Transcript and Safety of Etravirine

Pharmacokinetics and safety
of etravirine administered once
and twice daily and following
two weeks treatment with
efavirenz in healthy volunteers
Marta Boffito1, Akil Jackson1, Mohammed Lamorde1,3, David
Back2, Victoria Watson2, Jessica Taylor1, Laura Waters1,
David Asboe1, Brian Gazzard1, Anton Pozniak1
1St.
2Department
Stephen’s Centre, Chelsea and Westminster Hospital, London,
of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
3Department
of Pharmacology and Therapeutics, Trinity College Dublin, Ireland
Background
• NNRTI are widely used in combination with other ARVs
in the management of HIV infection
• First generation NNRTIs have low genetic barrier to
resistance and single mutations in the HIV reverse
transcriptase lead to class-wide resistance [1]
• Following treatment failure or toxicity, NNRTIs are
replaced by RTV boosted PIs. However, as new ARVs
with efficacy against resistant virus and improved safety
profiles are introduced, switching from NNRTIs to newer
ARVs including second generation NNRTIs will occur
• Efavirenz has long and variable half-life (40-55 h) at
steady state [2]
• Therapeutic concentrations measured up to several
weeks after drug intake cessation in some patients [3]
• Efavirenz is an inducer of CYP450 [4], leading to
reductions in concentrations of co-administered drugs
• Efavirenz is primarily metabolized by CYP3A4 and
CYP2B6
• Racially distributed pharmacogenetic differences in
CYP2B6 activity appear to contribute to the high interindividual variability in efavirenz exposure [5]
• Etravirine retains efficacy in the presence of some common NNRTI
associated resistance mutations
• A 40% decrease in etravirine concentrations was observed when coadministered with efavirenz [6]
• This appears to be mediated by the inductive effect of efavirenz on
CYP3A4, involved in etravirine metabolism
• Switching from efavirenz to etravirine appears feasible because of
development of resistance or toxicity [7,8]
• The effect of efavirenz on CYP3A4 may last longer than the drug
half-life and etravirine sub-therapeutic concentrations are at risk
after the switch
• PK 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
Objective
• To assess the PKs of etravirine
administered once or twice daily following
a 2-week treatment period with efavirenz
in healthy volunteers
• HIV negative healthy volunteers were
selected to minimize the potential for
development of resistance and preserve
treatment options for HIV-infected patients
Study design
= PK day
= Efavirenz and etravirine daily concentration measurement
ETR
400 mg OD
Arm 1
Day 1
Arm 2
WASH OUT
Day 14 Day 15
ETR
200 mg BD
EFV
600 mg OD
Day 28 Day 29
WASH OUT
ETR
400 mg OD
Day 42 Day 43
EFV
600 mg OD
Day 56
ETR
200 mg BD
• All subjects had serial blood samples for estimation of etravirine concentration collected on days 1, 14, 43
and 56 at the following times: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h post-dose
• Arm 1 subjects also provided blood 24 h post-dose for etravirine Ctrough determination
• Samples for the determination of etravirine were collected daily from days 2 to 13 and from days 44 to 55
• Samples for the determination of efavirenz concentrations were collected on days 42 and 43, 12 hours postdosing and daily at the same time every day until day 56
Pharmacokinetic and statistical analysis
•
Concentrations of etravirine in plasma were measured using a validated high performance liquid
chromatography (HPLC)-tandem mass spectrometry method. Intra-assay and inter assay 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 [9]
•
Cmax, Tmax, Ctrough and half-life (t½) were derived for etravirine and efavirenz. Area under the curve from 0
to 24 hours (AUC0-24) for once daily and 0 to 12 hours (AUC0-12) for twice daily etravirine were calculated
using WinNonLin version 4.01a (Mountain View, California, USA)
•
Inter individual variability in plasma concentrations during drug intake and following drug cessation was
assessed by measuring the coefficient of variation (CV = standard deviation / mean X100)
•
Within-subject changes for etravirine (prior to and after 14-day efavirenz intake period) were assessed by
calculating geometric means (GM) and ratios (GMR) 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 PK 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 exposure
(expressed as the ratio between AUC prior to and after 14-day efavirenz intake period) were assessed by
Pearson’s correlation (the groups were separated into halves by median weight and BMI)
•
Gender differences in drug exposure were calculated using analysis of variance (ANOVA)
•
P values  0.05 were considered statistically significant (SPSS, version 16.0, SPSS Inc. Headquarters)
Results
Demographic and clinical characteristics
• 25 subjects (12 in arm 1 and 13 in arm 2) completed the study
• 9 subjects were females, median (range) age, weight and BMI were
43 (20-59) years, 83 (54-116) kg and 26 (18–33) kg/m2
• 18 were Caucasian, 4 were of Asian origin and 3 were black
• The study drugs were well tolerated and no grade ¾ adverse events
were reported
Etravirine pharmacokinetics
• Etravirine PK 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
• While 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
• 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 etravirine Cmax, Ctrough and AUC0-24 22%,
33%, 29% lower after the efavirenz intake period
• Median (range) etravirine t½ was 16 (10-28) hours on
both days 14/15 (no efavirenz) and 56/57 (after
efavirenz)
• Steady-state etravirine CV for Cmax, Ctrough and AUC0-24
were 23%, 53% and 41% prior to efavirenz intake, and
37%, 80% and 62% after the efavirenz intake period
Etravirine 200 mg twice daily (arm 2)
• Steady-state etravirine Cmax, Ctrough and AUC0-12 were
21%, 37%, 28% lower after the efavirenz intake period
• Median (range) etravirine t½ was 13 (11-18) hours on day
14 and 8 (7-9) hours (43% lower) on day 56
• Steady state etravirine CV for Cmax, Ctrough and AUC0-12
were 35%, 42% and 38% prior to 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
•
t1/2 (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 > 1000 ng/mL on day 50
•
2 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
Caucasian
•
Both subjects in arm 2 were Caucasian females
•
Median (range) efavirenz concentrations 3, 7 and 10 days after
stopping efavirenz (days 46, 50, and 53) in male subjects (n=16) were
672 (398-4736), 339 (109-3020) and 166 (109-1982) ng/mL
•
In female subjects, they were 1349 (403-6580), 454 (131-3857) and
292 (109-3411) ng/mL
•
After adjusting for age, BMI, height and treatment arm there was no
significant effect of gender on efavirenz concentrations
•
Inter individual variability of efavirenz concentrations after drug
withholding was wide: CV was 97%, 127%, and 159% on study days
46, 50, and 53
•
Efavirenz concentrations were negatively correlated with etravirine AUC
and Ctrough ratios on corresponding days after / before efavirenz
•
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 day 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
•
For Ctrough ratios, they 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
Conclusions
• Efavirenz inducing effect persists after
stopping drug intake
• The decrease in etravirine is comparable
to that determined in the presence of
darunavir/ritonavir and is not considered
clinically significant
• Clinical studies in HIV-infected patients are
ongoing
References
1.
Wainberg MA. HIV resistance to nevirapine and other non-nucleoside reverse transcriptase inhibitors. J Acquir
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Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.
Clinical pharmacokinetics 2001,40:893-905.
3.
Taylor S, Boffito M, Khoo S, Smit E, Back D. Stopping antiretroviral therapy. AIDS 2007,21:1673-1682.
4.
Hariparsad N, Nallani SC, Sane RS, Buckley DJ, Buckley AR, Desai PB. Induction of CYP3A4 by efavirenz in
primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol 2004,44:1273-1281.
5.
Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of efavirenz and
central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004,18:2391-2400.
6.
Kakuda TN, Scholler-Gyure M, Woodfall B, De Smedt G, Peeters M, Vandermeulen K. TMC125 in combination
with other medications: summary of drug-drug interaction studies. In: Program and abstracts of the 8th
International Congress on Drug Therapy in HIV infection, Glasgow, Scotland; 2006.
7.
Scott C, Grover D, Nelson M. Is there a role for etravirine in patients with Nonnucleoside reverse transcriptase
inhibitor resistance? AIDS 2008,22:989-990.
8.
Lapadula G, Calabresi A, Castelnuovo F, Costarelli S, Quiros-Roldan E, Paraninfo G, et al. Prevalence and risk
factors for etravirine resistance among patients failing on non-nucleoside reverse transcriptase inhibitors. Antivir.
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Almond LM, Hoggard PG, Edirisinghe D, Khoo SH, Back DJ. Intracellular and plasma pharmacokinetics of
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Figure 1: Mean steady-state etravirine plasma concentrations before
(day 14) and after (day 56) efavirenz intake period
Bars indicate standard deviation (SD)
Arm 1: etravirine 400 mg once daily, n = 12
Before efavirenz (day 14)
Etravirine (ng/mL)
1100
1000
900
After efavirenz (day 56)
800
700
600
500
400
300
200
100
0
0
2
4
6
8
10
12
14
16
Time (hours)
18
20
22
24
Arm 2: etravirine 200 mg twice daily, n = 13
Before efavirenz (day 14)
After efavirenz (day 56)
Etravirine (ng/mL)
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
0
2
4
6
8
Time (hours)
10
12
Drug concentration (ng/mL)
Figure 2: Etravirine ( : twice daily; : once daily) trough concentrations
and efavirenz ( ) daily concentrations after stopping efavirenz intake
and restarting etravirine
10000
1000
100
10
0
1
2
3
4
5
6
7
8
9
10
11
12
Days after stopping efavirenz
13
14
Table 1: Etravirine pharmacokinetic parameters measured before (days
1 and 14) and after (days 43 and 56) the efavirenz intake period
Arm
1
400
mg
OD
Arm
2
200
mg
BID
Etravirine PK
parameter
Before EFV
GM (90% CI)
Day 1/2
After EFV
GM (90% CI)
Day 43/44
GMR
(90% CI)
Before EFV
GM (90% CI)
Day 14/15
After EFV
GM (90% CI)
Day 56/57
GMR
(90% CI)
AUC0-24h
(ng.h/mL)
2996
(2626-4070)
2245
(1899-3171)
0.74
(0.66-0.83)
11064
(9741-14077)
7677
(6373-11134)
0.71
(0.62-0.81)
Cmax
(ng/mL)
385
(345-476)
293
(246-405)
0.78
(0.76-0.90)
863
(796-972)
676
(597-832)
0.78
(0.70-0.86)
Ctrough
(ng/mL)
41
(36-67)
31
(26-55)
0.71
(0.59-0.85)
270
(243-389)
175
(142-296)
0.67
(0.49-0.91)
Day 1
Day 43
Day 14
Day 56
AUC0-12h
(ng.h/mL)
1399
(1259-1777)
1090
(930-1452)
0.78
(0.66-0.92)
8756
(7755-10848)
6481
(5881-7615)
0.72
(0.63-0.81)
Cmax
(ng/mL)
286
(250-372)
201
(168-277)
0.70
(0.57-0.86)
1001
(892-1219)
816
(744-949)
0.79
(0.70-0.90)
Ctrough
(ng/mL)
52
(48-74)
34
(30-51)
0.66
(0.51-0.85)
596
(528-769)
395
(354-486)
0.63
(0.54-0.73)
EFV – efavirenz, OD – once daily, BID – twice daily, AUC – area under the plasma concentration-time curve, Cmax – maximal
concentration, Ctrough – pre-dose concentration, GM – geometric mean, GMR – geometric mean ratio, CI – confidence interval