治疗性药物监测

 

Robert W. Shafer, M.D

Assistant Professor of Medicine

Division of Infectious Diseases and Geographic Medicine

Stanford University

Stanford, California

E-mail: rshafer@stanford.edu

 

Janell Kobayashi, Pharm. D.

Clinical Pharmacist

VA Palo Alto HCS, Department of Pharmacy, 119

3801 Miranda Avenue, Palo Alto, CA 94304

(650)493-5000#65836

E-mail: janellkobayashi@yahoo.com

 

译者：吴鹏 博士研究生

      北京协和医院 感染科

      wpnsync@163.com

  

校对：卢洪洲 教授 博士生导师

      上海市公共卫生临床中心感染一科

 

 

               The pharmacokinetics of antiretroviral drugs depend on their absorption, metabolism, protein binding, and interactions with other drugs. Inter-patient pharmacokinetic variability – not just variability in adherence – influences both the success of HAART and the risk of drug toxicity (3, 4, 7). There are large differences among patients in the pharmacokinetics of the protease inhibitors and to a lesser extent the non-nucleoside RT inhibitors (NNRTIs). Therefore, there is a strong rationale for measuring the serum levels of protease inhibitors and possibly NNRTIs so that drug dosages can be modified to maximize the virologic response to therapy while minimizing drug toxicity (5, 8). However, the practical application of therapeutic drug monitoring in routine clinical settings faces many hurdles (3).              

        抗反转录病毒药物的药代动力学因药物的吸收、代谢、蛋白结合率以及与其他药物的相互作用不同而存在差异。病人之间药代动力学的差异不仅仅是会影响HARRT成功率，以及药物毒副作用大小和服药依从性差异 (3, 4, 7)。患者群体中蛋白酶类抑制剂的药代动力学存在很大差异而非核苷类反转录酶抑制剂类的药代动力学差异次之。因此，对血浆蛋白酶抑制剂和非核苷类反转录酶抑制剂的血药浓度进行监测非常有必要，在此基础上可以调整药物服用量以优化HIV病毒抑制效果和减轻药物毒性(5, 8)。然而，治疗性药物监测在临床常规的开展中面临着许多困难(3)。      

Inter-Patient Differences In Pharmacokinetics

不同病人之间的药代动力学差异

               Protease inhibitors and NNRTIs are metabolized by the cytochrome P450 enzyme system, primarily by the 3A4 isoform (CYP3A4). Several membrane transporter proteins, particularly P-glycoprotein (PGP), also play a role in the pharmacokinetics of antiretroviral drugs. Increased PGP activity is expected to lower the antiretroviral activity of compounds affected by this transporter. PGP may also play a role in admittance of antiretroviral drugs to restricted compartments (6). 

        蛋白酶抑制剂和非核苷类反转录酶抑制剂通过人体内细胞色素P450酶系统代谢，其中，又主要经由3A4(CYP3A4)进行。一些膜转运蛋白，尤其是P-糖蛋白(PGP) 也会影响到抗反转录病毒药物的药代动力学。PGP活性的增加将会通过影响抗反转录病毒药物的转运而减低其活性。另外，PGP亦可能影响抗反转录病毒药物进入药物分布受限区域的效率(6)。              

               The genes coding for CYP450 enzymes and PGP are polymorphic, partially explaining inter-patient differences in activities. The activity of these enzymes is also be affected by other drugs (see Antiretroviral Drug Characteristics), commonly used herbs (e.g. St John's wort induces CYP3A4), liver disease, and pregnancy. The effect of serum binding proteins on antiretroviral activity also varies among patients because many of the proteins are acute phase reactants. 

        编码CYP450酶类和PGP的基因的多态性可以在一定程度上解释不同病人之间抗反转录病毒药物代谢的差异。这些酶类的活性同样会受到其他抗病毒药物（详见抗反转录病毒治疗药物特性）、常用的草药（如St John草药会诱导CYP3A4的活性）、肝脏疾病以及怀孕的影响。因为很多血浆蛋白是一些疾病急性期反应产物，因而在不同病人之间的影响抗反转录病毒药物活性的血浆结合蛋白的作用也是不同的。

Antiretroviral pharmacokinetics

抗反转录病毒的药代动力学 

               Cmin，Cmax，and AUC refer to the plasma trough level, plasma peak level, and area under the time-concentration curve, respectively. Intensive pharmacokinetic studies are used to measure AUC. Population-based studies are used to measure a drug's steady state Cmin. Although these parameters have been defined for most antiretroviral drugs, the therapeutic ranges — the range of concentrations within which the probability of an efficacious response is sufficiently greater than the probability of unwarranted toxicity (2) — for most antiretroviral drugs have not been established. Moreover, the therapeutic range for protease inhibitors may depend on the extent of drug resistance. In this situation the ratio of the Cmin to IC50, sometimes referred to as the inhibitory quotient (IQ), may be required to predict antiviral outcome (9). 

        Cmin，Cmax，AUC分别是指药物在血浆中的谷浓度，峰浓度以及药物浓度—时间曲线下的面积。精密的药代动力学研究要测量AUC。群体性研究则要测定药物稳态下的谷浓度。尽管大多数抗病毒药物的Cmin、Cmax、AUC已经确定，但对于有效药物浓度范围（所谓有效药物浓度范围是指药物在该浓度范围下发挥治疗作用的概率大大超过其在体内产生的毒性的风险(2)）大多数抗反转录病毒药物尚未建立。除此之外，蛋白酶抑制剂的有效药物浓度范围可能取决于病毒的耐药性。在这种情况下，Cmin 与IC50 的比值，有时被称作抑制指数(IQ)，就可能会用来预测蛋白酶抑制剂抗病毒的效果(9)。

Recommendations

一些建议 

               A recent consensus panel has listed those clinical situations where therapeutic drug monitoring is more likely to be of clinical benefit (3): (i) In pregnant women, in children, and in individuals with hepatic disease or with particularly low or high body weight, (ii) In cases of suspected drug interactions (e.g. ≥2 drugs with an influence on P450 activity), (iii) Suspected malabsorption or other condition that may cause abnormal drug levels, (iv) For evaluation of unsatisfactory virologic responses, (v) For patients with dose-related adverse drug reactions, (vi) For once daily regimens using ritonavir-boosted protease inhibitors, (vii) In deep salvage, to expose patients to maximal tolerable levels while limiting the risk of toxicity. 

        近来一个专家小组的研讨会指出：在以下情形下，进行治疗性药物监测的有着更大的临床意义(3)：(1)孕妇，儿童，以及有肝脏疾病或者是体重过高，过低的患者；(2)怀疑药物间存在相互作用（如两种或两种以上药物都可能影响P450的活性）；(3)怀疑有药物吸收不良或者其他情况导致药物浓度的异常；(4)抗病毒疗效不佳时分析潜在原因；(5)存在药物剂量相关的不良反应的病人；(6)利托那韦每天服用一次的蛋白酶抑制剂增效疗法作为治疗方案者；(7)挽救性治疗中，需要对病人使用最大可耐受剂量药物并限制药物毒性风险时。

               The accuracy and reproducibility of drug measurements within reputable laboratories is probably high enough for following individual patients; inter-laboratory reproducibility is likely to improve over time (1). For most protease inhibitors, the Cmin is obtained by measuring drug levels at the end of a dosing interval. Therapeutic drug monitoring for nelfinavir is complicated by delays in absorption and the presence of an active metabolite, M8. For efavirenz and nevirapine — the most commonly used NNRTIs — the half-life of drug elimination is so long that a steady-state level is often achieved, which can be measured at any time during the dosage schedule. Serum levels of NRTIs appear have less inter-patient variability. The extent to which they correlate with the more difficult to measure intracellular drug-triphosphate levels is not known (3). 

        在一些优秀的实验室，药物浓度测定的精确性和可重复性满足病人个体化用药的检测需求；不同实验室之间的可重复性也会逐步得到改善(1)。对于大多数蛋白酶类抑制剂来说，Cmin 都是在下次服药前检测得到的。由于奈非那韦在体内吸收迟缓并且它在体内以M8的活性代谢物形式存在，所以这个药的监测开展起来比较困难。对于最常用的两个非核苷类逆转录酶抑制剂依非韦仑和奈韦拉平而言，由于这两个药的半衰期很长所以它们在在服药周期内任何时间点的取血测定都可作为血浆稳态浓度值。核苷类逆转录酶抑制剂的血浆浓度似乎在不同患者之间变化不大。核苷类反转录酶抑制剂的血浆浓度与其在细胞内的更加难以测定的三磷酸盐浓度水平的相关性目前还不明确(3)。

               As a general rule, tough levels should be obtained as close as possible to the end of the dosing interval after at least 3 weeks of therapy, when steady-state is expected to be attained (2). For treatment-naοve patients without resistant virus, trough levels can be compared to reported trough ranges (see Table 1). Dose adjustments should be considered for sub-therapeutic levels after a thorough patient history has been taken to assess compliance, dietary changes affecting absorption, and recent additions of medications, including over-the-counter medications and herbal supplements. For treatment-experienced patients or patients with drug-resistant virus, phenotypic tests may provide a better estimate of target trough concentrations. With the currently available phenotypic tests, it is important to adjust for protein binding since only unbound drug is active. 

        一般而言，药物治疗至少3周以后体内才能达到血药稳态水平(2)，此时在尽可能接近下次服药的时间点取血测量则可认为是药物的谷浓度值。对于没有经过抗病毒治疗而且体内不存在耐药毒株的病人而言，他们体内药物的谷浓度可与研究报道的药物谷浓度有效治疗范围相比较（见表一），若病人的药物谷浓度低于有效药物浓度范围则应该在考虑到病人的依从性、饮食的改变是否影响药物吸收、最近用药情况如非处方药和草药的使用情况和剂量以后，尝试对病人进行用药的调整。对于已经过治疗或者体内有耐药毒株的病人而言，进行病毒表型检测是提供用药靶浓度范围估计值的更好方法。既然血浆中游离的药物成分才具有抗病毒活性，所以，目前的表型检测方法应当根据血浆蛋白结合率做出适当的调整以避免估算误差。 

 

Tables and Figures

图表以及数据

 

Table 1. Estimated Minimum Trough Concentration Ranges for Wild-Type Virus (2)

表1.野生型病毒有效治疗的最小谷浓度估计值

 

Drug

药物                                                                        

Concentration ranges (ng/ml)

治疗窗(ng/ml)

Saquinavir

沙奎那韦

100 – 250

Ritonavir

利托那韦

1500 – 2100 (single drug only) （单药使用时）

Indinavir

茚地那韦

80 – 120

Nelfinavir*

奈非那韦

700 – 1000

Amprenavir

安普那韦

150 – 400

Lopinavir/Ritonavir

洛匹那韦/利托那韦

700

Nevirapine

奈韦拉平

3400

Efavirenz

依非韦伦

1000 – 1100

* Measurable active (M8) metabolite

＊可测量的活性代谢物(M8)

 

REFERENCES

参考文献

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