Acute Porphyria Drugs

Acute Porphyria Drug Database

J02AB02 - Ketoconazole
Possibly porphyrinogenic
PSP
Important Information
The Committee for Medicinal Products for Human Use (CHMP) at European Medicines Agency (EMA) has recommended that ketoconazole tablets, for the systemic treatment of fungal infections, to be taken off the market. This is because of risk for serious hepatic toxicity and that there are other safer alternatives for treatment available. The potential benefits are therefore not considered to outweigh the potential risks.
Side effects
Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are abdominal pain, diarrhoea nausea and vomiting. Other common side effects are headache and liver function disturbances. The Committee for Medicinal Products for Human Use (CHMP) at European Medicines Agency (EMA) recommended ketoconazole tablets, for the systemic treatment of fungal infections, to be taken off the market. This is because of risk for serious hepatic toxicity and that there are other safer alternatives for treatment available. The potential benefits are therefore not considered to outweigh the potential risks. Ketoconazole has been reported to form reactive metabolites (Argoti 2005), which are associated with idiosyncratic liver disease (Walsh 2012). One mechanism behind drug induced liver injury is thought to be direct mitochondrial impairment (Russmann 2009). Reactive metabolites are thought to uncouple or inhibit the mitochondrial respiratory chain causing reduced β-oxidation and ATP depletion in the liver cells (Au 2011). In theory, the low-energy status of the liver cells may in turn activate the heme-biosynthesis, thus being potentially porphyrinogenic.
Rationale
Ketoconazole is a potent inhibitor of CYP3A4 in vivo and has been shown to be a reversible inhibitor in vitro. Ketoconazole is associated with risk of serious liver injury, which might be due to a reduced capacity in ATP generation. This low-energy state may potentially be porphyrinogenic by activating the heme biosynthesis.
Chemical description
Ketoconazole is an antimycotic for systemic use. It is an imidazole derivative.
Therapeutic characteristics
Ketoconazole is indicated for the treatment of fungal infections of the skin and hair, which cannot be treated topically, and in patients resistant to or intolerant of other treatments. Ketoconazole is also indicated for the treatment of endogenous Cushing’s syndrome. It is administered orally. Ketoconazole is contraindicated in patients with acute and chronic liver disease.
Hepatic exposure
Peak plasma concentration was 3.5 µg/ml, which is equivalent to 6.6 µM, following administration of a 200 mg tablet (SPC).
Metabolism and pharmacokinetics
Ketoconazole is metabolised mainly by CYP3A4 (SPC). Ketconazole is listed as a strong inhibitor of CYP3A in vivo (FDA, Isoherranen 2009, Pelkonen 2008 and SPC). The inhibition is non-time-dependent (Li 2001 and von Moltke 2000) and thought to be mixed competitive-noncompetitive in vitro (Greenblatt 2011, Pelkonen 2008). When ketoconazole was co-administered with midazolam it increased the AUC of midazolam significantly 10 times compared with the placebo phase (Olkkola 1994). Concomitant administration of ketoconazole and lurasidone resulted in a 9.4-fold increase in the AUC of lurasidone (Chiu 2014). Another in vivo study also showed that ketoconazole inhibited the CYP3A-mediated metabolism of midazolam (Fuchs 2013). These data confirm that ketoconazole is an inhibitor of CYP3A4. An in vitro study showed that inhibition of testosterone 6β-hydroxlation by ketoconazole was not enhanced by pre-incubation. This indicates that ketoconazole is a reversible inhibitor of CYP3A4 (Greenblatt 2011). Ketoconazole is listed as a weak inhibitor of CYP2C8 and CYP2C19 in vivo (FDA). In vitro data has indicated that ketoconazole is an antagonist of human glucocorticoid receptors, which results in down-regulation of drug metabolizing CYP2C9, CYP3A and several other proteins (Dovorak 2011 and Duret 2006). Other studies also showed that ketoconazole is an inhibitor of hPXR (Huang 2007) and can inhibit xenobiotic-inducible expression of CYP3A4 in vitro (Dvorak 2011 and Wang 2007). However, a drug-drug interaction study with St Johns wort, midazolam and ketoconazole showed that it does not inhibit PXR-mediated induction of CYP3A in vivo (Fuchs 2013).
Published experience
Ketoconazole is listed as unsafe for use in acute porphyria because it has been shown to be porphyrinogenic in animals or in vitro systems (Moore 1997).

References

  1. Scientific articles
  2. Argoti D, Liang L, et al. Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol. 2005 Oct;18(10):1537-44. PMID 16533017. #4501
  3. Au JS, Navarro VJ, et al. Review article: Drug-induced liver injury--its pathophysiology and evolving diagnostic tools. Aliment Pharmacol Ther. 2011 Jul;34(1):11-20. PMID 21539586. #4502
  4. Chiu YY, Ereshefsky L, et al. Lurasidone drug-drug interaction studies: a comprehensive review. Drug Metabol Drug Interact. 2014;29(3):191-202. PMID 24825095. #4503
  5. Duret C, Daujat-Chavanieu M, et al. Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329-39. PMID 16608920. #4504
  6. Dvorak Z. Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition. Toxicol Lett. 2011 Apr 25;202(2):129-32. PMID 21333771. #1670
  7. Fuchs I, Hafner-Blumenstiel V, et al. Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity. Eur J Clin Pharmacol. 2013 Mar;69(3):507-13. PMID 22968811. #4505
  8. Greenblatt DJ, Zhao Y, et al. Mechanism of cytochrome P450-3A inhibition by ketoconazole. J Pharm Pharmacol. 2011 Feb;63(2):214-21. #1673
  9. Huang H, Wang H, et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene. 2007 Jan 11;26(2):258-68. #1674
  10. Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
  11. Li AP, Doshi U. Higher throughput human hepatocyte assays for the evaluation of time-dependent inhibition of CYP3A4. Drug Metab Lett. 2011 Aug;5(3):183-91. PMID 21722087. #1675
  12. Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
  13. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994 May;55(5):481-5. PMID 7952798. #1678
  14. Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
  15. Russmann S, Kullak-Ublick GA, et al. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041-53. PMID 19689281. #4506
  16. von Moltke LL, Durol AL, Duan SX, Greenblatt DJ. Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. Eur J Clin Pharmacol. 2000 Jun;56(3):259-61. PMID 10952482. #4507
  17. Walsh RJ. Chemical and biochemical aspects of drug induced liver injury. Research-archive.liv.ac.uk. 2010. #1681
  18. Wang H, Huang H, et al. Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin Cancer Res. 2007 Apr 15;13(8):2488-95. PMID 17438109. #4508
  19. Government bodies
  20. European Medicines Agency (EMA). “Ketoconazole-containing medicines”. 26.07. 2013. Webhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Ketoconazole-containing_medicines/human_referral_000348.jsp&mid=WC0b01ac05805c516f&source=homeMedSearch&category=human #1671
  21. Norwegian medicines agency. “Anbefaler at Fungoral tabletter trekkes fra markedet”. 29.07.2013. Webhttp://legemiddelverket.no/Nyheter/Bivirkninger/Sider/Anbefaler-at-Fungoral-tabletter-trekkes-fra-markedet.aspx #1676
  22. U.S Food and Drug Administration (FDA). #1450
  23. Summary of Product Characteristics
  24. Norwegian medicines agency. Summary of Product Characteristics (SPC). Ketokonazol. #1677
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