Dosing Kaletra With Efavirenz
Study title: "Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir
in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase
Inhibitors in Extensively Pretreated Human Immunodeficiency
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
valuesÉ" suggesting perhaps adjustment of dosing for individuals with high
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
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 by more than 33%:
--area under the concentration-time curve over a 12-h dosing interval (AUC12)
--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
What is IQ: the relationship of PI concentrations to viral susceptibility, is
expressed as the inhibitory quotient (IQ). Viral susceptibility is phenotypic
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 pharmaco
dynamic 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
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-naive
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-in
fected 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
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
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
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