Clark Meredith R, Peet M Melissa, Davis Sarah, Doncel Gustavo F, Friend David R
CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Arlington, VA 22209, USA.
MPI Research, Mattawan, MI 49071, USA.
Pharmaceutics. 2014 Dec 8;6(4):616-631. doi: 10.3390/pharmaceutics6040616.
Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form.
阴道片正被开发作为凝胶剂的替代剂型，作为一种用于施用杀微生物剂的廉价、隐秘的剂型。这项工作描述了在体外和体内条件下，对含有替诺福韦（TFV，10毫克）、恩曲他滨（FTC，10毫克）以及替诺福韦和恩曲他滨组合（各10毫克）的快速崩解阴道片进行的药代动力学（PK）评估，并与临床用替诺福韦1%凝胶（一种处于III期临床试验的杀微生物剂产品）进行直接比较。在雌性兔阴道内给药后，也评估了片剂中替诺福韦和恩曲他滨的药代动力学。单剂量替诺福韦片（完整的或在10毫克/毫升预溶解）与替诺福韦1%凝胶的直接比较显示，各组之间替诺福韦的阴道药代动力学无差异；然而，替诺福韦从凝胶中的全身生物利用度显著更高。当兔用完整的替诺福韦片、恩曲他滨片或替诺福韦/恩曲他滨组合片给药一次或每日给药七天时，替诺福韦和恩曲他滨的阴道和全身浓度不受共同配方的影响。此外，单次给药或每日一次给药七次后的血浆药代动力学参数相似。给药后4小时，阴道上段中替诺福韦和恩曲他滨的组织浓度在104至105纳克/克之间。给药后4小时，阴道上段中替诺福韦二磷酸酯（TFV-DP，活性代谢物）的浓度也很高（超过103纳克/克或约3000至6000飞摩尔/毫克），与施用替诺福韦1%凝胶后测得的浓度相似。这些数据表明，快速崩解阴道片可能是一种合适的局部杀微生物剂剂型，其阴道替诺福韦药代动力学与替诺福韦1%凝胶相似。数据还支持在单一阴道片中将恩曲他滨与替诺福韦共同给药，以制成一种简单且廉价剂型的联合杀微生物剂。
