||Relationship between concentrations of antiretroviral drugs in plasma and saliva of HIV-1 infected individuals
Yamada, Eiko山田, 瑛子
学位の種類: 博士（歯学）. 報告番号: 甲第4005号. 学位記番号: 新大院博（歯）甲第318号. 学位授与年月日: 平成27年3月23日
Therapeutic drug monitoring (TDM) is valuable to evaluate the efficacy of a regimen or monitor the compliance of patients treated with a drug. However, TDM requires frequent blood sampling, which carries a risk of viral transmission to medical staff and causes pain to patients. In contrast, saliva sampling is safe and easily performed, so the possibility of using saliva for TDM as an alternative body fluid was examined. Firstly, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the determination of abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in human plasma and saliva was developed and validated. Analytes were detected using LC-MS/MS, and the linearity of the assay was assessed in the range 1–10,000 ng/mL for all four drugs. Within-run and between-run mean accuracy, precision, and the extraction recovery for all drugs were−14.5 to 18.1%, 1.2 to 13.1%, and 86.0 to 111.1%, respectively. The proposed assay is sufficiently sensitive and accurate to quantify these drugs in plasma and saliva. Secondly, the drug concentrations in plasma, plasma ultrafiltrate, and saliva of 30 human immunodeficiency virus (HIV)-1 infected outpatients who had been treated with these drugs for > 1 month were measured. Ratios of concentrations in saliva to plasma were 62.3% for ABC, 2.4% for TFV, 6.5% for DRV, and 13.5% for RAL. Significant correlations were evident between drug concentrations in saliva and those in plasma or plasma ultrafiltrate for ABC, DRV, and RAL, therefore the possibility of using saliva for TDM was suggested for these three drugs. Moreover, ABC, DRV, and RAL concentrations in saliva correlated more strongly with those in plasma ultrafiltrate than in plasma, suggesting that non-protein-bound drug may be secreted more easily to saliva. In contrast, saliva cannot be used for this purpose with TFV, which exhibited a very low saliva concentration and no correlation between concentrations in saliva and plasma. ABC was the most abundant in saliva, and those of ABC were above IC_<50> for half of patients. An ABC-containing regimen may be a candidate for pre-exposure prophylaxis against oral HIV transmission. In conclusion, this study facilitates the use of saliva as an alternative body fluid of blood for TDM of ART of HIV infection by developing the innovative method.