| |
Pharmacokinetics and Safety of Etravirine Administered Once or Twice Daily After 2 Weeks Treatment With Efavirenz in Healthy Volunteers
|
| |
| |
JAIDS Journal of Acquired Immune Deficiency Syndromes:
October 2009
Boffito, Marta MD, PhD; Jackson, Akil MBBS; Lamorde, Mohammed MBBS; Back, David PhD; Watson, Victoria MSc; Taylor, Jessica; Waters, Laura MBBS; Asboe, David MD; Gazzard, Brian MD; Pozniak, Anton MD
From the *Department of HIV/GUM Medicine, St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom; Department of Pharmacology and Therapeutics, Trinity College Dublin, Dublin, Ireland; ŕDepartment of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom; and ¤NIHR Biomedical Research Centre, Royal Liverpool Hospital Trust, Liverpool, United Kingdom.
"The induction effect of efavirenz persists for at least 2 weeks after stopping drug intake. The decrease in etravirine is not considered clinically significant. Further clinical data are warranted."
Abstract
Objective: To assess the pharmacokinetics of etravirine once and twice daily without and with a preceding efavirenz intake period in healthy volunteers.
Methods: Volunteers were randomized to receive etravirine 400 mg once daily (arm 1) or 200 mg twice daily (arm 2) for 14 days. All subjects underwent a washout period of 14 days and then took efavirenz 600 mg once daily for 14 days. Arm 1 and 2 restarted etravirine once and twice daily for 14 days. Etravirine pharmacokinetics was assessed for each phase (before and after efavirenz 14-day intake) on days 1 and 14. Efavirenz concentrations were measured daily for 14 days after intake withholding. Pharmacokinetic parameters were compared (before and after efavirenz 14-day intake) by determining geometric mean ratios and 90% confidence intervals.
Results: Twenty-five subjects (9 female) completed the study. Steady-state etravirine pharmacokinetic parameters were significantly lower after efavirenz intake in the once-daily and twice-daily arms: geometric mean ratios and 90% confidence intervals were 0.71 (0.62 to 0.81) for AUC 0-24, 0.78 (0.70 to 0.86) for Cmax, 0.67 (0.49 to 0.91) for Ctrough for once daily; and 0.72 (0.63 to 0.81) for AUC 0-12, 0.79 (0.70 to 0.90) for Cmax, and 0.63 (0.54 to 0.73) for Ctrough for twice daily. All subjects had detectable efavirenz concentrations 7 days after stopping efavirenz intake, 5 above the suggested minimum effective concentration of 1000 ng/mL.
Conclusions: The induction effect of efavirenz persists for at least 2 weeks after stopping drug intake. The decrease in etravirine is not considered clinically significant. Further clinical data are warranted.
INTRODUCTION
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination with other antiretroviral (ARV) agents in the management of HIV-1 infection. The first-generation NNRTIs (efavirenz, delavirdine, and nevirapine) have a low genetic barrier to resistance and single mutations in the HIV-1 reverse transcriptase lead to class-wide resistance and virological failure.1 Generally, after treatment failure or development of toxicity, NNRTIs are replaced by ritonavir-boosted protease inhibitors. However, as new ARVs with efficacy against resistant virus and improved safety profiles are introduced, it is foreseeable that switching from NNRTIs to newer ARVs including second-generation NNRTIs will occur in clinical practice.
Efavirenz has a long and variable half-life of 40-55 hours at steady state.2 Therapeutic concentrations have been measured up to several weeks after drug intake cessation in some patients.3 Efavirenz is an inducer of hepatic cytochrome P450 (CYP450), a group of enzymes involved in the metabolism of a wide variety of drugs.4 Induction of CYP3A4 leads to reductions in plasma concentrations of coadministered drugs that are metabolized by CYP3A4, potentially diminishing their therapeutic effects.5-7 Moreover, efavirenz itself is primarily metabolized by CYP2B6 and racially distributed pharmacogenetic differences in CYP2B6 activity seem to contribute to the high interindividual variability in efavirenz exposure.8
Etravirine, a next generation NNRTI, is approved for use in combination with other ARVs in treatment-experienced patients.9 Unlike older NNRTIs, etravirine retained efficacy in the presence of some common NNRTI-associated resistance mutations. During drug development studies, a 40% decrease in etravirine concentration was observed when coadministered with efavirenz.10 This drug interaction seems to be mediated by the inductive effect of efavirenz on CYP3A4, one of the main enzyme involved in etravirine metabolism. From a clinical point of view, it is not expected that etravirine will be coadministered with other NNRTIs. However, switching from efavirenz to etravirine seems feasible for the majority of patients because of development of resistance or toxicity to efavirenz.11,12 It is therefore important to be aware that the effect of efavirenz on CYP3A4 may last beyond discontinuation of efavirenz because of its long half-life and subtherapeutic concentrations of etravirine are at risk during the first few days after the switch. Pharmacokinetic evidence demonstrating adequate etravirine exposure after the switch from efavirenz is lacking, and the duration of CYP3A4 induction and its impact on etravirine concentrations in this scenario is unclear.
For most ARVs, it is critical that drug concentrations are maintained above the suggested minimum effective concentration throughout the dosing interval. Suboptimal ARV exposure may permit viral replication and predispose to the selection of drug-resistant virus. Resistant strains may thereafter lead to disease progression and treatment failure.
The primary objective of the study was to assess the pharmacokinetics of etravirine administered once or twice daily after a 2-week treatment period with efavirenz in healthy volunteers. Because of the possibility of directly extrapolating the results to HIV-infected patients, HIV-negative healthy volunteers were selected to minimize the potential for development of resistance and preserve treatment options for HIV-infected patients.
DISCUSSION
This study investigated the pharmacokinetics of etravirine, administered 400 mg once daily or 200 mg twice daily, before and after a 14-day efavirenz intake period. There is no prior data on the pharmacokinetics of etravirine after a switch from efavirenz. However, Winston et al14 investigated the effect of a switch from efavirenz on the pharmacokinetics of nevirapine initiated either at 200 mg once daily or 200 mg twice daily in HIV-infected adults. In that study, nevirapine concentrations were subtherapeutic when initiated at 200 mg once daily. Therefore, commencement of nevirapine at 200 mg twice daily was recommended.
In our study, decreases in etravirine pharmacokinetic parameters after efavirenz intake were modest (between 21% and 37%). These changes are unlikely to be clinically significant as all subjects had etravirine concentrations well above the median protein binding adjusted EC50 of 4 ng/mL (concentration to inhibit 50% of viral replication in vitro).15 Moreover, the reductions in etravirine concentration are comparable to those seen in clinical trials when etravirine was coadministered with darunavir/ritonavir.16 High rates of efficacy were described when etravirine 200 mg twice daily and darunavir/ritonavir were coadministered in patients with extensive resistance, despite a 30% decrease in etravirine pharmacokinetic parameters (compared with historical controls).17 In recent large randomized trials, twice-daily etravirine resulted in additional antiviral effect versus placebo despite the concomitant administration of a boosted protease inhibitor.18,19 Furthermore, in a pooled analysis of these trials, no association between etravirine pharmacokinetics and 48-week efficacy (viral load < 50 copies/mL) was found.20
In the present study, efavirenz persisted for several days after drug withholding and showed highly variable pharmacokinetics. The latter may, in part, be explained by single nucleotide polymorphisms influencing efavirenz pharmacokinetics. Importantly, these polymorphisms have been shown to be associated with excessive efavirenz exposure after treatment discontinuation in some individuals.21 As our knowledge of single nucleotide polymorphisms involved in the metabolism of efavirenz increases, genome variation has assumed greater importance as a factor responsible for interindividual variability.22 However, there is ongoing discussion as to the role of CYP2B6 genotyping to optimize efavirenz treatment.23 Because of the high interindividual variability in efavirenz persistence, the study subjects were randomized to once versus twice-daily dosing and not by period (etravirine without and with efavirenz pretreatment). This may be considered a study limitation.
Our study was insufficiently powered to evaluate the impact of gender on efavirenz pharmacokinetics. Nevertheless, we observed greater variability in efavirenz pharmacokinetics among female subjects, confirming findings from earlier work.24 Furthermore, although no etravirine pharmacokinetic differences between men and women have been reported25 or were observed in our study, possibly because of the wide interindividual variability masking these differences, males showed larger reductions in etravirine concentrations than females, after efavirenz intake. Although this is not always true for non ARV drugs,26 HIV-infected women have been shown to have reduced CYP3A4 activity, and sometimes higher drug concentrations, than men.27 This may be the reason behind the different exposure ratios (before:after efavirenz) because etravirine reduction is likely to be due to efavirenz induction of CYP3A4 activity.
In terms of the relationship between efavirenz and etravirine pharmacokinetics, subjects with higher efavirenz concentrations persisting after the switch had greater proportional decreases in etravirine concentrations. A possible explanation for this finding is that the degree of induction of the enzyme responsible for metabolism of etravirine (CYP3A4) is dependent on the systemic efavirenz exposure. In an earlier study in healthy volunteers, increasing doses of efavirenz resulted in greater induction of hepatic CYP3A4.27 This suggests that individuals with extremely high efavirenz concentrations for prolonged periods after stopping drug intake (ie, efavirenz slow metabolizers) may be at greater risk of suboptimal etravirine exposure. For HIV therapy, maintenance of adequate drug concentrations throughout the dosing interval is essential for therapeutic success and prevention of emergence of resistant virus. Therefore, identification of patients with extremely high efavirenz concentrations may be of clinical value.
Switching from efavirenz to etravirine is feasible and well tolerated and no dose adjustments seemed to be needed in the period after the switch, especially when this occurs for toxicity reasons in the presence of an undetectable viral load.
The clinical significance of the modest decrease in etravirine plasma exposure after efavirenz intake is unclear and clinical trials in HIV-infected subjects are being conducted. However, despite the reduction in plasma concentrations of etravirine, these are likely to be sufficient to maintain HIV replication suppression, suggesting no dose adjustments would be needed for either once-daily or twice-daily etravirine dosing.
RESULTS
Demographic and Clinical Characteristics
Twenty-five subjects (12 in arm 1 and 13 in arm 2) completed the study. Median (range) age, weight, and BMI were 45 (19-61) years, 73 (54-116) kg, and 25 (19-32) kg/m2. Nine subjects were females, 18 were white, 4 were of Asian origin, and 3 were black.
The study drugs were well tolerated, and no grade 3 or grade 4 adverse events were reported.
Etravirine Pharmacokinetics
Etravirine pharmacokinetic parameters before and after the efavirenz intake period at initiation (day 1 and day 42) and at steady state (day 14 and day 56) are shown in Table 1.
Arm 1 and arm 2 steady-state etravirine concentrations before and after the efavirenz intake period are shown in Figure 1. Daily etravirine Ctrough after efavirenz intake are shown in Figure 2.
Although weight and BMI did not correlate with the ratio (before:after efavirenz) of etravirine AUC, Ctrough, or Cmax, a significant effect of gender on the ratio of etravirine AUC and Ctrough was observed at steady state (day 14:day 56). A decrease in AUC of 26.5% in males versus 7.5% in females (P = 0.050) and 35% decrease in Ctrough in males versus 2.4% in females (P = 0.017) was apparent.
Etravirine 400 mg Once Daily (Arm 1)
Steady-state (GM, 90% CI) Cmax, Ctrough, and AUC0-24 were 863 (796 to 972) ng/mL, 270 (243 to 389) ng/mL and 11,064 (9741 to 14077) ngáh-1ámL-1 before efavirenz intake and 676 (597 to 832) ng/mL (22% lower), 175 (142 to 296) ng/mL (33% lower), and 7677 (6373 to 11134) ngáh-1ámL-1 (29% lower) after the efavirenz intake period.
Steady-state etravirine CV for Cmax, Ctrough, and AUC0-24 were 23%, 53%, and 41% before efavirenz intake and 37%, 80%, and 62% after the efavirenz intake period.
Etravirine 200 mg Twice Daily (Arm 2)
Steady-state (GM, 90% CI) Cmax, Ctrough, and AUC0-12 were 1001 (892 to 1219) ng/mL, 596 (528 to 769) ng/mL, and 8756 (7755 to 10,848) ngáh-1ámL-1 before efavirenz intake and 816 (744 to 949) ng/mL (21% lower), 395 (354 to 486) ng/mL (37% lower), and 6481 (5881 to 7615) ng ngáh-1ámL-1 (28% lower) after the efavirenz intake period.
Steady-state etravirine CV for Cmax, Ctrough, and AUC0-12 were 35%, 42%, and 38% before efavirenz intake and 27%, 36%, and 29% after the efavirenz intake period.
Efavirenz Pharmacokinetics
Efavirenz intake was stopped on day 42 after a 14-day treatment period. Terminal half-life (median, range) for subjects enrolled in arm 1 was 83 (45-183) hours and 64 (30-185) hours for subjects in arm 2. All subjects had detectable efavirenz concentrations 7 days after stopping efavirenz intake (day 50). In 5 subjects (3 in arm 1), concentrations measured above 1000 ng/mL on day 50. Two participants (1 in each arm) weighed less than 60 kg. Of the 3 subjects in arm 1 (1 female), 2 were of Asian origin and 1 was white. Both subjects in arm 2 were white females. Median (range) efavirenz concentrations 3, 7, 10, and 13days after stopping efavirenz intake (days 46, 50, 53, and 56) in male subjects (n = 16) were 672 (398-4736) ng/mL, 339 (110-3020) ng/mL, 166 (110-1982) ng/mL, and 120 (110-1605) ng/mL, respectively. In female subjects, they were 1349 (403-6580) ng/mL, 454 (131-3857) ng/mL, 292 (110-3411) ng/mL, and 171 (110-2241) ng/mL. After adjusting for age, BMI, height, and treatment arm, there was no significant effect of gender on efavirenz concentrations.
Interindividual variability of efavirenz concentrations after drug withholding was very wide: CV was 97%, 127%, and 159% on study days 46, 50, and 53, respectively.
Efavirenz concentrations were negatively correlated with etravirine AUC and Ctrough ratios on corresponding days after and before the efavirenz intake period. Correlation coefficients (P values) for efavirenz concentrations on day 50 and day 56 and etravirine AUC ratio at initiation (AUC day 43/AUC day 1) were -0.60 (P = 0.005), -0.62 (P = 0.004), respectively. Correlations coefficients for efavirenz concentrations on days 50 and 56 and etravirine AUC ratio at steady state (AUC day 56/AUC day 14) were -0.48 (P = 0.032) and -0.45 (P = 0.049), respectively. Correlation coefficients for Ctrough ratios were -0.54 (P = 0.013) and -0.53 (P = 0.017) at initiation and -0.39 (P = 0.089) and -0.393 (P = 0.086) at steady state.
METHODS
Subjects
Male and nonpregnant nonlactating female subjects were eligible for enrollment if they provided written informed consent and met the following criteria: age between 18 and 65 years and body mass index (BMI) 18-35 kg/m2. Women of childbearing potential were required to use a suitable contraceptive method during the study and for 1 month after study completion.
Subjects were excluded if they had any significant acute or chronic medical illness; abnormal physical examination, electrocardiogram, or clinical laboratory determinations; positive screen to HIV and hepatitis B or C; current or recent (within 3 months) gastrointestinal disease; clinically relevant alcohol or drug use that the investigator felt would adversely affect compliance with trial procedures; exposure to any investigational drug or placebo within 4 weeks of first dose of study drug; consumption of grapefruit or Seville oranges or any grapefruit- or Seville orange-containing product during the study; use of any other drugs, including over-the-counter medications and herbal preparations, within 2 weeks before first dose of study drug; and previous allergy to any of the constituents of the pharmaceuticals administered during the trial.
Study Design
This was a 57-day, open-label, randomized, prospective, 2-treatment arm, pharmacokinetic study conducted at the Pharmacokinetic Unit of the St. Stephen's Centre, Chelsea and Westminster Hospital, London. The study protocol was reviewed and approved by the Riverside Research Ethics Committee, London. All subjects provided written informed consent, and the trial was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki, and applicable regulatory requirements (EudraCT 2007-003540-29).
At screening, subjects had a clinical assessment and routine laboratory investigations performed. The safety and tolerability of study medications were evaluated throughout the study using the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS table for grading the severity of adult and pediatric adverse events to characterize abnormal findings (published December 2004), vital signs, physical examinations, clinical laboratory investigations, and serial electrocardiogram.
After successful screening, subjects were randomized 1:1 to arm 1 or arm 2. Subjects in arm 1 were assigned to receive etravirine 400 mg (4 x 100 mg tablets) once daily, whereas arm 2 received etravirine 200 mg (2 x 100 mg tablets) twice daily throughout the study. For both arms, subjects received their respective doses of etravirine with food daily for 14 days (1-14) followed by a 14 days of washout period (15-28). They then commenced efavirenz 600-mg once-daily (on an empty stomach) intake and continued for the next 14 days (29-42). Etravirine was then administered again for an additional 14 days (43-56).
After a standardized breakfast, all subjects had serial blood samples for estimation of etravirine concentration collected on days 1, 14, 43, and 56 at the following times: predose, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after administration of etravirine. Arm 1 subjects (etravirine 400 mg once daily) also provided blood 24 hours postdose for etravirine trough concentration (Ctrough) determination. Samples for the determination of etravirine were collected daily from days 2 through 13 and from days 44 through 55. Samples for the determination of efavirenz concentrations were collected on days 42 and 43, 12 hours postdosing and, after stopping efavirenz, daily at the same time every day until day 56.
Analytical Methods
Concentrations of etravirine in plasma were measured using a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method. In brief, etravirine was extracted from heat-inactivated plasma (100 µL; 58°C, 40 minutes) using acetonitrile (500 µL) after the addition of an internal standard (6,7-dimethyl-2,3-di-(2-pyridyl)-quinoxaline; Sigma Chemical Co, Bellefonte, PA). After centrifugation, the organic layer was separated and 200 µL water plus 0.05% formic acid added to each tube. Analytes were separated on a Ascentis C18 column (3 µm; 100 mm x 2.1 mm; Supelco, Bellefonte, PA). The HPLC system consisted of a Surveyor AS autosampler, a photo diode array detector, and LC pump interfaced with and ion trap LCQ Deca XP Plus mass spectrometer with an electrospray ionization source (Thermo Electron Corporation, Hemel Hempstead, United Kingdom). Recovery of etravirine was >90%; the lower limit of quantification was taken as the lowest point on the standard curve (5 ng/mL) and the upper limit of quantification was 2497 ng/mL. Intra-assay and interassay coefficient of variation at the low, medium, and high quality controls were <11%.
Concentrations of efavirenz were determined using a validated HPLC method as previously described.13 The lower limit of quantification was taken as the lowest point on the standard curve (110 ng/mL). The laboratory participates in an external quality assurance programme [Association for Quality Assessment and Clinical Toxicology (KKGT), The Netherlands], however, currently this does not include etravirine.
Pharmacokinetic and Statistical Analysis
Etravirine maximum plasma concentration (Cmax), time to Cmax (Tmax), and Ctrough were derived. Area under the curve from 0 to 24 hours (AUC0-24) for once-daily etravirine and from 0 to 12 hours (AUC0-12) for twice-daily etravirine were calculated using WinNonLin version 5.2 (Mountain View, CA), by noncompartmental linear-linear trapezoidal method. Interindividual variability in plasma concentrations during drug intake and after drug cessation was assessed by measuring the coefficient of variation (CV = standard deviation/mean x 100). Within-subject changes for etravirine concentrations (before and after 14-day efavirenz intake period) were assessed by calculating geometric means (GMs) and geometric mean ratios (GMRs) and 90% confidence intervals (CIs). The CIs were first determined using logarithms of the individual GMR values and then expressed as linear values. The changes in pharmacokinetic parameters were considered significant when the CI for the GMR did not cross the value of 1.
Relationships between weight and BMI and efavirenz daily concentrations or etravirine plasma exposure (expressed as the ratio between AUC before and after 14-day efavirenz intake period) were assessed by Pearson correlation (the groups were separated into halves by median weight and BMI). Gender differences in drug exposure were calculated using analysis of variance. The P values ≤0.05 were considered statistically significant. Statistical analysis was performed using SPSS (version 16.0, SPSS Inc Headquarters, Chicago, IL).
|
|
| |
| |
|
|
|
