Albrecht Marco, Kogan Yuri, Kulms Dagmar, Sauter Thomas
Systems Biology Group, Department of Life Science and Medicine, Université du Luxembourg, 4367 Belvaux, Luxembourg.
esqLABS GmbH, 26683 Saterland, Germany.
Pharmaceutics. 2022 Jan 28;14(2):310. doi: 10.3390/pharmaceutics14020310.
Dabrafenib inhibits the cell proliferation of metastatic melanoma with the oncogenic BRAF(V600)-mutation. However, dabrafenib monotherapy is associated with pERK reactivation, drug resistance, and consequential relapse. A clinical drug-dose determination study shows increased pERK levels upon daily administration of more than 300 mg dabrafenib. To clarify whether such elevated drug concentrations could be reached by long-term drug accumulation, we mechanistically coupled the pharmacokinetics (MCPK) of dabrafenib and its metabolites. The MCPK model is qualitatively based on in vitro and quantitatively on clinical data to describe occupancy-dependent CYP3A4 enzyme induction, accumulation, and drug-drug interaction mechanisms. The prediction suggests an eight-fold increase in the steady-state concentration of potent desmethyl-dabrafenib and its inactive precursor carboxy-dabrafenib within four weeks upon 150 mg b.d. dabrafenib. While it is generally assumed that a higher dose is not critical, we found experimentally that a high physiological dabrafenib concentration fails to induce cell death in embedded 451LU melanoma spheroids.
达拉非尼可抑制携带致癌性BRAF（V600）突变的转移性黑色素瘤的细胞增殖。然而，达拉非尼单药治疗与pERK重新激活、耐药性及随之而来的复发相关。一项临床药物剂量确定研究表明，每日服用超过300 mg达拉非尼时pERK水平会升高。为了阐明长期药物蓄积是否能达到如此高的药物浓度，我们从机制上耦合了达拉非尼及其代谢物的药代动力学（MCPK）。该MCPK模型定性基于体外实验，定量基于临床数据，以描述 occupancy 依赖性CYP3A4酶诱导、蓄积及药物-药物相互作用机制。预测表明，每日两次服用150 mg达拉非尼四周后，强效去甲基达拉非尼及其无活性前体羧基达拉非尼的稳态浓度会增加八倍。虽然一般认为更高剂量并不关键，但我们通过实验发现，生理浓度较高的达拉非尼无法诱导包埋的451LU黑色素瘤球体发生细胞死亡。
