英文药名: Kaletra(Lopinavir/Ritonavir Capsules)

中文药名: 洛匹那韦利托那韦胶囊

品牌药生产厂家: Abbott

药品简介

商品名（中文）: 克力芝
在抗HIV联合治疗中，使用每日一次洛匹那韦／利托那韦配方（Kaletra，雅培），可能与每日两次给药同样有效，并且可改善依从性。
药理毒理

*药效学：
洛匹那韦是一种HIV-1和HIV-2的蛋白酶的抑制剂。作为复方制剂，利托那韦可以抑制CYP3A介导的洛匹那韦代谢，从而提高血浆中洛匹那韦的药物浓度。
作用机理：洛匹那韦可以阻断Gag-Pol聚蛋白的分裂，导致产生未成熟的、无感染力的病毒颗粒。
体外抗病毒活性：洛匹那韦对于实验室HIV链和临床的HIV分离毒株分别在急性感染的淋巴母细胞系和外周血淋巴细胞显示出体外抗病毒活性。在不加人血清的情况下，洛匹那韦对五种不同HIV-1实验室毒株的50%有效浓度（EC50）在10～27nM（0.006～0.017μg/mL，1μg/mL=1.6μM）之间，对几种临床分离毒株的50%有效浓度在4～11nM（0.003～0.007μg/mL）之间（n=6）。在含50%人血清时，洛匹那韦对这五种实验室毒株的平均EC50为65～289nM（0.04～0.18μg/mL），升高了7至11倍。洛匹那韦与其它蛋白酶抑制剂或逆转录酶抑制剂的联合用药活性研究尚在继续进行当中。
耐药性：已在体外筛选出了对洛匹那韦敏感性下降的HIV-1分离株。利托那韦的存在似乎不影响对洛匹那韦耐药病毒株的体外筛选。
*交叉耐药-临床前研究
在蛋白酶抑制剂中观察到了不同程度的交叉耐药性。研究者对早先使用过单一蛋白酶抑制剂的患者的临床分离株进行了洛匹那韦的体外活性测定。对奈非那韦（n=13）和沙奎那韦（n=4）敏感性下降4倍以上的分离株，对洛匹那韦的敏感性下降倍数低于4。对茚地那韦（n=16）和利托那韦（n=3）敏感性下降4倍以上的分离株，对洛匹那韦的敏感性分别下降了5.7和8.3倍。以前接受过两个或更多蛋白酶抑制剂治疗的患者的分离株对洛匹那韦的敏感性下降程度更大。
*交叉耐药-洛匹那韦/利托那韦治疗期间
有关在洛匹那韦/利托那韦治疗过程中对洛匹那韦敏感性下降的病毒的交叉耐药性的资料很有限。通过从4名以前接受过一种或更多蛋白酶抑制剂治疗的患者中分离的病毒株研究发现在洛匹那韦/利托那韦治疗期间会增加洛匹那韦的表型耐药，表现为持续的交叉耐药或增加对利托那韦，茚地那韦和奈非那韦的耐药。所有反跳的病毒株对安泼那韦仍保有完全的敏感性或经证实其敏感性只有适当的下降（当洛匹那韦耐药增加99倍时，其耐药最多增加8.5倍）。从2名以前未接受沙奎那韦治疗的患者中分离的反跳病毒株仍对沙奎那韦保有完全的敏感性。
药代动力学

人们已对洛匹那韦与利托那韦合并给药时在健康成年志愿者和HIV感染患者的药代动力学特性进行了研究；这两组人群没有明显差异。洛匹那韦基本上全部由肝脏CYP3A代谢。利托那韦抑制肝脏CYP3A对洛匹那韦的代谢，从而提高洛匹那韦的血浆浓度。在不同试验中，HIV感染患者服用本品400/100mg、每日两次（BID）后，所得洛匹那韦的平均稳态血浆浓度比利托那韦高15～20倍。利托那韦的血浆浓度比其按600mg、每日两次给药所得浓度的7%还低。洛匹那韦的体外抗病毒EC50约比利托那韦低10倍。因此，本品的抗病毒活性是由洛匹那韦产生。
与食物合用后，服用本品200/50mg2片与服用3粒洛匹那韦与利托那韦133/33mg胶囊后的血浆浓度相当，其药代动力学差异少。
1.吸收
在一项HIV阳性受试者的药物动力学研究中（n=19），本品400/100mg，BID与食物合用，多次给药，连续3周，结果洛匹那韦血浆峰浓度（Cmax）为9.8±3.7μg/mL（均值±SD），约在给药后4小时达到峰浓度。清晨给药前的平均稳态谷浓度为7.1±2.9μg/mL。给药间期的最低血浓度为5.5±2.7μg/mL，洛匹那韦在12小时给药间隔内的AUC平均为92.6±36.7μg·h/mL。尚未确定洛匹那韦与利托那韦合并给药时在人体的绝对生物利用度。
*食物对口服吸收的影响
与禁食状态相比，本品400/100mg与食物同服（高脂肪饮食，872kcal，56%热量来自脂肪），AUC和Cmax的改变没有显著的临床意义。因此，本品可以与食物同服或不与食物同服。与食物同服的条件下，本品的药代动力学与Kaletra胶囊的差异很少。
2.分布
稳态时，洛匹那韦约有98-99%与血浆蛋白结合。洛匹那韦与α-1-酸性糖蛋白（AAG）和白蛋白均可结合；但它与AAG的亲和力更高。在稳态下，洛匹那韦/利托那韦400/100mg BID给药后，洛匹那韦的蛋白结合在观察到的浓度范围内保持恒定，健康志愿者和HIV阳性患者之间情况相似。
3.代谢
用人肝微粒体进行的体外实验表明，洛匹那韦主要经氧化代谢。洛匹那韦被肝细胞色素P450系统广泛代谢，且几乎专门由CYP3A同功酶代谢。利托那韦是一个强效的CYP3A抑制剂，可抑制洛匹那韦的代谢，因此能够提高洛匹那韦的血浆浓度。一项人体14C-洛匹那韦研究表明，单次给予本品400/100mg后，血浆放射活性的89%来自母体化合物。在人体中至少已鉴别出13个洛匹那韦的氧化代谢物。实验表明利托那韦能够诱导代谢酶，从而诱导它自身的代谢。在多次给药过程中，洛匹那韦在给药前的浓度随时间下降，约在10至16天后达到稳定。
4.消除
给予14C-洛匹那韦/利托那韦400/100mg8天后，在尿和粪便中检测到的14C-洛匹那韦分别占给药剂量的10.4±2.3%和82.6±2.5%。单次给药后，从尿和粪便中检测的原形洛匹那韦分别约占给药剂量的2.2%和19.8%。多次给药后，以原形从尿中排泄的洛匹那韦不到给药剂量的3%。洛匹那韦的表观口服清除率（CL/F）为5.98±5.75L/hr（均值±标准差.N=19）。
5.特殊人群
*性别，种族和年龄
尚未在老年患者中研究洛匹那韦的药代动力学。成年患者未见与性别相关的药代动力学差异。尚未发现由种族引起的具有重要临床意义的药代动力学差异。
*儿童患者
在53名年龄在6个月至12岁的儿童患者研究了本品300/75mg/m2 BID和230/57.5mg/m2 BID的药代动力学。230/57.5mg/m2 BID（不给奈韦拉平）方案和300/75mg/m2 BID（给奈韦拉平）方案得到的洛匹那韦血浆浓度与在接受400/100mg BID方案（不给奈韦拉平）的成年患者得到的血浆浓度相近。
在给予本品230/57.5mg/m2 BID（不给奈韦拉平）（n=12）或300/75mg/m2 BID（给奈韦拉平）（n=12）后，洛匹那韦的平均稳态AUC值、Cmax和Cmin分别为72.6±31.1μg·h/mL、8.2±2.9μg/mL、3.4±2.1μg/mL和85.8±36.9μg·h/mL、10.0±3.3μg/mL、3.6±5.5μg/mL。其中奈韦拉平给药方案为7mg/kg BID（6个月至8岁）或4mg/kg BID（8岁以上）。
*肾功能不全
未在肾功能不全患者研究洛匹那韦的药代动力学；但是，因为洛匹那韦的肾清除微乎其微，估计肾功能不全患者不会发生总体清除率的下降。
*肝损伤
洛匹那韦主要经肝脏代谢和消除。本品400mg/100mg，一日两次，用于HIV合并HCV感染，伴随轻到中度肝功能损害的患者，与肝功能正常的HIV感染受试者相比较，洛匹那韦的AUC值升高了30%，血浆峰浓度升高了20%。另外，在轻度或中度肝功能损伤的患者中洛匹那韦的血浆蛋白结合率低于对照组（分别为99.09%和99.31%）。目前没有本品对于严重肝功能损害HIV患者药代动力学的研究。
适应症

本品适用于与其它抗逆转录病毒药物联合用药，治疗HIV感染。

包装规格：133.3/13.3mg *180 软胶囊 /盒/瓶

Kaletra
Generic Name: lopinavir and ritonavir (loe PIN a vir and ri TOE na veer)
Brand Names: Kaletra
What is Kaletra?
Kaletra contains a combination of lopinavir and ritonavir. Lopinavir and ritonavir are antiviral medications that prevent human immunodeficiency virus (HIV) cells from multiplying in your body

Kaletra is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Kaletra is not a cure for HIV or AIDS.

Kaletra may also be used for purposes not listed in this medication guide.

Important information about Kaletra
There are many other drugs that can cause serious or life threatening medical problems if you take them together with Kaletra. The following drugs should not be used while you are taking Kaletra: alfuzosin (Uroxatrol), lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin), St. John's wort, pimozide (Orap), midazolam (Versed) or triazolam (Halcion), rifampin (Rimactane, Rifadin, Rifater, Rifamate), sildenafil (Revatio for pulmonary arterial hypertension), or an ergot medicine such as D.H.E. 45, Ergomar, Cafergot, Ergotrate, Methergine, Migergot, or Migranal.

Many other medicines can interact with Kaletra. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Taking Kaletra will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Before taking Kaletra
You should not use Kaletra if you are allergic to lopinavir or ritonavir. There are many other drugs that can cause serious or life threatening medical problems if you take them together with Kaletra. The following drugs should not be used while you are taking this medication: alfuzosin (Uroxatrol), lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin), St. John's wort, pimozide (Orap), midazolam (Versed) or triazolam (Halcion), rifampin (Rimactane, Rifadin, Rifater, Rifamate), sildenafil (Revatio for pulmonary arterial hypertension), or an ergot medicine such as D.H.E. 45, Ergomar, Cafergot, Ergotrate, Methergine, Migergot, or Migranal.

To make sure you can safely take Kaletra, tell your doctor if you have any of these other conditions:

liver disease (especially hepatitis B or C);
heart disease or a heart rhythm disorder;

a personal or family history of "Long QT Syndrome";

pancreas problems;

diabetes;

low levels of potassium in your blood;

a bleeding disorder such as hemophilia;

high cholesterol or triglyceride levels in your blood; or

if you have ever used a protease inhibitor in the past.

FDA pregnancy category C. It is not known whether Kaletra will harm an unborn baby. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection. Kaletra can make birth control pills or patches less effective. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking Kaletra. Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk. Do not give Kaletra to a child younger than 14 days old without medical advice. Premature infants should not receive Kaletra until it has been 14 days after their original due date.
How should I take Kaletra?
Take Kaletra exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label, especially when giving the medicine to a child.

Kaletra tablets may be taken with or without food.

Do not crush, chew, or break a Kaletra tablet. Swallow the pill whole. Kaletra liquid should be taken with food.

Measure Kaletra liquid with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

To be sure Kaletra is helping your condition, your blood may need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.

Store the liquid medicine in the refrigerator or at room temperature, away from heat or moisture. If you store the medicine at room temperature you must use it within 60 days. Store the tablets at room temperature, away from heat and moisture. Keep the pills in their original container with the cap tightly closed.

What happens if I miss a dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of Kaletra oral liquid could be fatal to a child.

What should I avoid while taking Kaletra?
If you take Kaletra liquid and you also take didanosine (Videx), take the didanosine at least 1 hour before or 2 hours after you take Kaletra liquid.

Kaletra liquid contains of alcohol. Avoid drinking alcohol while using this medicine. Tell your doctor if you also take metronidazole (Flagyl) or disulfiram (Antabuse), which can cause severe nausea and vomiting when taken with Kaletra liquid. Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Kaletra side effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking Kaletra and call your doctor at once if you have any of these serious side effects:

dizziness, fainting, fast or pounding heartbeats;

vision changes;

increased urination or extreme thirst;

penis erection that is painful or lasts longer than 4 hours;

signs of a new infection, such as fever or chills, cough, or flu symptoms;

severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

loss of appetite, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Less serious side effects may include:

mild nausea, vomiting, diarrhea, upset stomach;

mild skin rash;

headache, weakness, feeling tired; or

changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.