/13/10/1054 |
| _version_ | 1797573020761456640 |
|---|---|
| author | Debbie S. Deben Luc J. J. Derijks Bianca J. C. van den Bosch Rob H. Creemers Annick van Nunen Adriaan A. van Bodegraven Dennis R. Wong |
| author_facet | Debbie S. Deben Luc J. J. Derijks Bianca J. C. van den Bosch Rob H. Creemers Annick van Nunen Adriaan A. van Bodegraven Dennis R. Wong |
| author_sort | Debbie S. Deben |
| collection | DOAJ |
| description | Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined <i>TPMT</i> genotypes (2016–2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant <i>TPMT</i> genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. <i>TPMT</i> genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT. |
| first_indexed | 2024-03-10T21:03:29Z |
| format | Article |
| id | doaj.art-5fbf9405476044e988f385599d3ddcd0 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T21:03:29Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-5fbf9405476044e988f385599d3ddcd02023-11-19T17:19:48ZengMDPI AGMetabolites2218-19892023-10-011310105410.3390/metabo13101054Implications of Tioguanine Dosing in IBD Patients with a TPMT DeficiencyDebbie S. Deben0Luc J. J. Derijks1Bianca J. C. van den Bosch2Rob H. Creemers3Annick van Nunen4Adriaan A. van Bodegraven5Dennis R. Wong6Department of Clinical Pharmacy, Clinical Pharmacology and Toxicology, Zuyderland Medical Centre, 6162 BG Sittard, The NetherlandsDepartment of Clinical Pharmacy and Pharmacology, Máxima Medical Centre, 5504 DB Veldhoven, The NetherlandsDepartment of Clinical Genetics, Maastricht University Medical Centre (MUMC+), 6229 HX Maastricht, The NetherlandsDepartment of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The NetherlandsDepartment of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The NetherlandsDepartment of Gastroenterology, Zuyderland Medical Centre, 6162 BG Sittard, The NetherlandsDepartment of Clinical Pharmacy, Clinical Pharmacology and Toxicology, Zuyderland Medical Centre, 6162 BG Sittard, The NetherlandsTioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined <i>TPMT</i> genotypes (2016–2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant <i>TPMT</i> genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. <i>TPMT</i> genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.https://www.mdpi.com/2218-1989/13/10/1054thiopurine S-methyl transferase (TPMT)tioguanineinflammatory bowel disease (IBD)TPMT deficiency |
| spellingShingle | Debbie S. Deben Luc J. J. Derijks Bianca J. C. van den Bosch Rob H. Creemers Annick van Nunen Adriaan A. van Bodegraven Dennis R. Wong Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency Metabolites thiopurine S-methyl transferase (TPMT) tioguanine inflammatory bowel disease (IBD) TPMT deficiency |
| title | Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency |
| title_full | Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency |
| title_fullStr | Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency |
| title_full_unstemmed | Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency |
| title_short | Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency |
| title_sort | implications of tioguanine dosing in ibd patients with a tpmt deficiency |
| topic | thiopurine S-methyl transferase (TPMT) tioguanine inflammatory bowel disease (IBD) TPMT deficiency |
| url | https://www.mdpi.com/2218-1989/13/10/1054 |
| work_keys_str_mv | AT debbiesdeben implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT lucjjderijks implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT biancajcvandenbosch implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT robhcreemers implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT annickvannunen implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT adriaanavanbodegraven implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency AT dennisrwong implicationsoftioguaninedosinginibdpatientswithatpmtdeficiency |