Kearney Brian P, Yale Kitty, Shah Jaymin, Zhong Lijie, Flaherty John F
Gilead Sciences Inc., Foster City, California 94404, USA.
Clin Pharmacokinet. 2006;45(11):1115-24. doi: 10.2165/00003088-200645110-00005.
Tenofovir disoproxil fumarate is the prodrug of the acyclic nucleotide reverse transcriptase inhibitor tenofovir that is indicated for use in the treatment of HIV. Tenofovir is eliminated as unchanged drug in the urine, with a significant component of active tubular secretion. The aim of this study was to evaluate the pharmacokinetics of tenofovir in subjects with renal or hepatic impairment, both of which are common in HIV-infected individuals.
HIV seronegative and otherwise healthy subjects with varying degrees of renal or hepatic function were recruited, and tenofovir pharmacokinetics were evaluated over 48 hours (hepatic impairment study) and 96 hours (renal impairment study) following a single tenofovir disoproxil fumarate 300 mg dose. Subjects with hepatic dysfunction were categorised based upon Child-Pugh-Turcotte score, and subjects with renal impairment were categorised based upon their calculated creatinine clearance (CL(CR)) using the Cockcroft-Gault method.
As expected for a renally eliminated drug, subjects with and without hepatic impairment displayed similar tenofovir systemic exposures without evidence of substantial alterations in drug disposition, and therefore no dosage adjustments were warranted in these patients. In contrast, in subjects with renal impairment, two distinct groups were observed: (i) subjects with CL(CR)>/=50 mL/min in whom tenofovir pharmacokinetics were similar to subjects with normal renal function; and (ii) subjects with CL(CR) <50 mL/min (moderate or severe impairment) in which tenofovir renal clearance was substantially reduced and thus drug exposures increased. Subjects with end-stage renal disease (ESRD) demonstrated no extrarenal route of tenofovir elimination. Simulations of once-daily or modified dosing regimens demonstrated the need for tenofovir disoproxil fumarate dose-interval adjustment to prevent unnecessary drug accumulation. In patients with ESRD, high-flux haemodialysis efficiently removed tenofovir, with an elimination rate of 134 mL/min and an extraction coefficient of 54%.
No tenofovir disoproxil fumarate dose adjustment is warranted in the setting of hepatic impairment. Tenofovir disoproxil fumarate 300 mg every 48 hours in individuals with moderate renal impairment and twice weekly corresponding to every 72-96 hours in those with severe renal impairment is recommended in order to target steady-state tenofovir exposures consistent with those observed in subjects with normal renal function receiving tenofovir disoproxil fumarate 300 mg once daily. For subjects receiving thrice-weekly 4-hour maintenance haemodialysis sessions, tenofovir disoproxil fumarate 300 mg administered every 7 days after a haemodialysis session is recommended. HIV-infected patients with significant end-organ dysfunction should be monitored in accordance with clinical practice, including close management of their viral suppression and clinical chemistries.
富马酸替诺福韦二吡呋酯是无环核苷酸逆转录酶抑制剂替诺福韦的前体药物，用于治疗HIV。替诺福韦以原形药物经尿液排泄，其中肾小管主动分泌占很大比例。本研究旨在评估替诺福韦在肾或肝功能受损患者中的药代动力学，这两种情况在HIV感染者中都很常见。
招募了具有不同程度肾功能或肝功能的HIV血清阴性且其他方面健康的受试者，在单次服用300mg富马酸替诺福韦二吡呋酯后，分别在48小时（肝功能受损研究）和96小时（肾功能受损研究）评估替诺福韦的药代动力学。肝功能不全的受试者根据Child-Pugh-Turcotte评分进行分类，肾功能受损的受试者根据使用Cockcroft-Gault方法计算的肌酐清除率（CL(CR)）进行分类。
正如肾排泄药物所预期的那样，有或无肝功能损害的受试者显示出相似的替诺福韦全身暴露量，且药物处置无明显改变，因此这些患者无需调整剂量。相比之下，在肾功能受损的受试者中，观察到两个不同的组：（i）CL(CR)≥50 mL/min的受试者，其替诺福韦药代动力学与肾功能正常的受试者相似；（ii）CL(CR)<50 mL/min（中度或重度损害）的受试者，其替诺福韦肾清除率大幅降低，因此药物暴露量增加。终末期肾病（ESRD）患者未显示替诺福韦有肾外排泄途径。每日一次或调整给药方案的模拟表明，需要调整富马酸替诺福韦二吡呋酯的剂量间隔以防止不必要的药物蓄积。在ESRD患者中，高通量血液透析能有效清除替诺福韦，清除率为134 mL/min，提取系数为54%。
在肝功能损害的情况下，无需调整富马酸替诺福韦二吡呋酯的剂量。对于中度肾功能损害的个体，建议每48小时服用300mg富马酸替诺福韦二吡呋酯，对于重度肾功能损害的个体，建议每周两次（相当于每72 - 96小时一次），以使替诺福韦的稳态暴露量与肾功能正常的受试者每日一次服用300mg富马酸替诺福韦二吡呋酯时观察到的暴露量一致。对于接受每周三次4小时维持性血液透析的受试者，建议在每次血液透析后每7天服用300mg富马酸替诺福韦二吡呋酯。应根据临床实践对有严重终末器官功能障碍的HIV感染患者进行监测，包括密切管理其病毒抑制和临床化学指标。
