title: Altered pharmacokinetics of indinavir by a novel nonnucleoside reverse transcriptase inhibitor (HBY-097): a pharmacokinetic evaluation in HIV-positive patients.
abstract: HBY-097 (HBY), an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI), and indinavir (IDV) share a common metabolic pathway, cytochrome P4503A4 (CYP3A4), and may clinically be used together as well as with zidovudine (ZDV). Thus, the potential pharmacokinetic (PK) interaction between these drugs was evaluated. HBY (500 mg Q8H), IDV (800 mg Q8H), and ZDV (200 mg Q8H) were given to 8 HIV-infected subjects. Serial plasma samples were collected at baseline (ZDV and IDV alone) and day 11 (all 3 drugs) to determine PK parameters using noncompartmental analysis. PK parameters for ZDV in the presence and absence of HBY were not appreciably different. However, both the maximum (Cmax) and minimum (Cmin) concentrations of IDV were significantly reduced, from a mean of 7514 +/- 1636 and 146 +/- 81 mcg/L to 4725 +/- 2494 mcg/L and 54 +/- 24 mcg/L (p < .05) after addition of HBY. Furthermore, apparent clearance (CL/F) of IDV before and after 11 days of concomitant HBY administration was significantly higher, from 0.69 +/- 0.14 to 1.94 +/- 0.63 L/h/kg (p < .05) with an associated reduction in area under the curve (AUC0-8) from 16,034 +/- 4903 to 6134 +/- 2701 mg/L/h (p < .05). The increase in IDV CL/F is consistent with the observed metabolic induction effects of other NNRTIs. The results of this trial showed that HBY significantly alters the pharmacokinetic parameters of IDV at the dose studied.
authors.affiliation: Department of Clinical Pharmacy, University of California, San Francisco 94143-0622, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: D
authors.initials: D
authors.lastname: Jayesekera
authors.forename: A
authors.initials: A
authors.lastname: Jayewardene
authors.forename: A
authors.initials: A
authors.lastname: Shah
authors.forename: L
authors.initials: L
authors.lastname: Thevanayagam
authors.forename: F
authors.initials: F
authors.lastname: Aweeka
mesh_terms: D000328:Adult; D000998:Antiviral Agents; D019540:Area Under Curve; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006679:HIV Seropositivity / Q000188:drug therapy; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015215:Zidovudine / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019469:Indinavir; C093110:HBY 097