Pharmacokinetics and safety of etravirine administered once and twice daily and following two weeks treatment with efavirenz in healthy volunteers

1
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. Stephens Centre, Chelsea and Westminster
  Hospital, London,
• 2Department of Pharmacology and Therapeutics,
  University of Liverpool, Liverpool, UK
• 3Department of Pharmacology and Therapeutics,
  Trinity College Dublin, Ireland

2
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

3

• 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 inter-individual variability in efavirenz
  exposure 5

4

• Etravirine retains efficacy in the presence of
  some common NNRTI associated resistance mutations
• A 40 decrease in etravirine concentrations was
  observed when co-administered 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

5
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

6
Study design
PK day Efavirenz and etravirine daily
concentration measurement
ETR 400 mg OD
WASH OUT
EFV 600 mg OD
ETR 400 mg OD
Arm 1
Day 1 Day 14 Day 15 Day 28
Day 29 Day 42 Day 43 Day 56
ETR 200 mg BD
WASH OUT
EFV 600 mg OD
ETR 200 mg BD
Arm 2

• 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 post-dosing and daily at the same time
  every day until day 56

7
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 lt11
• 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 Pearsons 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)

8
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 (1833) 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

9
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 (beforeafter 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 (p0.050) and 35 decrease in
  Ctrough in males versus -2.4 in females
  (p0.017) was apparent

10
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

11
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

12
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 (45183) hours and 64 (30185) 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 gt 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 (n16) were 672
  (398-4736), 339 (109-3020) and 166 (109-1982)
  ng/mL

13

• 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 (p0.005), -0.62
  (p0.004), 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 (p0.032) and -0.45 (p0.049),
  respectively
• For Ctrough ratios, they were -0.54 (p0.013) and
  -0.53 (p0.017) at initiation, and -0.39
  (p0.089) and -0.393 (p0.086) at steady state

14
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

15
References

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16
Figure 1 Mean steady-state etravirine plasma
concentrations before (day 14) and after (day 56)
efavirenz intake periodBars indicate standard
deviation (SD)
Arm 1 etravirine 400 mg once daily, n 12
17
(No Transcript)
18
Figure 2 Etravirine ( twice daily once
daily) trough concentrations and efavirenz ( )
daily concentrations after stopping efavirenz
intake and restarting etravirine
19
Table 1 Etravirine pharmacokinetic parameters
measured before (days 1 and 14) and after (days
43 and 56) the efavirenz intake period

  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)
Arm 1 400 mg OD 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)
Arm 1 400 mg OD 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)
Arm 1 400 mg OD 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
Arm 2 200 mg BID 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)
Arm 2 200 mg BID 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)
Arm 2 200 mg BID 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