采用贝叶斯基于机制的药代动力学模型评价 4β-羟基胆固醇作为 CYP3A4 药物相互作用的临床生物标志物。
Evaluation of 4β-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model.
机构信息
Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, Lawrenceville, New Jersey, USA.
出版信息
CPT Pharmacometrics Syst Pharmacol. 2014 Jun 25;3(6):e120. doi: 10.1038/psp.2014.18.
A Bayesian mechanism-based pharmacokinetic/pharmacodynamic model of cytochrome P450 3A4 (CYP3A4) activity was developed based on a clinical study of the effects of ketoconazole and rifampin on midazolam exposure and plasma 4β-hydroxycholesterol (4βHC) concentrations. Simulations from the model demonstrated that the dynamic range of 4βHC as a biomarker of CYP3A4 induction or inhibition was narrower than that of midazolam; an inhibitor that increases midazolam area under the curve by 20-fold may only result in a 20% decrease in 4βHC after 14 days of dosing. Likewise, an inducer that elevates CYP3A4 activity by 1.2-fold would reduce the area under the curve of midazolam by 50% but would only increase 4βHC levels by 20% after 14 days of dosing. Elevation in 4βHC could be reliably detected with a twofold induction in CYP3A4 activity with study sample sizes (N ~ 6-20) typically used in early clinical development. Only a strong CYP3A4 inhibitor (e.g., ketoconazole) could be detected with similar sample sizes.
建立了基于酮康唑和利福平对咪达唑仑暴露和血浆 4β-羟胆固醇（4βHC）浓度影响的临床研究的细胞色素 P450 3A4（CYP3A4）活性的贝叶斯机制为基础的药代动力学/药效动力学模型。该模型的模拟表明，4βHC 作为 CYP3A4 诱导或抑制标志物的动态范围比咪达唑仑窄；在 14 天的治疗后，增加咪达唑仑 AUC 20 倍的抑制剂可能仅导致 4βHC 降低 20％。同样，将 CYP3A4 活性提高 1.2 倍会使咪达唑仑的 AUC 降低 50％，但在 14 天的治疗后仅使 4βHC 水平增加 20％。使用早期临床开发中通常使用的研究样本量（N ~ 6-20），可以可靠地检测到 CYP3A4 活性增加两倍的 4βHC。只有使用类似的样本量，才能检测到强 CYP3A4 抑制剂（例如酮康唑）。
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