A Multi-Compartment, Single and Multiple Dose Pharmacokinetic Study of the Vaginal Candidate Microbicide 1% Tenofovir Gel

BackgroundTenofovir (TFV) gel is being evaluated as a microbicide with pericoital and daily regimens. To inhibit viral replication locally, an adequate concentration in the genital tract is critical.
Methods and FindingsForty-nine participants entered a two-phase study: single-dose (SD) and multi-dose (MD), were randomized to collection of genital tract samples (endocervical cells [ECC], cervicovaginal aspirate and vaginal biopsies) at one of seven time points [0.5, 1, 2, 4, 6, 8, or 24 hr(s)] post-dose following SD exposure of 4 mL 1% TFV gel and received a single dose. Forty-seven were randomized to once (QD) or twice daily (BID) dosing for 2 weeks and to collection of genital tract samples at 4, 8 or 24 hrs after the final dose, but two discontinued prior to gel application. Blood was collected during both phases at the seven times post-dose. TFV exposure was low in blood plasma for SD and MD; median Cmax was 4.0 and 3.4 ng/mL, respectively (C≤29 ng/mL). TFV concentrations were high in aspirates and tissue after SD and MD, ranging from 1.2×104 to 9.9×106 ng/mL and 2.1×102 to 1.4×106 ng/mL, respectively, and did not noticeably differ between proximal and distal tissue. TFV diphosphate (TFV-DP), the intracellular active metabolite, was high in ECC, ranging from 7.1×103 to 8.8×106 ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×102 to 3.5×104 ng/mL. AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID.
ConclusionsSingle-dose and multiple-dose TFV gel exposure resulted in high genital tract concentrations for at least 24 hours post-dose with minimal systemic absorption. These results support further study of TFV gel for HIV prevention.
Trial registrationClinicalTrials.gov NCT00561496

**背景**：特诺福韦（Tenofovir, TFV）凝胶作为杀微生物剂，正被评估用于围性交期及每日给药方案。为在局部抑制病毒复制，生殖道内达到足够药物浓度至关重要。

**方法与结果**：本研究分为两阶段，共纳入49名受试者：单剂量给药（SD）组与多剂量给药（MD）组。受试者在单次使用4mL 1% TFV凝胶后，被随机分配至给药后0.5、1、2、4、6、8或24小时这7个时间点中的1个采集生殖道样本，包括宫颈内膜细胞（endocervical cells, ECC）、宫颈阴道抽吸液及阴道活检组织。另有47名受试者被随机分配至每日一次（QD）或每日两次（BID）给药方案，持续2周，并在末次给药后4、8或24小时采集生殖道样本，但其中2人在使用凝胶前退出试验。两个阶段均在给药后的7个预设时间点采集血液样本。
单剂量与多剂量给药后，受试者血浆中的TFV暴露水平均较低，中位峰浓度（Cmax）分别为4.0 ng/mL与3.4 ng/mL（最高浓度≤29 ng/mL）。单剂量与多剂量给药后，抽吸液与组织中的TFV浓度均较高，范围分别为1.2×10^4 至9.9×10^6 ng/mL、2.1×10^2 至1.4×10^6 ng/mL，且近端与远端组织间无显著差异。细胞内活性代谢产物二磷酸特诺福韦（TFV diphosphate, TFV-DP）在ECC中的水平较高，范围为7.1×10^3 至8.8×10^6 ng/mL；约40%的组织样本中可检测到TFV-DP，浓度范围为1.8×10^2 至3.5×10^4 ng/mL。多剂量给药后组织中TFV-DP的药时曲线下面积（AUC）较单剂量给药高两个数量级，而每日一次与每日两次给药方案间无显著差异。

**结论**：单剂量与多剂量使用TFV凝胶后，给药后至少24小时内生殖道内药物浓度均维持在较高水平，且全身吸收极少。本研究结果支持进一步开展TFV凝胶用于艾滋病病毒（HIV）预防的相关研究。

**临床试验注册**：ClinicalTrials.gov NCT00561496