PURPOSE/AIMS Cyclophosphamide (CP) and thiotepa (TT) are frequently administered simultaneously in high-dose chemotherapy regimens. The prodrug CP shows strong autoinduction resulting in increased formation of its activated metabolite 4-hydroxycyclophosphamide (4OHCP). TT inhibits this bioactivation of CP. Previously, we successfully modelled CP bioactivation and the effect of TT on the autoinduction. Recently we suggested that CP may also induce the conversion of TT in to its metabolite tepa (T). The aim of the current study was to investigate whether the influence of CP on TT metabolism can be described with a population pharmacokinetic model and whether this interaction can be incorporated in an integrated model describing both CP and TT pharmacokinetics. METHODS Plasma samples were collected from 49 patients receiving 86 courses of a combination of high-dose CP (4000 or 6000 mg/m2), TT (320 or 480 mg/m2) and carboplatin (1067 or 1600 mg/m2) given in short infusions during four consecutive days. For each patient, approximately 20 plasma samples were available per course. Concentrations of CP, 4OHCP, TT and T were determined using GC and HPLC. Kinetic data were processed using NONMEM. RESULTS The pharmacokinetics of TT and T were described with a two-compartment model. TT was eliminated through a non-inducible and an inducible pathway, the latter resulting information of T (ClindTT = 12.4 l/hr, ClnonindTT = 17.0 l/hr). Induction of TT metabolism was mediated by a hypothetical amount of enzyme, different from that involved in CP induction, whose amount increased with time in the presence of CP. The amount of enzyme followed a zero-order formation and a decrease with a first-order elimination rate constant of 0.0343 hr(-1) (t1/2 = 20 hr). This model was significantly better than a model lacking the induction by CP. The model was successfully incorporated into the previously published pharmacokinetic model for CP, and resulted in comparable parameter estimates for this compound and its metabolite 4OHCP. CONCLUSION The pharmacokinetics of TT, when administered in combination with CP, were successfully described. The model confirms induction of TT metabolism with time and it appears likely that CP is responsible for this phenomenon. The existence of a mutual pharmacokinetic interaction between CP and TT, as described in our integrated model, may be relevant in clinical practice.

中文翻译：

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环磷酰胺和thiotepa的综合种群药代动力学模型表明相互的药物相互作用。

目的/目的在高剂量化疗方案中，环磷酰胺（CP）和噻替帕（TT）经常同时给药。前药CP显示出强烈的自诱导作用，导致其活化代谢物4-羟基环磷酰胺（4OHCP）的形成增加。TT抑制了CP的这种生物活化。以前，我们成功地模拟了CP的生物激活以及TT对自动诱导的影响。最近，我们建议CP也可能诱导TT转化为其代谢产物tepa（T）。本研究的目的是调查是否可以使用总体药代动力学模型描述CP对TT代谢的影响，以及是否可以将这种相互作用纳入描述CP和TT药代动力学的集成模型中。方法从49例患者中收集血浆样本，这些患者接受了86个疗程的短剂量高剂量CP（4000或6000 mg / m2），TT（320或480 mg / m2）和卡铂（1067或1600 mg / m2）的联合治疗连续四天输注。对于每个患者，每个疗程大约可提供20个血浆样品。CP，4OHCP，TT和T的浓度使用GC和HPLC测定。使用NONMEM处理动力学数据。结果用两室模型描述了TT和T的药代动力学。TT通过不可诱导和诱导途径消除，后者产生T信息（ClindTT = 12.4 l / hr，ClnonindTT = 17.0 l / hr）。TT代谢的诱导是由一种假设的酶介导的，该酶的数量不同于CP诱导所涉及的酶，在CP存在时，其酶的含量随时间增加。酶的量遵循零级形成和减少，其一级消除速率常数为0.0343 hr（-1）（t1 / 2 = 20 hr）。该模型明显优于缺少CP归纳的模型。该模型已成功整合到先前发布的CP药代动力学模型中，并对该化合物及其代谢物4OHCP进行了可比的参数估算。结论成功地描述了与CP联合使用时TT的药代动力学。该模型证实了随着时间的推移会诱发TT代谢，并且CP可能是造成这种现象的原因。如我们的集成模型中所述，CP和TT之间存在相互的药代动力学相互作用，可能与临床实践有关。