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Pharmacokinetic Interaction Between Norgestimate/Ethinyl Estradiol and EVG/COBI/FTC/TDF Single Tablet Regimen Polina German, Maggie Wang, David Warren and Brian Kearney Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Introduction
Elvitegravir (EVG) is an HIV-1 integrase inhibitor Cobicistat (COBI) is a potent, mechanism-based inhibitor of Cytochrome P450 3A (CYP3A) EVG and COBI have been co-formulated with NRTI backbone FTC/TDF into a single tablet (EVG/COBI/FTC/TDF: FDC) for HIV-1 treatment in treatment-naïve patients – FDC is presently being evaluated in Phase 3 Ortho Tri-Cyclen Lo® is a combination oral contraceptive containing progestational and estrogenic compounds – Norgestimate: 0.180 mg, 0.215 mg and 0.250 mg Drug interactions between hormonal contraceptives and antivirals have been documented 1,2,3,4 Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Objectives
Primary Objective
 To determine the effect of EVG/COBI/FTC/TDF on the
pharmacokinetics of Ortho Tri-Cyclen® Lo Secondary Objective
 To evaluate the safety and tolerability of administration of
EVG/COBI/FTC/TDF and Ortho Tri-Cyclen® Lo Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Open-label, fixed-sequence, two-parts study – Part A (lead-in): required for subjects not taking Ortho-Tri-Cyclen Lo® – Part B (main study): enrolled subjects who had taken Ortho-Tri- Cyclen Lo® for at least 1 full month prior to Day 1 Lead in: Part A
Screening
Baseline
1 21 28 1 12 21
Baseline
FDC: EVG/COBI/FTC/TDF
Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA All treatments administered with a standard meal In Part B, PK samples collected over 24 hours on Day 21 of each cycle for EE, NGMN (NGM metabolite), and on Day 21 of the second cycle for EVG and COBI Plasma concentrations of EVG, COBI, EE and NGMN measured using LC/MS/MS PK parameters calculated by noncompartmental analysis (WinNonlin 5.3, Pharsight) Geometric least-squares mean ratios and 90% confidence intervals (Test: Reference) estimated using ANOVA for AUC , and C EVG and COBI exposures descriptively compared to historical data Exploratory analysis of PD parameters progesterone, FSH and LH was carried out in both cycles Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Demographics
•
– 19 enrolled in Part A; 16 subjects enrolled in Part B from Part A– 2 enrolled in Part B directly– 15 subjects completed the study Mean weight (range): 64.4 kg (48.5, 83.3) – White: 66.7%– Black: 19.0%– Asian: 9.5%– American Indian or Alaska Native: 4.8% – Hispanic/Latino: 33.3%– Non-Hispanic/Latino: 66.7% Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Safety
•
No Grade 3 or 4 AE or SAE reported in the study All treatment-emergent AEs were Grade 1 or Grade 2 Gastrointestinal Disorders
Nervous System Disorders
Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA NGMN Pharmacokinetics
NGM/EE + FDC
Time (hr)
NGMN Parameter
NGM/EE + FDC
GMR (90% CI)
n = 15, mean (%CV); FDC: EVG/COBI/FTC/TDF Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA EE Pharmacokinetics
NGM/EE + EVG/COBI/FTC/TDF
Time (hr)
EE Parameter
NGM/EE + FDC
GMR (90% CI)
n = 15, mean (%CV); FDC: EVG/COBI/FTC/TDF Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA EVG and COBI Pharmacokinetics
EVG and COBI exposures are within the range of those reported in previous studies Parameter EVG COBI
Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Exploratory Pharmacodynamics
ent 3
onc 2
Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA Conclusions
Study treatments were generally well-tolerated EVG and COBI exposures were within the range of those reported in previous studies OC is to contain 30 µg of EE if administered with FDC to assure Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA References
Reyataz® (atazanavir sulfate) Capsules. US Prescribing Information. Bristol-Myers Squibb Company, Princeton, NJ, USA. Revised April 2010.
Sekar VJ, Lefebvre E, Guzman SS, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther. 2008;13(4):563-569. SUSTIVA® (efavirenz) capsules and tablets. US Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. March 2010.
KALETRA® (lopinavir/ritonavir) tablets (lopinavir/ritonavir) oral solution US Prescribing Information. Abbott Laboratories. North Chicago, IL. Revised June 2010. Madden S, Back DJ. Metabolism of norgestimate by human gastrointestinal mucosa and liver microsomes in vitro. J Steroid Biochem Mol Biol. Apr 1991;38(4):497-503. ORTHO TRI-CYCLEN® Lo Tables (norgestimate/ethinyl estradiol). US Prescribing Information. Janssen Ortho, LLC. Manati, Puerto Rico. Revised August 2008.
Zhang H, Cui D, Wang B, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet. 2007;46(2):133-157.
Presented at the 12th Int. Workshop on Clin. Pharmacology of HIV Therapy, 13-15 April 2011, Miami, Fl, USA

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