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Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in
Combination with Efavirenz and Two Nucleoside Reverse Transcriptase
Inhibitors in Extensively Pretreated Human Immunodeficiency
Virus-Infected Patients
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Brief study summary: When Kaletra is taken with efavirenz, efavirenz lowers the levels of Kaletra in the body and in the blood. Efavirenz has this effect on other protease inhibitors. Thus an additional dose of Kaletra is required to achieve the levels of Kaletra obtained when using the standard dose of Kaletra which is 400/100 mg twice daily. This study examined an increased dose of Kaletra and identifed the dose of Kaletra required to compensate for the reduction in Kaletra levels that result from taking efavirenz along with it. 533/133 mg of Kaletra taken twice daily compensates. This study found that when using the 533/133 mg dose twice daily comparable levels of Kaletra were obtained when combined with efavirenz as when using Kaletra 400/100 mg twice a day without efavirenz.
"...lopinavir and ritonavir AUC12, Cpredose, Cmax, and Cmin values were either marginally or significantly correlated with body weight (P < 0.064), with a larger body weight associated with lower pharmacokinetic parameter values..." suggesting perhaps adjustment of dosing for individuals with high weight.
The purpose of this study was to examine the blood levels of Kaletra and efavirenz when administered together. In scientific terms this study examined 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 in a phase II, open-label, randomized, parallel arm study.
Lopinavir/r is Kaletra. Kaletra contains lopinavir and low dose ritonavir in one capsule. The low dose of ritonavir boosts the blood levels of lopinavir to high levels. Subjects in both arms were to initiate these regimens with lopinavir/r dosing of 400/100 mg (as three coformulated capsules) BID, 600 mg of efavirenz given once daily at bedtime, and investigator-selected NRTIs. After 14 days some subjects switched to the 533/133 mg dose of Kaletra (4 capsules twice daily), while the other patients remained on the lower dose of 400/100 mg. Patients were followed for 24 weeks.
57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor HIV-infected subjects were studied. 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 (blood), particularly Cmin, than were observed in previous studies of lopinavir/r administered without efavirenz. The Cmin is the level of lopinavir in the blood at the end of the dosing period. So 12 hours after taking Kaletra the Cmin is the level of Kaletra in the blood after 12 hours and just before taking the next dose. The Cmin is important because usually the effectiveness of a drug, its antiviral potency, is associated with high Cmin levels.
Increasing the lopinavir/r dose from 400/100 mg to 533/133 mg, by 33%, increased the lopinavir more than 33%:
--area under the concentration-time curve over a 12-h dosing interval (AUC12) by +46%
--predose concentration by +70%
--and perhaps most importantly increased the Cmin by +141%
The increase in lopinavir Cmax (33%,) did not reach statistical significance. The Cmax is the maximum concentration of lopinavir in the blood which is often referred to as the peak level and occurs several hours after taking a dose of Kaletra or any drug. The peak level is of interest because often it is felt that side effects are associated with high peak levels.
Ritonavir AUC12 (area under the curve, blood levels, during the 12-hour dose period), Cmax, Cpredose (predose concentration), and Cmin 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.
What is IQ: the relationship of PI concentrations to viral susceptibility, is expressed as the inhibitory quotient (IQ). Viral susceptibility is phenotypic resistsance.
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.
All of the lopinavir IQ parameters (IQ Ctrough, IQ Cmin, IQ Cmax, and IQ AUC) were marginally or statistically significantly associated with week 24 virologic response, with P values ranging from 0.022 to 0.078. As detailed elsewhere, the lopinavir baseline phenotype was also statistically significantly correlated (P = 0.006) with the week 24 virologic response (28a). The baseline efavirenz IQ was also statistically significantly correlated with the week 24 virologic response (P = 0.027).
Week 24 virologic response rates were 70, 80, and 100% for subjects with lopinavir IQ Cpredose values of <4, 4 to 15, and >15, respectively
(P = 0.047). Thus, 100% of patients had a viral response when their IQ was >15.
Predose concentration (Cpredose) was not associated with viral response.
A total of 51 subjects were included in the pharmacodynamic analyses. The median baseline viral load for the 51 subjects included in the pharmacodynamic analyses was 4.56 log10 copies/ml, and the median baseline CD4 count was 220 cells. At week 24, the mean CD4 increase from
baseline was 49 cells, and 82% (42 of 51) of the subjects had a viral load of <400 copies/ml.
Comments by study authors: although IQ is expected to provide a better estimate of antiviral activity than drug concentration or viral susceptibility alone, it is important to appreciate the dynamic relationship between IQ and virologic response; hence, the limitations of IQ utility in clinical settings. For example, for patients with highly resistant viruses, desirable IQ values may not be accessible even with higher doses. Under such conditions, virologic response is likely to be predicted equally well by the individual's viral susceptibility data alone. Also, in treatment-naive patients, Cpredose alone may be sufficient to predict virologic response, provided that uniformly susceptible viruses can be assumed in this population (i.e., a low incidence of transmitted drug-resistant virus). Furthermore, virologic response to antiviral treatment is also governed by factors such as viral infectivity and replication capacity, individual immunologic characteristics, and patient adherence.
The inhibitory quotient, which is the ratio of drug concentration to individual baseline viral susceptibility, the individual baseline viral susceptibility, and the number of active NRTIs, the efavirenz IQ, and body weight were statistically significant predictors of antiviral response to lopinavir/r-based therapy. Validation of these pharmacokinetic-pharmacodynamic relationships in larger clinical trials could help to support the use of such metrics in treatment decision in antiretroviral agent-experienced patients.
Antimicrobial Agents and Chemotherapy, January 2003, p. 350-359, Vol. 47, No. 1. Ann Hsu,* Jeffrey Isaacson, Scott Brun, Barry Bernstein, Wayne Lam, Richard Bertz, Cheryl Foit, Karen Rynkiewicz, Bruce Richards, Martin King, Richard Rode, Dale J. Kempf, G. Richard Granneman, and Eugene Sun. Abbott Labs.
Excerpts from article:
PI-based combination regimens can lead to profound and sustained suppression
of viral replication; however, these regimens eventually fail to control replication in a significant portion of patients, leading to the eventual development of resistant viruses. Although failure of PI-based therapy has a complex and multifactorial etiology, inadequate drug concentrations in plasma due to poor or variable pharmacokinetics and/or inconsistent
adherence appear to be important factors.
Lopinavir is an HIV PI that is rapidly and essentially exclusively metabolized by cytochrome P450 3A isoenzymes (CYP3A). Lopinavir, when given alone, yields very low concentrations in plasma. However, when administered with ritonavir, a potent inhibitor of lopinavir metabolism, at the standard lopinavir-ritonavir
(lopinavir/r) dose of 400/100 mg twice a day (BID), lopinavir predose concentrations achieved in HIV-positive subjects typically exceed the serum protein binding-adjusted 50% inhibitory concentration (IC50) for wild-type HIV type 1 by at least 50-fold. In antiretroviral agent-na•ve patients lopinavir/r. in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) has demonstrated substantial and durable antiviral activity (76%, <50 copies/ml at week 144, intent-to-treat [ITT] analysis) through 3 years in a phase II clinical trial. Comparable data have been generated in children 6 months to 12 years old. In a randomized, double-blind, phase III clinical trial conducted in adult antiretroviral-naive HIV patients, lopinavir/r appeared to exhibit superior antiviral activity compared to nelfinavir (63% versus 51%, <50 copies/ml at week 60, ITT analysis, P < 0.001) (41).
The pharmacokinetic characterization of this efavirenz administered with Kaletra was essential because efavirenz, like lopinavir/r, is both an inhibitor and an inducer of CYP-mediated metabolism. Thus, a potential drug-drug interaction with efavirenz may result in increased or decreased concentrations of PIs. Furthermore, Burger et al. have shown that coadministration of nevirapine, another CYP inducer, with indinavir/ritonavir (800/100 mg
BID) significantly lowers concentrations of indinavir in plasma. The pharmacokinetic interaction between lopinavir/r and efavirenz was previously studied in healthy volunteers but was incompletely characterized due to the small sample size of that study. Nonetheless, the available results suggest that efavirenz decreased the lopinavir area under the concentration-time curve (AUC) and Cmin values (by 19 and 39%, respectively) (lopinavir/r package insert). Thus, the present study was designed to further characterize the interaction between lopinavir/r and efavirenz in HIV-infected subjects and to identify a lopinavir/r dose that was likely to yield lopinavir predose levels similar to those achieved at the standard dose of lopinavir/r without efavirenz.
Since drug resistance testing has become widely available, a number of studies have also demonstrated that baseline viral susceptibility to individual
drugs, whether expressed as a function of genotype or phenotype, also correlates with virologic response in patients previously treated with antiretroviral medications. The correlation of baseline phenotype and genotype with the virologic response to lopinavir/r has been characterized elsewhere.
We hypothesized that the pharmacodynamic parameter most relevant to PI-based treatment response is the relationship of PI concentrations to viral
susceptibility, expressed as the inhibitory quotient (IQ). The present study provided an opportunity to test this hypothesis because it represented patients with both a population distribution of drug concentrations and a wide range of drug susceptibilities at baseline.
Subjects were required to have previously received at least two PIs for at least 12 weeks each (sequentially or concomitantly), including treatment with a stable PI regimen for at least 8 weeks prior to study entry. They were to have HIV RNA levels of >1,000 copies/ml, have had no prior NNRTI treatment, be 18 years in age, and have a Karnofsky score 70.
The mean numbers of prior PIs and total antiretroviral agents used were 2.9 and 7.1, respectively. Of the 50 subjects with evaluable pharmacokinetic data, 86% were Caucasian (with 10% black and 4% Hispanic) and 82% were male.
Sixty-eight percent of baseline viral isolates demonstrated a 4-fold increase in
IC50 to 3 licensed PIs by phenotypic analysis. The mean susceptibility to lopinavir at baseline was 16-fold above the susceptibility of the wild-type virus.
The estimated effects of efavirenz on lopinavir AUC and Cmax were similar to those observed for indinavir (decreases in AUC by 31%; Cmax, 16%) but smaller than those observed for saquinavir (decreases in AUC by 62%; Cmax by 50%) when the two PIs were used in combination with efavirenz (efavirenz package insert).
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