Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors.
Dolutegravir (DTG), elvitegravir (EVG) and raltegravir (RAL) are members of the latest class of antiretrovirals (ARVs) that have become available to treat human immunodeficiency virus (HIV) infection: integrase strand transfer inhibitors (INSTIs). INSTIs are potent inhibitors of the HIV integrase enzyme, with protein binding-adjusted concentration inhibiting viral replication by 90/95 % [IC90/95] values in the low nanogram per millilitre range, and they retain antiviral activity against strains of HIV with acquired resistance to other classes of ARVs. Each of the INSTIs has unique pharmacokinetic/pharmacodynamic properties, influencing its role in clinical use in specific subsets of patients. RAL and DTG have minimal drug-drug interaction profiles, as their metabolism has minimal cytochrome P450 (CYP) involvement. Conversely, EVG metabolism occurs primarily via CYP3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. EVG and DTG have the added benefit of availability of fixed-dose combination tablets, allowing for convenient and simplified ARV regimens. RAL is the only INSTI to be listed as a preferred agent in the current US perinatal treatment guidelines. All three INSTIs are recommended regimens for treatment-naïve individuals in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the INSTIs, and describes specific pharmacokinetic considerations for special patient conditions: hepatic impairment, renal dysfunction, pregnancy and co-infections.
Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, 986000 Nebraska Medical Center, Omaha, NE, 68198-6000, USA.
Anthony T
AT
Podany
Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, 986000 Nebraska Medical Center, Omaha, NE, 68198-6000, USA.
Kimberly K
KK
Scarsi
Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, 986000 Nebraska Medical Center, Omaha, NE, 68198-6000, USA. cfletcher@unmc.edu.
Courtney V
0000-0002-3703-7849
CV
Fletcher
D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D060085:Coinfection; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D006207:Half-Life; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D017093:Liver Failure / Q000378:metabolism; D008657:Metabolic Clearance Rate; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D011485:Protein Binding; D011728:Pyridones; D015363:Quinolones / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068898:Raltegravir Potassium / Q000493:pharmacokinetics / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000378:metabolism; D000099226:Dolutegravir
D044966:Anti-Retroviral Agents; D051544:Cytochrome P-450 CYP3A; D004338:Drug Combinations; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1