Morse G D, Fischl M A, Shelton M J, Cox S R, Driver M, DeRemer M, Freimuth W W
Department of Pharmacy Practice, State University of New York at Buffalo, USA.
Antimicrob Agents Chemother. 1997 Jan;41(1):169-74. doi: 10.1128/AAC.41.1.169.
Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [+/- standard deviation] CD4+ cell count, 304 +/- 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (Cmax) was reduced from 7.22 +/- 4.0 to 3.51 +/- 1.9 microM, and the area under the concentration-time curve from 0 h to infinity (AUC0-->infinity) was reduced from 22.5 +/- 14 to 14 +/- 5.7 microM.h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC0-->infinity to the delavirdine AUC0-->infinity, was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a Cmax reduction from 4.65 +/- 2.0 to 3.22 +/- 0.59 microM and an AUC0-->infinity reduction from 7.93 +/- 3.9 to 6.54 +/- 2.3 microM.h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC0-->infinity of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.
地拉韦啶是一种非核苷类逆转录酶抑制剂，具有体外抗1型人类免疫缺陷病毒（HIV-1）的活性，目前正在与包括去羟肌苷在内的多种核苷类似物联合用药方案中进行评估。由于地拉韦啶的溶解度依赖于pH值，去羟肌苷制剂中的缓冲剂可能会降低地拉韦啶的吸收。为了评估这些药物之间的潜在相互作用，12名HIV感染患者（平均[±标准差]CD4+细胞计数为304±213/mm³）参与了一项三交叉单剂量研究。评估了去羟肌苷（125至200mg，以缓冲片形式给药）和甲磺酸地拉韦啶（400mg）在每种药物单独给药时（分别为治疗A和B）、两种药物同时给药时（治疗C）以及地拉韦啶给药1小时后给予去羟肌苷时（治疗D）的药代动力学。同时给予去羟肌苷会降低地拉韦啶的暴露量。血清中的最大药物浓度（Cmax）从7.22±4.0降至3.51±1.9μM，浓度-时间曲线从0小时至无穷大的面积（AUC0→∞）从22.5±14降至14±5.7μM·h。整个研究治疗过程中，以N-去烷基化地拉韦啶AUC0→∞与地拉韦啶AUC0→∞的比值表示的N-去烷基化程度没有变化（P = 0.708）。在与地拉韦啶同时给药期间观察到去羟肌苷暴露量减少，Cmax从4.65±2.0降至3.22±0.59μM，AUC0→∞从7.93±3.9降至6.54±2.3μM·h。因此，同时给予地拉韦啶和去羟肌苷可能会降低两种药物的AUC0→∞，尽管这种降低的临床意义尚不清楚。在去羟肌苷给药前1小时给予地拉韦啶可避免相互作用。由于本研究的单剂量性质，这些发现需要在稳态下进一步评估。
