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Current Status of the Pharmacokinetics and Pharmacodynamics of HIV-1 Entry Inhibitors and HIV Therapy

[ Vol. 18 , Issue. 8 ]

Author(s):

Fengyan Xu , Edward P. Acosta, Liyu Liang, Yingchun He, Juan Yang, Corenna Kerstner-Wood, Qingshang Zheng, Jihan Huang* and Kun Wang*   Pages 769 - 781 ( 13 )

Abstract:


Background: Human Immunodeficiency Virus (HIV) entry inhibitors target the first step of the HIV life cycle and efficiently inhibit HIV from infecting the immune cells which is a key prerequisite for viral spread. Because of their unique mechanism of action on cell-cell transmission, they may provide a promising perspective for the treatment of AIDS.

Method: Maraviroc (MVC) and Enfuvirtide (ENF) have been approved by the FDA for the treatment of HIV-1 infection. Attachment inhibitors (BMS-663068 and TNX-355) and co-receptor inhibitors (PRO-140 and cenicriviroc (CVC)) have reached phase II or III clinical trials. These entry inhibitors show beneficial pharmacokinetics and substantial reductions of plasma HIV-1 RNA load in HIV infected patients.

Results: Most entry inhibitors are generally safe, without serious Adverse Event (AE) or AE leading to discontinuation. The pharmacokinetics of MVC, CVC and BMS-663068 was affected by CYP3A4 inhibitors or inducers. The FDA has proposed that the dosage of MVC (300 mg, BID, orally) be adjusted to half or two-fold for patients if it is combined with a major CYP3A4 inhibitor or inducer, respectively. Researchers suggested that the dosage of CVC (50-75 mg, QD, orally) may also need adjustment but the dosage of BMS-663068 (600 mg, BID, orally) does not.

Conclusion: The standard, recommended ENF dosage is 90 mg BID, injected subcutaneously for adults, and 2 mg/kg BID, up to a maximum dose of 90 mg, injected subcutaneously for pediatric patients. TNX-355 (10-15 mg/kg, BID, intravenously) and PRO-140(5-10 mg/kg, BID, intravenously; 324 mg, biweekly, subcutaneously) are administered by intravenous infusion or subcutaneous injection.

Keywords:

Pharmacokinetics, pharmacodynamics, HIV entry inhibitors, maraviroc, enfuvirtide, fostemsavir, ibalizumab, cenicriviroc, PRO- 140.

Affiliation:

Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Division of Clinical Pharmacology, University of Alabama at Birmingham, School of Medicine, Birmingham 35294-0019, AL, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Division of Clinical Pharmacology, University of Alabama at Birmingham, School of Medicine, Birmingham 35294-0019, AL, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203

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