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Pharmacokinetic targets for efavirenz might be too high

Polly Clayden, HIV i-Base

CROI 2014 logo-190Results from a substudy of ENCORE1 – looking at 400 vs 600 mg efavirenz daily – challenge the current pharmacokinetic (PK) targets for treatment success of this drug. [1]

ENCORE1 is an ongoing trial in treatment-naïve adults randomised to receive either reduced (400 mg), or standard (600 mg) dose efavirenz, both with TDF/FTC. At 48 weeks 400 mg efavirenz was virologically non-inferior to 600 mg. Viral suppression was high with 90% vs 86% <50 copies/mL in the 400 mg vs 800 mg arms, respectively. [2]

A poster presented at CROI 2014 – authored by Laura Dickinson and Rebekah Puls from University of Liverpool and University of New South Wales, on behalf of the substudy group – showed findings from an intensive PK analysis comparing efavirenz plasma exposures between the two doses in a subset of trial participants.

Sampling was undertaken at steady state between 4 to 8 weeks of treatment: pre-dose, 2, 4, 8, 12, 16 and 24 hours post dose. Efavirenz plasma concentrations were determined by LC-MS/MS with lower and upper limits of quantification of 0.025 and 10 mg/L.

The investigators also performed genotyping for CYP2B6 516G>T and 983T>C in order to evaluate the influence of host genetics on efavirenz exposure.

Forty-six participants (28 and18 from the 400 and 600 mg groups respectively) were enrolled at four study sites in South Africa, Thailand, UK and Argentina. Fifteen participants were women and 37% African, 22% Asian and 41% white. Mean age, weight and baseline CD4 were: 36 years, 71 kg, and 289 cells/mm3 respectively.

The results of the PK evaluation are summarised in Table 1.

Table 1: Efavirenz PK parameters ENCORE 1 (n=46)

Parameter GM (90% CI) 400 mg 600 mg GMR (90% CI) p
AUC0-24 (mg.h/L) 38.0 (34.4-54.0) 54.2 (47.8-75.8) 0.70 (0.54-0.91) 0.007
CL/F (L/h) 10.5 (10.2-13.2) 11.1 (9.96-15.0) 0.95 (0.73-1.23) 0.857
Cmax (mg/L) 2.65 (2.46-3.36) 4.09 (3.72-5.23) 0.65 (0.52-0.81) 0.002
C12 (mg/L) 1.50 (1.36-2.25) 2.05 (1.81-2.92) 0.73 (0.55-0.97) 0.029
C24 (mg/L) 1.12 (1.01-1.72) 1.52 (1.33-2.47) 0.73 (0.54-1.01) 0.065

The evaluation revealed AUC0-24, Cmax and C12 were significantly lower for 400 mg efavirenz compared to 600 mg. C12 and C24 were below the previously calculated minimum effective concentration (MEC) of 1.0 mg/L in 25 (46%) and 6 (28%) of participants receiving 400 and 600 mg efavirenz respectively.

Genotype data were available for 44/46 participants: 52%, 35% and 9% were CYP2B6 516 GG, GT and TT respectively and 93%, 2% and 0% were CYP2B6 TT, TC and CC respectively.

Multivariate analysis found CYP2B6 516 G>T, dose and participants weight were independently associated with AUC0-24; and CYP2B6 516 G>T and dose with C24 (both p=0.0001).

Overall 78% of participants had viral load <50 copies/mL at 48 weeks (missing data classified as detectable).

The investigators noted that because the sample size was small, a formal PK-pharmacodynamic (PD) evaluation was not possible. At 48 weeks 5/28 (18%) participants had detectable viral loads in the 400 mg group of which two were <1.0 mg/L for C12 and C24. In the 600 mg group 5/18 (28%) had detectable viral loads and one was below the MEC at C24.

The investigators concluded that participants in the substudy receiving 400 mg efavirenz had comparable viral suppression to 600 mg – as in the main ENCORE1 study – despite significantly lower exposure and higher proportions of C12 and C24 below the suggested MEC.

“These data challenge the currently defined PK targets for therapeutic success”, they wrote.

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PK-PD modelling of the data from ENCORE1 is currently ongoing to help better understand predictors of efavirenz PK and response in a heterogeneous population.

Since the announcement of the trial results last year, there has been a great deal of discussion about recommending the reduced dose of efavirenz, particularly in low-income countries where the resulting cost savings would be considerable. Questions about whether or not 400 mg will be robust enough in the third trimester of pregnancy and in the presence of concomitant treatment for TB have delayed recommendations from WHO and national guidelines.

A forthcoming research letter to AIDS from Hill et al cites five studies that include 235 women treated with 600 mg efavirenz in pregnancy in which drug concentrations were not significantly affected and there were high rates of viral load suppression in the mothers at the time of delivery. [3] The authors conclude that the results suggest that pregnancy has slight if any clinically important effects on efavirenz PK.

For rifampicin, there have been a number of short-term PK studies with 600 mg efavirenz showing reduction in efavirenz plasma concentrations. It is unclear how useful these results are when efavirenz has not reached steady state. Longer-term studies in HIV positive people have shown increased Cmin or no effect. [4] In order to determine whether the PK interaction between rifampicin and EFV is different using the 400mg dose (there may be different induction effects) a new PK study is probably needed.

It seems that to recommend 400 mg efavirenz widely PK studies with rifampicin and in pregnant women will have to be conducted. One question will be, what target to aim for treatment success?

It is also important to remember that in the early DMP-266 005 trial of efavirenz there was no difference in viral suppression between people receiving 200, 400 and 600 mg at 16 weeks. [5]

In the UK, there is talk of exploring the 200 mg dose.

References

  1. Dickinson L et al. Efavirenz (EFV) 400 Versus 600 mg daily: results of the ENCORE1 intensive PK substudy 21st CROI. 3-6 March 2014. Boston. Poster abstract 510.
    http://croiconference.org/sites/all/abstracts/510.pdf (PDF)
  2. ENCORE1 Study Group. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. The Lancet. Early online publication. 10 February 2014.
    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62187-X/abstract?rss%3Dyes
  3. Hill A et al. Does pregnancy affect the pharmacokinetics of efavirenz? AIDS. Forthcoming 2014.
  4. Hill A. Presentation to WHO adult ARV group. March 2014/personal communication.
  5. Haas D et al. A phase II, double-blind, placebo-controlled, dose-ranging study to assess the antiretroviral activity and safety of efavirenz (DMP-266) in combination with open-label zidovudine (ZDV) with lamivudine (3TC) at 24 weeks (DMP 266–005). 5th CROI. February 1998. Chicago. Poster abstract 698.

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