title: Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients.
abstract: The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C(min), than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC(12)), C(predose), and C(min) by 46, 70, and 141%, respectively. The increase in lopinavir C(max) (33%,) did not reach statistical significance. Ritonavir AUC(12), C(max), C(predose), and C(min) values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. annhsu@aol.com
authors.forename: Ann
authors.initials: A
authors.lastname: Hsu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Isaacson
authors.forename: Scott
authors.initials: S
authors.lastname: Brun
authors.forename: Barry
authors.initials: B
authors.lastname: Bernstein
authors.forename: Wayne
authors.initials: W
authors.lastname: Lam
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
authors.forename: Cheryl
authors.initials: C
authors.lastname: Foit
authors.forename: Karen
authors.initials: K
authors.lastname: Rynkiewicz
authors.forename: Bruce
authors.initials: B
authors.lastname: Richards
authors.forename: Martin
authors.initials: M
authors.lastname: King
authors.forename: Richard
authors.initials: R
authors.lastname: Rode
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: G Richard
authors.initials: GR
authors.lastname: Granneman
authors.forename: Eugene
authors.initials: E
authors.lastname: Sun
mesh_terms: D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines; D001682:Biological Availability; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000187:drug effects*; D006801:Humans; D016015:Logistic Models; D061466:Lopinavir; D010078:Oxazines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D054303:HIV Reverse Transcriptase; C098320:efavirenz; D019438:Ritonavir