Dickschen Kristin J R, Willmann Stefan, Hempel Georg, Block Michael
Computational Systems Biology, Bayer AG Leverkusen, Germany.
Clinical Pharmacometrics, Bayer Pharma AG Wuppertal, Germany.
Front Pharmacol. 2017 Mar 14;8:67. doi: 10.3389/fphar.2017.00067. eCollection 2017.
Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes. A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios. Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days. The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses.
他莫昔芬是激素阳性乳腺癌最常见的治疗药物之一。尽管其耐受性良好，但多年来患者的依从性逐渐下降，影响了治疗效果。应用生理药代动力学（PBPK）模型来证明停药期对不同CYP2D6基因型患者他莫昔芬及其活性代谢物4-羟基他莫昔芬血浆水平的影响。开展了一项针对24000名患者的虚拟研究，以调查不同CYP2D6基因型患者群体中他莫昔芬稳态动力学的变化情况。假设停药期情况不断变化，研究了停药期对稳态动力学的影响。CYP2D6快代谢型和中代谢型（EMs、IMs）患者停药超过1个月会导致4-羟基他莫昔芬稳态谷浓度降至对照组第5百分位数以下。假设停药1、2或3个月，并给予20mg他莫昔芬和3mg 4-羟基他莫昔芬的固定剂量组合，EMs患者在5、8和9天后4-羟基他莫昔芬稳态谷浓度恢复。接受相同固定剂量组合的IMs患者在7、10和11天后4-羟基他莫昔芬稳态谷浓度恢复。PBPK模型令人印象深刻地证明了不同CYP2D6基因型停药期对药代动力学的影响。群体模拟结果表明，尽管他莫昔芬半衰期较长，但停药超过2周会导致血浆水平大幅下降。为提高治疗效果，PBPK模型有助于识别停药期后药代动力学的基因型特异性差异，并通过负荷剂量进行适当治疗。
