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.

Selection of Resistance in Protease Inhibitor-Experienced, Human Immunodeficiency Virus Type 1-Infected Subjects Failing Lopinavir- and Ritonavir-Based Therapy: Mutation Patterns and Baseline Correlates

“…However, to date, the development of resistance to LPV has not been observed among ARV-naive patients treated with an LPV-RTV-based combination regimen for up to 4 years in clinical trials (14,23), and only recently have isolated anecdotes of primary resistance in previously untreated patients been reported (7,9). This apparently high barrier to resistance is consistent with the observation that the mean plasma LPV trough levels exceed the serum-adjusted 50% inhibitory concentration (IC 50 ) of LPV for wild-type HIV substantially and suggests that considerably reduced susceptibility to LPV is required for a compromised virologic response (3,16). In multiple PI-and nucleoside reverse transcriptase inhibitor (NRTI)-experienced, nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients, maximal virologic response to treatment with LPV-RTV plus efavirenz (EFV) and NRTIs was observed in patients with baseline viruses containing up to five protease mutations associated with LPV resistance and/or displaying up to 10-fold reduced susceptibility to LPV (lower clinical breakpoint).…”

“…Both NVP and EFV lower LPV trough concentration levels through hepatic induction. Some, but not all of the subjects in recent studies were receiving an additional capsule of LPV-RTV, which mostly compensates for the negative drug-drug interactions (16,36). Therefore, the upper breakpoints estimated in this analysis may be slightly higher for other combination regimens where LPV-RTV is used at the standard dose without an NNRTI.…”

Estimation of Serum-Free 50-Percent Inhibitory Concentrations for Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

“…Originally envisioned as a pharmacodynamic model for the in vivo activity of antibacterial agents (8), the IQ has been adapted for PIs as the minimal total drug concentration in plasma (C trough )/IC 50 ratio. The IQ has been shown to be predictive of the virologic response to PI-based antiretroviral therapy (13,29); however, there is wide disagreement on the optimal method for estimating the IQ based on in vitro assays (2,20,26). In vitro tissue culture assays maximally tolerate ca.…”

The Design and Implementation of A5146, a Prospective Trial Assessing the Utility of Therapeutic Drug Monitoring Using an Inhibitory Quotient in Antiretroviral-Experienced HIV-Infected Patients

“…The patient IQ was the ratio of the patient trough PI concentration to the patient's virus' fold-change in IC 50 for that PI, obtained at screening (Figure 2). The reference IQ for each PI was calculated using the mean trough concentration divided by the mean fold-change in IC 50 for clinical cohorts that had high rates of virologic suppression 12,13,26,37,38 (Table 1). …”

“…There are a number of potential explanations for this result. First, this trial did not utilize an inhibitory quotient (IQ), which incorporates both drug exposure and viral drug resistance and has been shown in several studies to correlate with virologic responses in treatment-experienced patients [12][13][14][15][16][17][18][19][20][21][22][23] . Second, the majority of subjects in the TDM arm did not undergo a dose adjustment 11 .…”