Coadministration of oral contraceptives with protease inhibitors is complicated by drug interactions. An open-label three-period single-sequence study assessed the effect of coadministration of atazanavir (ATV)/ritonavir (RTV) with Ortho Tri-Cyclen® and with Ortho Tri- Cyclen® LO (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) on the pharmacokinetics (PK) of ethinyl estradiol (EE), norgestimate (NGM), ATV and RTV.
Methods
A total of 20 healthy women aged 18–45 years received study treatments. In the lead-in period and in period 1, participants received a full cycle of Ortho Tri- Cyclen (EE 35 μg with NGM 0.18/0.215/0.25 mg) from days 1–28. In period 2, participants received a full cycle of Ortho Tri-Cyclen LO (EE 25 μg with NGM 0.18/0.215/0.25 mg) plus ATV/RTV (300/100 mg once daily) on days 29-42. PK assessments were performed on days 14 and 42 in periods 1 and 2, respectively.
Results
ATV/RTV with dose-normalized EE/NGM resulted in geometric mean reductions of 16% in EE peak plasma concentration (C), 19% in EE area under the concentration-max time curve for a dosing interval (AUC[τ]) and 37% in EE lowest plasma concentration (Cmin), compared with EE 35 μg with NGM in the absence of ATV/RTV. NGM with EE and ATV/RTV 300/100 mg once daily resulted in increases of approximately 68%, 85% and 102% in 17-deacetyl NGM Cmax, AUC(τ) and Cmin, respectively. Two participants discontinued the study because of adverse events.
Conclusions
ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 μg of EE.
References
1.
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. December 1, 2009. Department of Health and Human Services (Accessed 10 December 2009.) Available from http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
CalderoniM.E., CoupeyS.M.Combined hormonal contraception. Adolesc Med Clin2005; 16: 517–537.
4.
TackettD., ChildM., AgarwalaS.Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects.10th Conference on Retroviruses and Opportunistic Infections. 10–14 February 2003, Boston, MA, USA. Abstract 543.
5.
BackD.J., OrmeM.L.Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet1990; 18: 472–484.
6.
ShelepovaT., NafzigerA.N., VictoryJ.Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. J Clin Pharmacol2005; 45: 1413–1421.
7.
GibaldiM., PerrierD.Pharmacokinetics. New York: Informa Health Care1982.
8.
Ortho Tri-Cyclen (norgestimate/ethinyl estradiol). US prescribing information2007. Ortho-McNeil-Janssen Pharmaceuticals Inc.Raritan, NJ, USA.
9.
Ortho Tri-Cyclen LO (norgestimate/ethinyl estradiol).US prescribing information2008. Ortho-McNeil-Janssen Pharmaceuticals Inc.Raritan, NJ, USA.
10.
RoyP., JakateA.S., PatelA.Effect of multiple-dose dexloxiglumide on the pharmacokinetics of oral contraceptives in healthy women. J Clin Pharmacol2005; 45: 329–336.
11.
GolzieherJ.W.Pharmacokinetics and metabolism of ethinyl estrogens. In GolzieherJ.W., FotherbyK. (Editors). Pharmacology of the contraceptive steroids. New York: Raven Press1994; pp. 127–151.
12.
OrmeM.L., BackD.J.Factors affecting the enterohepatic circulation of oral contraceptive steroids. Am J Obstet Gynecol1990; 163: 2146–2152.
13.
ZhangD., ChandoT.J., EverettD.W., PattenC.J., DehalS.S., HumphreysW.G.In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos2005; 33: 1729–1739.
OuelletD., HsuA., QianJ.Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol1998; 46: 111–116.
16.
SonodaJ., XieW., RosenfeldJ.M., BarwickJ.L., GuzelianP.S., EvansR.M.Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc Natl Acad Sci U S A2002; 99: 13801–13806.
17.
LuoG., CunninghamM., KimS.CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos2002; 30: 795–804.
18.
Kaletra (lopinavir/ritonavir).US prescribing information2007. Abbott LaboratoriesChicago, IL, USA.
19.
FaucetteS.R., WangH., HamiltonG.A.Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos2004; 32: 348–358.
20.
WangB., SanchezR.I., FranklinR.B., EvansD.C., HuskeyS.E.The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos2004; 32: 1209–1212.
21.
YehR.F., GaverV.E., PattersonK.B.Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr2006; 42: 52–60.
22.
RossmanithW.G., SteffensD., SchrammG.A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity. Contraception1997; 56: 23–30.
23.
RosenbergM.J., MeyersA., RoyV.Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception1999; 60: 321–329.
24.
PoindexterA.N., BurkmanR., FisherA.C., LaGuardiaK.D.Cycle control, tolerability, and satisfaction among women switching from 30–35 microg ethinyl estradiol-containing oral contraceptives to the triphasic norgestimate/25 microg ethinyl estradiol-containing oral contraceptive Ortho Tri-Cyclen LO. Int J Fertil Womens Med2003; 48: 163–172.
25.
KasserraC.Effect of vicriviroc with and without ritonavir on oral contraceptive pharmacokinetics.XVII International AIDS Conference. 3–8 August 2008, Mexico City, Mexico. Abstract TUBE0043.
26.
KaunitzA.M.Enhancing oral contraceptive success: the potential of new formulations. Am J Obstet Gynecol2004; 190Suppl 4: S23–S29.
27.
ColeJ.A., NormanH., DohertyM., WalkerA.M.Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol2007; 109: 339–346.
28.
JickS.S., KayeJ.A., RussmannS., JickH.Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. Contraception2006; 73: 566–570.
29.
LondonR.S., ChapdelaineA., UpmalisD., OlsonW., SmithJ.Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive. Acta Obstet Gynecol Scand Suppl1992; 156: 9–14.
30.
Reyataz (atazanavir). US prescribing information2009. Bristol–Myers SquibbPrinceton, NJ, USA.
