Pharmacokinetics of Tac in Patients With Ulcerative Colitis
Pharmacokinetics of Tac in Patients With Ulcerative Colitis
In our department, therapy with Tac is indicated for UC patients with moderate-to-severe activity who are resistant to prednisolone (PSL) and other drugs. Many cases are severe, and inpatient therapy is the fundamental approach when starting Tac. As a rule, the initial dose is 0.05 mg/kg twice daily for patients ingesting food and 0.04 mg/kg twice daily for patients who are fasting. To monitor blood levels of Tac, trough levels are normally measured at least on days 2–5 and 7–10 during the early period of therapy. Measurement of Tac blood levels is contracted to SRL, Inc. (Tokyo, Japan), and ELISA is done using the PRO-TRAC II TM FK 506 (Bio-Rad Laboratories, Inc., Los Angeles, CA, USA). Depending on the trough level results on days 2–5 and 7–10 during the remission induction period, the Tac dose is then adjusted to achieve the optimal trough level of 10–15 ng/mL. The equation (previous dose × 12.5 mg/mL/the blood trough level) was used for the dose adjustment of Tac. Patients with frequent diarrhea or severe abdominal pain are managed by fasting with total parenteral nutrition for about 2 weeks. Seventy patients with UC were treated by Tac in our department between February 2001 and February 2012. Of these patients, full explanations of the present study were given to 45 patients examined in our hospital between August 2011 and May 2012. There was no special selection; all 45 of these patients undergoing follow-up at our hospital during this period were the subjects of this study. Genotyping analysis of CYP3A5, CYP3A4, and ABCB1 was contracted to SRL, Inc., and gene analysis was done by fluorescence correlation spectroscopy.
The initial dose, trough level, and dose-adjusted trough level on days 2–5 and 7–10, and the percentages of patients achieving the optimal trough level on days 2–5 and 7–10 were compared by CYP3A5 and ABCB1 genotypes.
Various factors affecting the achievement of the optimal trough level were compared between the achievement and non-achievement groups. A univariate analysis was done first, followed by a multivariate analysis for items with P < 0.25.
The remission rate after 4 weeks was compared between the Exp and Non-Exp groups.
In our hospital, subjective and objective findings needed for the disease activity index (DAI, also known as the "Sutherland index") or other activity indices are entered in electronic medical records daily for hospitalized UC patients, and blood tests are performed at least once a week. For severe colitis, blood tests are usually checked twice per week. Thus, the DAI score can be calculated accurately even retrospectively.
In this study, the DAI entered in patients' medical records was used to evaluate activity. However, because all patients did not undergo endoscopy 4 weeks after the start of therapy, a partial DAI (pDAI) score excluding the endoscopic subscore was used to define remission. Patients with pDAI ≤ 1 were defined as in remission, and patients with other scores and patients who underwent surgery within 4 weeks after the start of therapy were defined as being in non-remission.
The frequency and types of adverse effects were investigated. When Tac is used in patients aged 60 years or older in our hospital, cotrimoxazole is administered at the usual dosage with the aim of preventing Pneumocystis pneumonia (PCP).
An unpaired t-test was used to test for differences in mean values, and the chi-square test or Fisher's exact test was used to compare frequencies. Multivariate analysis was used to analyze factors involved in achieving the optimal trough levels. All statistical analyses were done using SPSS ver. 16.0 (SPSS Inc., Chicago, IL, USA).
Written, informed consent was obtained from all subjects. This study was approved by the ethical review board of Fukuoka University.
Methods
Patients and Genotyping Analysis
In our department, therapy with Tac is indicated for UC patients with moderate-to-severe activity who are resistant to prednisolone (PSL) and other drugs. Many cases are severe, and inpatient therapy is the fundamental approach when starting Tac. As a rule, the initial dose is 0.05 mg/kg twice daily for patients ingesting food and 0.04 mg/kg twice daily for patients who are fasting. To monitor blood levels of Tac, trough levels are normally measured at least on days 2–5 and 7–10 during the early period of therapy. Measurement of Tac blood levels is contracted to SRL, Inc. (Tokyo, Japan), and ELISA is done using the PRO-TRAC II TM FK 506 (Bio-Rad Laboratories, Inc., Los Angeles, CA, USA). Depending on the trough level results on days 2–5 and 7–10 during the remission induction period, the Tac dose is then adjusted to achieve the optimal trough level of 10–15 ng/mL. The equation (previous dose × 12.5 mg/mL/the blood trough level) was used for the dose adjustment of Tac. Patients with frequent diarrhea or severe abdominal pain are managed by fasting with total parenteral nutrition for about 2 weeks. Seventy patients with UC were treated by Tac in our department between February 2001 and February 2012. Of these patients, full explanations of the present study were given to 45 patients examined in our hospital between August 2011 and May 2012. There was no special selection; all 45 of these patients undergoing follow-up at our hospital during this period were the subjects of this study. Genotyping analysis of CYP3A5, CYP3A4, and ABCB1 was contracted to SRL, Inc., and gene analysis was done by fluorescence correlation spectroscopy.
CYP3A5 and ABCB1 Genotypes and Pharmacokinetics of Tac
The initial dose, trough level, and dose-adjusted trough level on days 2–5 and 7–10, and the percentages of patients achieving the optimal trough level on days 2–5 and 7–10 were compared by CYP3A5 and ABCB1 genotypes.
Achieving the Optimal Trough Level
Various factors affecting the achievement of the optimal trough level were compared between the achievement and non-achievement groups. A univariate analysis was done first, followed by a multivariate analysis for items with P < 0.25.
Short-term Clinical Remission
The remission rate after 4 weeks was compared between the Exp and Non-Exp groups.
In our hospital, subjective and objective findings needed for the disease activity index (DAI, also known as the "Sutherland index") or other activity indices are entered in electronic medical records daily for hospitalized UC patients, and blood tests are performed at least once a week. For severe colitis, blood tests are usually checked twice per week. Thus, the DAI score can be calculated accurately even retrospectively.
In this study, the DAI entered in patients' medical records was used to evaluate activity. However, because all patients did not undergo endoscopy 4 weeks after the start of therapy, a partial DAI (pDAI) score excluding the endoscopic subscore was used to define remission. Patients with pDAI ≤ 1 were defined as in remission, and patients with other scores and patients who underwent surgery within 4 weeks after the start of therapy were defined as being in non-remission.
Safety
The frequency and types of adverse effects were investigated. When Tac is used in patients aged 60 years or older in our hospital, cotrimoxazole is administered at the usual dosage with the aim of preventing Pneumocystis pneumonia (PCP).
Statistical Analysis
An unpaired t-test was used to test for differences in mean values, and the chi-square test or Fisher's exact test was used to compare frequencies. Multivariate analysis was used to analyze factors involved in achieving the optimal trough levels. All statistical analyses were done using SPSS ver. 16.0 (SPSS Inc., Chicago, IL, USA).
Ethical Considerations
Written, informed consent was obtained from all subjects. This study was approved by the ethical review board of Fukuoka University.
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