HTB

Drug-drug interactions between efavirenz and levonorgestrel influenced by genetic variants 

Polly Clayden, HIV i-Base

CYP2B6 genetic variants influence levonorgestrel (LNG) pharmacokinetics when combined with efavirenz (EFV)-based ART. These findings, from a Ugandan study, were presented at the 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. [1] 

The study investigators from University of Nebraska, Makerere University and University of Liverpool previously described 45–57% lower LNG concentrations in women using the LNG implant (150 mg) plus EFV 600 mg-based ART compared to ART-naive women. [2]

To overcome this interaction, they looked at the effect of doubling the LNG implant dose (300 mg; 2 implants) with EFV-based ART (DoubLNG). [3, 4]

In spite of the dose adjustment, LNG exposure remained 34% lower in the DoubLNG group compared to the same group of ART-naive Ugandan women in the previous study.

The investigators had also identified that CYP2B6 single nucleotide polymorphisms (SNPs) associated with slow EFV metabolism were linked to lower LNG exposure when the standard dose LNG implant was combined with EFV. [5]

To further explore those findings, they investigated potential associations between CYP2B6 metaboliser status and LNG pharmacokinetics (PK) in DoubLNG.

The study included 28 Ugandan women receiving EFV-based ART with undetectable viral load. An LNG implant was placed in each arm at study entry. All women were black African with median age of 33 years and weight 58 kg.

The investigators genotyped three SNPs (CYP2B6 rs3745274 516G→T, CYP2B6 rs28399499 983T→C, CYP2B6 rs4803419 15582C→T) for classification of normal, intermediate, and slow CYP2B6 metaboliser status.

Median LNG concentrations at week 24 for normal, intermediate, and slow metabolisers, were: 534 pg/mL (IQR: 507 to 577), 310.0 pg/mL (IQR: 279 to 346) and 167 pg/mL (IQR: 103 to 301), p= 5.16 x 10-5, β = –0.21. Compared with normal metabolisers, LNG was 42% and 69% lower in intermediate and slow metabolisers respectively.

LNG AUC0-24wks (median) was 34% and 46% lower in intermediate and slow metabolisers compared with normal metabolisers.

At week 24, higher EFV concentrations were associated with lower LNG concentrations, p= 3.37 x 10ˉ⁷ log10,β = –0.56, correlation coefficient –0.8.

Normal metabolisers receiving double dose had similar LNG exposure to historical controls (less than 5% decrease in LNG exposure) but intermediate and slow metabolisers had statistically lower LNG than historical controls: normal to ART-naive p=0.474; intermediate to ART-naive p=0.014; slow to ART-naive p=0.003.

The investigators summarised that in women receiving EFV 600 mg-based ART plus LNG implants double dose (300mg) of LNG in those with normal CYP2B6 metaboliser status result in comparable LNG exposure to standard dose LNG (150mg) in mixed-genotype ART-naive controls. And intermediate and slow CYP2B6 metaboliser status is associated with lower LNG concentrations, irrespective of LNG dose

They suggested that higher EFV exposure results in increased induction of CYP3A41. And that the potential for stratified LNG dosing based on CYP2B6 genotype and EFV dose is worthy of further investigation.

comment

This excellent body of work continues to underline the complexities of using hormonal contraception with EFV-based ART.

Reference

  1. Pham M et al. Effect of CYP2b6 metabolizer status on levonorgestrel pharmacokinetics when combined with efavirenz-based antiretroviral therapy. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. 14–16 May 2019, Noordwijk, the Netherlands. Oral abstract 7.
    http://regist2.virology-education.com/presentations/2019/20AntiviralPK/21_Pham.pdf(slides)
  2. Scarsi K et al. Unintended pregnancies observed With combined sse of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Clinical Infectious Diseases. Volume 62, Issue 6. 15 March 2016.
    https://academic.oup.com/cid/article/62/6/675/2462703
  3. Scarsi K et al. Double-dose levonorgestrel implant does not fully overcome interaction with efavirenz. CROI 2019. Seattle. 4–7 March 2019. Oral abstract 51.
    http://www.croiconference.org/sessions/double-dose-levonorgestrel-implant-does-not-fully-overcome-interaction-efavirenz(abstract)
    http://www.croiwebcasts.org/p/2019croi/51 (webcast)
  4. Clayden P. Double-dose levonorgestrel implant does not overcome interaction with efavirenz. HTB. 28 March 2019.
    http://i-base.info/htb/35918
  5. Neary N et al. Theeffect of gene variants on levonorgestrel pharmacokinetics when combined with antiretroviral therapy containing efavirenz or nevirapine. Clin Pharmacol Ther. 2017 Sep; 102(3): 529–536.

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