Avihingsanon Anchalee, Kerr Stephen J, Punyawudho Baralee, van der Lugt Jasper, Gorowara Meena, Ananworanich Jintanat, Lange Joep M A, Cooper David A, Phanuphak Praphan, Burger David M, Ruxrungtham Kiat
1 HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center Bangkok , Bangkok, Thailand .
AIDS Res Hum Retroviruses. 2013 Dec;29(12):1541-6. doi: 10.1089/aid.2013.0069. Epub 2013 Oct 2.
Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC(0-24) 71.2 vs. 53.1 mg·h/liter, C(max) 8.5 vs. 5.5 mg/liter, and C(trough) 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV C(trough) levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.
衰老的生理影响使老年人群更容易发生药物不良事件和药物相互作用。我们评估了年龄和性别对22例HIV感染得到有效抑制的患者每日一次（qd）服用300/100mg阿扎那韦/利托那韦（ATV/r）药代动力学（PK）的影响。这是一项为期24小时的强化PK研究。受试者为年龄≥18岁、HIV RNA<50拷贝/ml的HIV-1感染成人，接受每日一次300/100mg阿扎那韦/利托那韦加两种核苷类逆转录酶抑制剂（NRTIs）治疗至少2周。阿扎那韦和利托那韦的血浆浓度通过经验证的高效液相色谱（HPLC）测定。血浆PK参数采用非房室方法计算。由于50%的患者年龄大于42岁，因此选择42岁作为老年（>42岁）组的分界点。两组在性别、体重、阿扎那韦/利托那韦治疗持续时间以及接受含替诺福韦酯（TDF）方案治疗的比例方面无差异。老年组患者的肌酐清除率降低（91对76 ml/min）。老年组阿扎那韦的暴露量更高，中位AUC(0 - 24)为71.2 vs. 53.1mg·h/升，C(max)为8.5 vs. 5.5mg/升，C(trough)为1.17 vs. 0.78mg/升，表观清除率较慢（3.5 vs. 4.8升/小时）。老年组10例患者（91%）和年轻组36%的患者阿扎那韦C(trough)水平高于提议的0.85mg/升毒性上限。女性体重（BW）低于男性（46对63kg），但女性体内阿扎那韦浓度更高。然而，在多变量分析中，年龄增长是阿扎那韦浓度升高的唯一显著预测因素。调整性别和体重后，年龄与阿扎那韦AUC的参数估计值为2.17（$95%$CI 1.01 - 3.33）。也就是说，年龄每增加一岁，AUC大约增加2mg·h/升。年龄似乎是影响阿扎那韦药代动力学的一个重要因素。与年轻组相比，老年组患者的阿扎那韦暴露量似乎更高。有必要对极老年人群中的阿扎那韦进行进一步的PK研究。
