Tolerability of Erythrocyte Ribavirin Triphosphate Concentrations Depends on the ITPA Genotype.

BACKGROUND: Ribavirin (RBV) is an antiviral drug that is part of the current standard therapy for chronic hepatitis C (CHC). It is enzymatically converted to ribavirin triphosphate (RTP) that inhibits the activity of viral RNA polymerase, thereby preventing viral replication. However, one of its adverse effects includes hemolytic anemia that limits its application. The variant of ITPA (inosine triphosphatase), which dephosphorylates inosine triphosphate to inosine monophosphate, is a protective factor for RBV-induced anemia. RTP is an important metabolite required for ribavirin action. This study evaluated the time-dependent association of RTP concentrations in erythrocytes, RBV-induced toxicity, and virological response to RBV treatment for hepatitis C. METHODS: A total of 28 Japanese patients with CHC were treated with RBV/peg-interferon/simeprevir or RBV/sofosbuvir and were genotyped for ITPA variants (rs1127354 and rs7270101). We measured RTP concentrations in erythrocytes in a total of 76 samples collected at 4, 8, and 12 weeks from the initiation of treatment. RESULTS: The ITPA rs1127354 variant was found in 7 patients. This was associated with significantly higher RTP concentrations in erythrocytes than in the wild-type patients (P < 0.001). Moreover, a significant correlation was observed between RTP concentrations and decline in hemoglobin (Hb) levels from baseline values in ITPA wild type and rs1127354 variant 12 weeks after treatment initiation (P < 0.01; r = -0.618 and -0.967, respectively). Multiple regression analysis revealed that ITPA genotype and erythrocyte RTP concentrations were major factors associated with reduced Hb levels in RBV therapy for CHC. However, we did not find any association between erythrocyte concentrations and virological response. CONCLUSIONS: The increased tolerability to RTP concentrations in erythrocytes in the ITPA variant rs1127354 plays a role in preventing RBV-induced severe anemia in this ITPA variant.

Rapidity and Severity of Hemoglobin Decreasing Associated with Erythrocyte Inosine Triphosphatase Activity and ATP Concentration during Chronic Hepatitis C Treatment.

The purpose of this study was to evaluate the association between therapy-induced hemoglobin (Hb) decreasing rapidity and severity with erythrocyte inosine triphosphatase (ITPase) activity and ATP concentration in chronic hepatitis C patients receiving chronic hepatitis C (HCV) treatment. Forty-three Japanese patients were included in the study. Erythrocyte ITPase activity before therapy was determined by HPLC-UV. Erythrocyte ATP concentrations before and during therapy were determined by luciferase assay. Genotyping for ITPA 94C>A (rs1127354) and IVS2+21 A>C (rs7270101) was conducted using TaqMan probes. The median ITPase activity (µmol/h/g hemoglobin) of ITPA 94 CC, CA, and AA genotypes was 136.8 (range, 80.4-289.6), 41.1 (24.3-93.1), and 11.8, respectively. ITPase activity and Hb decreasing showed a significantly inverse relationship at therapeutic weeks 2, 4, and 6 (p<0.01). Erythrocyte ATP concentration was decreased by therapy, and Hb decreasing was significantly and inversely correlated with erythrocyte ATP concentration at week 4 and after week 8 (p<0.001 and 0.05, respectively). ATP concentration for patients with ITPA 94CA was significantly lower than ITPA 94CC at week 4 (p=0.045). We concluded that ITPase activity plays an important function and that ATP concentration changes due to therapy are related to the Hb decreasing mechanism in the early period of therapy with HCV treatment.

Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia.

Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49-20·80; P = 2·7 × 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients.

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27-11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children.

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 µmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.

Pharmacokinetics and postoperative analgesia of epidural tramadol: A prospective, pilot study.

BACKGROUND: Tramadol, a centrally acting analgesic drug, can be administered via multiple routes and is generally well tolerated. OBJECTIVE: This study was designed to assess the pharmacokinetics of epidural tramadol administered preoperatively in Japanese patients undergoing upper abdominal surgery. METHOD: Japanese patients who were scheduled to undergo upper abdominal surgery in The Kitasato Institute Hospital, Tokyo, Japan, were included. Patients received tramadol 2 mg/kg with 5 mL of 1% mepivacaine epidurally 10 minutes before incision. The serum concentration of tramadol was determined by high-performance liquid chromatography for 21 hours after administration. Serum concentration was determined before tramadol administration and 10, 20, 30, and 60 minutes after tramadol administration, first postoperative night, and first postoperative day. Pain score and adverse events (AEs) were assessed at 1, 3, 6, 12, 18, 24, 36, and 48 hours after surgery by patient interview. RESULTS: Eleven patients were assessed for enrollment. Seven patients (6 men, 1 woman; mean [SD] age, 61.3 [12.6] years; mean [SD] weight, 59.9 [8.9] kg) provided consent and completed the study. The mean (SD) serum Cmax of tramadol was 1385.5 (390.8) ng/mL, Tmax was 0.33 (0.22) hour, and terminal elimination half-life (t1/2ß) was 10.5 (2.3) hours. Four patients complained of nausea; however, only 1 patient was administered an antiemetic. No other AEs were reported. CONCLUSION: This pilot study found that epidural tramadol administered before incision induced a Cmax within 30 minutes of administration. The drug was detected in serum at ∼21 hours after surgery.