The rate of carriers with the UGT1A1 gene polymorphism has been reported to vary depending on race. The allele frequency of the *28 homozygote has been reported to be approximately 30–40% in Caucasian and African American populations , and 10–13% in Japanese populations [10, 12]. In contrast, the *6 homozygote is rarely detected in Caucasian and African American populations but is specifically found in Asian populations with a frequency of approximately 16% . Similar allele frequencies were found in this study, and, therefore, the subjects are unlikely to deviate from a general Japanese population.
In this study, the median DTG trough concentration of the *6 homozygous patients was approximately 1.7 times higher than that of the subjects carrying both normal alleles. On the other hand, in our previous study on RAL, the median RAL trough concentration of *6 homozygous patients was approximately 10 times higher than that of patients carrying both normal alleles . These observations indicate that the UGT1A1*6 had a smaller effect on the DTG trough concentration than it did on the RAL trough concentration. However, this interpretation is limited by the small number of *6 homozygous patients in both studies. Possible factors for the differential effects include a difference in the mediating metabolic pathway between RAL and DTG. RAL is predominantly metabolized by the UGT1A1 pathway and is not a substrate of CYP enzymes. In contrast, the principal pathway responsible for metabolizing approximately 70% of DTG involves UGT1A1, while CYP3A and other enzymes are involved in the secondary metabolic pathway of the remaining 30% . This secondary metabolic pathway could reduce the effect of UGT1A1*6 on the plasma DTG concentration.
Unexpectedly, age < 40 years was an independent factor associated with high DTG trough concentrations. Drug blood concentrations increase with age. However, a population pharmacokinetic analysis in a previous study also showed the association between older age and decreased DTG plasma trough concentration . Several factors could be considered responsible for this observation, including reduced absorption of DTG in the gastrointestinal tract, increased clearance of DTG due to low levels of plasma albumin resulting in an increased unbound fraction of plasma DTG [8, 24], and altered body fat, which affects the distribution of highly lipid-soluble drugs . However, these reasons seem to be unlikely in this study because these physiological changes are apparent in the elderly [25, 26], and 93% of the subjects in this study were 20–50 years old. Further study is required to clarify the reason for the age effect.
This study demonstrated that plasma DTG trough concentrations were higher in the cases with NP-AEs than in those without NP-AEs. In addition, an association between UGT1A1 gene polymorphism and NP-AEs was suggested. The mechanism of the latter seems to be that reduced-function alleles of UGT1A1 can induce NP-AEs by increasing plasma DTG concentrations. In addition, UGT1A1 gene polymorphism, age, gender, body weight, smoking, and food consumption were reported to affect the pharmacokinetics of DTG . Therefore, it seems reasonable that plasma DTG trough concentration showed a stronger association with NP-AEs than UGT1A1 gene polymorphism. Similar to the effect of DTG in this study, plasma efavirenz (EFV) concentration was reported to be associated with toxicities of the central nervous system . That study suggested that a 1–4 μg/mL range at mid-dosing interval was a suitable target for plasma EFV concentration. However, it was difficult to set a cut-off value for DTG in our study, because we did not include patients who stopped taking DTG within 150 days of initiation. In a retrospective study about cases of DTG discontinuation, the median DTG trough concentration of 12 cases was reported to be 1.72 μg/mL . Considering these observations, more detailed pharmacokinetics about the DTG discontinuation cases may be required to set appropriate cut-off values to predict the risk of NP-AEs after the use of DTG.
This study has some limitations. For example, this was an observational study with a limited number of patients at a single center. Especially, the number of *6 and *28 homozygous and *6/*28 compound heterozygous patients was small. The plasma DTG concentration was evaluated only using trough concentration. Furthermore, our cohort may not be representative of the entire population and the discontinuation rate of DTG in this study may differ from that of a typical setting in Japan. Possible reasons for these differences include that we could not recruit patients who stopped taking DTG before plasma DTG concentrations reached steady state, and that the subjects were selected without use of random sampling techniques. Recently, it was reported that gene polymorphisms of drug transporters influenced plasma RAL peak concentrations . It is likely that gene polymorphisms of drug transporters can affect the pharmacokinetics of DTG as well. Gene polymorphisms CYP3A4*22 and CYP3A5*3 could also alter the pharmacokinetics of DTG, because DTG is partially metabolized by CYP3A and these polymorphisms were reported to change the metabolism of tacrolimus . Further studies should be conducted to examine the pharmacokinetics of DTG and the associated factors in addition to UGT.