Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.
BACKGROUND:Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. METHODS:Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg o...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4726617?pdf=render |
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| author | Lawrence Soon-U Lee Kok-Yong Seng Ling-Zhi Wang Wei-Peng Yong Kim-Hor Hee Thomas I Soh Andrea Wong Pei F Cheong Richie Soong Nur S Sapari Ross Soo Lu Fan Soo-Chin Lee Boon C Goh |
| author_facet | Lawrence Soon-U Lee Kok-Yong Seng Ling-Zhi Wang Wei-Peng Yong Kim-Hor Hee Thomas I Soh Andrea Wong Pei F Cheong Richie Soong Nur S Sapari Ross Soo Lu Fan Soo-Chin Lee Boon C Goh |
| author_sort | Lawrence Soon-U Lee |
| collection | DOAJ |
| description | BACKGROUND:Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. METHODS:Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. RESULTS:SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. CONCLUSION:Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. TRIAL REGISTRATION:Clinicaltrials.gov NCT00808184. |
| first_indexed | 2024-12-20T09:25:59Z |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T09:25:59Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-6295a6cdf52940d7a4543df1021b51442022-12-21T19:45:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01111e014768110.1371/journal.pone.0147681Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.Lawrence Soon-U LeeKok-Yong SengLing-Zhi WangWei-Peng YongKim-Hor HeeThomas I SohAndrea WongPei F CheongRichie SoongNur S SapariRoss SooLu FanSoo-Chin LeeBoon C GohBACKGROUND:Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. METHODS:Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. RESULTS:SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. CONCLUSION:Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. TRIAL REGISTRATION:Clinicaltrials.gov NCT00808184.http://europepmc.org/articles/PMC4726617?pdf=render |
| spellingShingle | Lawrence Soon-U Lee Kok-Yong Seng Ling-Zhi Wang Wei-Peng Yong Kim-Hor Hee Thomas I Soh Andrea Wong Pei F Cheong Richie Soong Nur S Sapari Ross Soo Lu Fan Soo-Chin Lee Boon C Goh Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. PLoS ONE |
| title | Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. |
| title_full | Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. |
| title_fullStr | Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. |
| title_full_unstemmed | Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. |
| title_short | Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. |
| title_sort | phenotyping of ugt1a1 activity using raltegravir predicts pharmacokinetics and toxicity of irinotecan in folfiri |
| url | http://europepmc.org/articles/PMC4726617?pdf=render |
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