Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug–drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART

Roberts, Owain, Rajoli, Rajith KR ORCID: 0000-0002-6015-5712, Back, David J, Owen, Andrew ORCID: 0000-0002-9819-7651, Darin, Kristin M, Fletcher, Courtney V, Lamorde, Mohammed, Scarsi, Kimberly K and Siccardi, Marco ORCID: 0000-0002-3539-7867 (2018) Physiologically based pharmacokinetic modelling prediction of the effects of dose adjustment in drug–drug interactions between levonorgestrel contraceptive implants and efavirenz-based ART. Journal of Antimicrobial Chemotherapy, 73 (4). pp. 1004-1012.

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Official URL: https://academic.oup.com/jac/article/73/4/1004/481...

Abstract

Background HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy. Objectives To investigate clinically applicable dose-adjustment strategies to overcome the known drug–drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz. Results No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively). Conclusions These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz–levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants.

Item Type:	Article
Uncontrolled Keywords:	plasma drug concentration, drug interactions, efavirenz, contraceptive agents, levonorgestrel, implants
Depositing User:	Symplectic Admin
Date Deposited:	19 Feb 2018 10:58
Last Modified:	19 Jan 2023 06:39
DOI:	10.1093/jac/dkx515
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3018224