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June Wilkins
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1 We have some trouble with special characters and displaying monographs ATC code: G03AC09 Classification: PRP - Probably porphyrinogenic Substance: Desogestrel Rationale for risk classification: Progestogens are considered as potentially porphyrinogenic substances and are known to have caused porphyric attacks in susceptible carriers of acute porphyria. Both pharmacodynamic and pharmacokinetic properties can explain the triggering effect in acute porphyria. Studies have shown that these hormones can affect CYP enzymes by induction and mechanism-based inhibition. Although these effects are described to a limited extent in drug-drug interactions studies in general, it is likely that they have a role in a probable upregulation of the heme biosynthesis. Desogestrel have been reported to elicit an acute attack in a previously presymptomatic AIP female. Chemical description: Progestogen steroid, 19-nortestosterone derivative Therapeutic characteristics: Desogestrel is used as an oral contraception. The half-life of the active metabolite etonogestrel is 30 hours. Side effects or other pharmacodynamic effetcs of relevance to acute porphyria: A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mpralpha-pgrmc2 receptor complex (Thomas 2013), which is accompanied by heme binding (Rohe 2009), and may therefore result in a heme drain. A decreased cellular heme pool may then upregulate ALAS-1 (Besur 2014). In addition, the heme-sensing receptor, Rev-erb-alpha, will sense the decreased level of the regulatory heme pool and reduce its repressor effect on PGC-1alpha (Wu 2009). PGC-1alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005). Extent of hepatic exposure: Peak serum concentration of the active metabolite etonogestrel is 640 pg/ml after oral administration of 75 µg Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 1/6

2 desogestrel (Grandi 2014). This is equivalent to 2.06 nm. Metabolism and pharmacokinetics: Desogestrel is rapidly converted to the active metabolite etonogestrel. In vitro studies suggest that CYP2C9 is involved in this bioactivation (Gentile 1998), however an in vivo study found that neither CYP2C9, nor CYP3A4 is involved (Korhonen 2005). The further metabolism of etonogestrel is mediated by CYP3A4 (Gentile 1998, Korhonen 2005). The active metabolite, etonogestrel, is found to be an in vitro inhibitor of CYP2C9, CYP2C19 and CYP3A4 (Back 1991, Laine 2003, Zingone 2009). Several different 17?-substituted progestins have been found to show some degree of mechanism-based inhibition of CYP3A4 in vitro, and etonogestrel was among them (Guengerich 1990). Progesterone and synthetic progestogens activate PXR (Kliewer 1998). Progestogens are not listed as significant inducers of CYP 3A4 in most interaction databases (Preissner 2010, NOMA, Lexi-Interact, The Danish Health and Medicines Authority, Micromedex). Results from clinical studies suggest that the increased hormonal levels in pregnancy have the potential to alter hepatic cytochrome P450 drug metabolism (Anderson 2005). Also, in vitro studies have shown increased CYP mrna after exposing hepatocytes to progesterone and estradiol levels equal to the high hormonal levels typically seen in the third trimester of pregnancy (Choi 2013). Hormonal therapy generally leads to a much lower plasma concentration relative to the levels of endogenous hormones in pregnancy and may explain the lack of observed significant effects of administered hormones on CYP 3A4 in vivo. However, since both ethinyl estradiol and the progestin component have the potential to induce ALAS1 through PXR activation and at the same time cause mechanism-based inhibition of CYP 3A4, this may explain the absence of observed pharmacokinetic drug-drug interactions. For an evaluation of the porphyrinogenicity of these drugs it is important to realize that the inhibitory effect can mask the inductive power and that an increased de novo synthesis of CYP3A4 can take place irrespective of negative results from in vivo DDI-studies. The effects of concomitant induction and inhibition have in general been discussed by Wei et al. for other drugs (Wei 2016). Since CYP3A4 quantitatively is the largest CYP isoenzyme, an increased de novo synthesis of CYP3A4, although masked, will give an upregulation of ALAS-1and thereby a higher flux through the heme biosynthesis. Such a mechanism can possibly in part explain the observed porphyrinogenic effects of these drugs. Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 2/6

3 Studies have shown that women with acute porphyria have an altered 5alpha-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alpha reductase pathway to formation of 5beta steroid metabolites that may be more potent inductors of ALAS1 (Innala 2012, Anderson 1979, Jacobs 2005). Published clinical experience: It is from clinical observations well known that progestogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014). EPNET drug reports: One very well documented report of attack requiring hospitalisation and treatment with heme arginate in a 17 year-old previously presymptomatic AIP female. Uneventful use reported in 4 patients with acute porphyria. References: Andersson C, Innala E, et al. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med Aug;254(2): Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10): Anderson KE, Bradlow HL, et al. Studies in porphyria. VIII. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria. Am J Med Apr;66(4): Back DJ, Houlgrave R, et al. Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes. J Steroid Biochem Mol Biol Feb;38(2): Besur S, Hou W, et al. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites Nov 3;4(4): Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 3/6

4 Choi S-Y, Koh KH, et al. Isoform-specific regulation of cytochrome P450 expression by estradiol and progesterone. Drug Metab Dispos 2013 Feb. 41: Gentile DM, Verhoeven CH, et al. The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. J Pharmacol Exp Ther Dec;287(3): Grandi G, Cagnacci A, et al. Pharmacokinetic evaluation of desogestrel as a female contraceptive. Expert Opin Drug Metab Toxicol Jan;10(1):1-10. Guengerich FP. Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol Dec;163(6 Pt 2): Handschin C, Lin J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell Aug 26;122(4): Innala E, Bäckström T et al. Women with acute intermittent porphyria have a defect in 5alpha-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand Dec;91(12): Jacobs MN, Nolan GT, Hood SR. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharmacol Dec 1;209(2): Kliewer SA, Moore JT, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell Jan 9;92(1): Korhonen T, Tolonen A, et al. The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel. Br J Clin Pharmacol Jul;60(1):69-75 Lexi-Interact, via UpToDate. (Accessed: ). Micromedex 2.0 (online). Drug Interactions). ( ). Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 4/6

5 Norwegian medicines agency (NOMA). Find medicine. (Accessed: ). Preissner S, Kroll K, rt al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res Jan;38(Database issue):d Rohe HJ, Ahmed IS, et al. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacol Ther Jan;121(1):14-9. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Cerazette. (Last edition: ). Thomas P, Pang Y, et al. Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mpr alpha) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology Mar;155(3): Thunell S. Genetik och metabola förlopp bakom den akuta porfyriattacken - Mer än hundra läkemedel är potentiellt livshotande vid akut porfyri. Lakartidningen Sep 9;113. Wei Y, Tang C, et al. A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism? Curr Pharmacol Rep Aug;2(4): White IN, Muller-Eberhard U. Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol. Biochem J Jul 15;166(1): Wu N, Yin L, et al. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erb-alpha. Genes Dev Sep 15;23(18): Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 5/6

6 Zingone MM, Guirguis AB, et al. Probable drug interaction between warfarin and hormonal contraceptives. Ann Pharmacother Dec;43(12): Copyright The Norwegian Porphyria Centre (NAPOS) and The Swedish Porphyria Centre. All rights reserved.page 6/6

Pharmacokinetic Interaction Between Norgestimate/Ethinyl Estradiol and EVG/COBI/FTC/TDF Single Tablet Regimen

Pharmacokinetic Interaction Between Norgestimate/Ethinyl Estradiol and EVG/COBI/FTC/TDF Single Tablet Regimen Polina German, Maggie Wang, David Warren and Brian Kearney Gilead Sciences Foster City, CA,