Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C₀) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300-400 mg/d, a target nilotinib C₀ of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C₀ of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher Cmax or C₂ (above 50 ng/mL) to obtain a clinical response and a lower C₀ (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.

Mycophenolic acid (MPA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the phenolic MPA glucuronide (MPAG). MPAG is excreted by transporters such as organic anion-transporting polypeptide (gene SLCO), multidrug resistance protein 2 (gene ABCC2), breast cancer resistance protein (BCRP, gene ABCG2) or P-glycoprotein (gene ABCB1). This study investigated the association of UGTs, SLCOs, ABCB1, ABCC2, and ABCG2 polymorphisms with MPAG pharmacokinetics in 80 Japanese renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (0900 and 2100). On day 28, after renal transplantation, plasma concentrations of MPA and MPAG were measured by high-performance liquid chromatography. There were no significant differences in the area under the plasma concentration-time curve (AUC) ratio of MPAG/MPA between UGT1A1, UGT1A6, UGT1A7, UGT1A8, and UGT1A9 I399C/T genotypes. On the other hand, the median dose-adjusted AUC0-12 of MPAG in SLCO1B1 1a/1a+1a/1b+1b+1b (n = 53) and 1a/*15 + 1b/*15+*15/*15 (n = 27) were 1549 and 1134 mg.h L g, respectively (P = 0.03004 in multivariate analysis). The median dose-adjusted AUC0-12 of MPAG in SLCO1B3 334T/T+T/G (699G/G+G/A, n = 46) and 334G/G (699A/A, n = 34) was 1191 and 1580 mg.h L g, respectively (P = 0.02792 in multivariate analysis). There were no significant differences in the dose-adjusted AUC0-12 of MPAG between the ABCB1 C3435T and ABCC2 C-24T genotypes. However, the dose-adjusted AUC0-12 of MPAG was significantly lower in recipients with ABCG2 421C/A+A/A (n = 44) than in those with C/C (n = 36) (P = 0.0295). In conclusion, our findings showed that MPAG pharmacokinetics were significantly influenced by SLCO1B1 and SLCO1B3 polymorphisms and not by UGT polymorphisms. BCRP rather than multidrug resistance protein 2 seems to be the transporter associated with biliary excretion of MPAG.