Owain Roberts1, Rajith K R Rajoli1, David J Back1, Andrew Owen1, Kristin M Darin2, Courtney V Fletcher3, Mohammed Lamorde4, Kimberly K Scarsi3, Marco Siccardi1. 1. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK. 2. School of Professional Studies, Northwestern University, Chicago, IL, USA. 3. College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA. 4. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.
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.
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.
Authors: Bryan A Ward; J Christopher Gorski; David R Jones; Stephen D Hall; David A Flockhart; Zeruesenay Desta Journal: J Pharmacol Exp Ther Date: 2003-04-03 Impact factor: 4.030
Authors: Kimberly K Scarsi; Kristin M Darin; Catherine A Chappell; Stephanie M Nitz; Mohammed Lamorde Journal: Drug Saf Date: 2016-11 Impact factor: 5.606
Authors: M Neary; M Lamorde; A Olagunju; K M Darin; C Merry; P Byakika-Kibwika; D J Back; M Siccardi; A Owen; K K Scarsi Journal: Clin Pharmacol Ther Date: 2017-05-30 Impact factor: 6.875
Authors: Chelsea B Polis; Sarah E K Bradley; Akinrinola Bankole; Tsuyoshi Onda; Trevor Croft; Susheela Singh Journal: Contraception Date: 2016-03-24 Impact factor: 3.375
Authors: Rajith K R Rajoli; Paul Curley; Justin Chiong; David Back; Charles Flexner; Andrew Owen; Marco Siccardi Journal: J Infect Dis Date: 2019-05-05 Impact factor: 5.226
Authors: Megan Neary; Catherine A Chappell; Kimberly K Scarsi; Shadia Nakalema; Joshua Matovu; Sharon L Achilles; Beatrice A Chen; Marco Siccardi; Andrew Owen; Mohammed Lamorde Journal: J Antimicrob Chemother Date: 2019-10-01 Impact factor: 5.790
Authors: David W Haas; Yoninah S Cramer; Catherine Godfrey; Susan L Rosenkranz; Francesca Aweeka; Baiba Berzins; Robert Coombs; Kristine Coughlin; Laura E Moran; David Gingrich; Carmen D Zorrilla; Paxton Baker; Susan E Cohn; Kimberly K Scarsi Journal: Pharmacogenet Genomics Date: 2020-04 Impact factor: 2.000
Authors: Craig R Rayner; Patrick F Smith; David Andes; Kayla Andrews; Hartmut Derendorf; Lena E Friberg; Debra Hanna; Alex Lepak; Edward Mills; Thomas M Polasek; Jason A Roberts; Virna Schuck; Mark J Shelton; David Wesche; Karen Rowland-Yeo Journal: Clin Pharmacol Ther Date: 2021-03-09 Impact factor: 6.875
Authors: Ahizechukwu C Eke; Adeniyi Olagunju; Brookie M Best; Mark Mirochnick; Jeremiah D Momper; Elaine Abrams; Martina Penazzato; Tim R Cressey; Angela Colbers Journal: Clin Pharmacokinet Date: 2020-10 Impact factor: 6.447