Saltzstein Daniel, Shore Neal D, Moul Judd W, Chu Franklin, Concepcion Raoul, de la Motte Stephan, McLane John A, Atkinson Stuart, Yang Alex, Crawford E David
Urology San Antonio, 18139 Meisner Drive San Antonio, TX 78258 USA.
Carolina Urologic Research Center, Myrtle Beach, SC, USA.
Ther Adv Urol. 2017 Nov 22;10(2):43-50. doi: 10.1177/1756287217738150. eCollection 2018 Feb.
The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection.
A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA ( = 16) or IM-LA ( = 16) in this phase I, open-label, parallel-group study. PK was assessed LA concentrations, and PD serum luteinizing hormone (LH) and testosterone (T) concentrations.
The initial surge of LA was higher for IM-LA than SC-LA (C 27 ± 4.9 19 ± 8.0 ng/ml, respectively), with a shorter t (1.0 ± 0.4 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated.
Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility.
本研究旨在比较两种不同剂型醋酸亮丙瑞林（LA）的药代动力学（PK）和药效学（PD）；皮下（SC）注射和肌肉注射（IM）。
在这项I期开放标签平行组研究中，共32名健康男性被随机接受单次7.5mg的SC-LA（n = 16）或IM-LA（n = 16）注射。通过LA浓度评估PK，通过血清促黄体生成素（LH）和睾酮（T）浓度评估PD。
IM-LA的LA初始峰浓度高于SC-LA（分别为27±4.9与19±8.0 ng/ml），tmax更短（1.0±0.4与2.1±0.8小时）。SC-LA的可量化LA浓度持续时间更长（SC-LA和IM-LA分别长达56和42天）。两组的LH中位数浓度均迅速升高，随后逐渐下降。然而，SC-LA表现出更长的LH抑制持续时间，至第56天中位数水平仍低于1.0 IU/l，而IM-LA组LH在第35天开始上升。因此，IM-LA组血清T在第42天开始升高，只有4名受试者维持水平≤50 ng/dl，而SC-LA组有14名受试者。至第56天，13名SC-LA受试者维持血清T水平≤50 ng/dl。SC-LA和IM-LA耐受性均良好。
两种剂型在1个月内均显示出一致的药物递送；然而，基于给药间隔，SC-LA的作用持续时间比预期更长。这一特征表明SC-LA将在更长时间内有效抑制T，允许更大的注射时间安排灵活性。
