LETTERS TO THE EDITOR

 

Dosage adjustment for hepatic dysfunction

Dosificación de fármacos en insuficiencia hepática crónica

 

 

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Key words: Liver disease. Dosage adjustment. Pharmacokinetics.

Palabras clave: Insuficiencia hepática. Ajuste de dosis. Farmacocinética.

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Dear Editor,

Periáñez-Párraga et al. (1) provide dose adjustment recommendations for 186 drugs in hospitalized patients with chronic liver dysfunction (LD). In this article, a literature review about dosage adjustment was performed and, in case no information was found, the adjustment recommendations were given according to the process defined by Delcò et al. (2).

The final recommendation was established for 186 reviewed drugs; 73.1 % of them needed quantitative or qualitative adjustment. Recommendation was defined according to the product characteristics summary in 92 drugs (49.5 %), DrugDex Micromedex 49 (26.3 %) and WHO 35 (18.8 %). The recommendations of 6 drugs (3.2 %) were based on previous publications for the group of antimicrobials in 2009 and in 4 drugs a theoretical adjustment recommendation based on the proposal defined by Delcò et al. (2) was given.

We performed a literature search in Medline database using the combination of the following keywords: "pharmacokinetics", "liver disease", "hepatic metabolism", "dose adjustment" and the specific generic name of each drug evaluated. The references of the papers found were screened for additional information in product characteristics summary, DrugDex-Micromedex (3); Drug information handbook (4); British National Formulary (5); FDA (6) and EMEA (7) guidelines as well as WHO recommendations (8). Final recommendation is different in 46 drugs comparing with those provided by Periañez-Parraga et al. (1) (Table I).

 

 

In this review, 136 drugs needed dose adjustment, requiring qualitative recommendation in 64.7 % of them. In our review, 195 drugs need dose adjustment (oncology therapy was not included); 69.7 % of the recommendations obtained were unspecific. Protein binding ≥ 90 % was registered in 75 (38.5 %) drugs, < 90 % in 109 (55.9 %) drugs and no data was obtained in 11 (5.6 %) drugs. Hepatic extraction ratio (E) was < 0.3 in 19 drugs (31.6 % of drugs with E data available). These data coincide with those obtained by Periáñez-Párraga L et al. (1). In 60 drugs (30.8 %), E was obtained through the bibliography, while Periañez-Párraga L et al. (1) only found information of 11.5 % of the reviewed drugs.

Moreover, for 103 drugs not included in their review, dosage adjustment requirements in LD were found: Albendazole, alfentanil, magnesium hydroxide, amiodarone, amodiaquine, amprenavir, atorvastatin, bisoprolol, bupropion, buspirone, candesartan, carvedilol, chloramphenicol, chlomethiazole, clorphenamine/clorpheniramine, cholestyramina, cinacalcet, clofazimine, clomiphene, clonidine, colestipol, dabigatran, dapsone, diltiazem, dipyridamole, disopyramide, eprosartan, ergometrine (ergonovine), escitalopram, esomeprazole, ethionamide, everolimus, fenofibrate, fentanyl, flecainide, fluphenazina, fluvastatin, fusidic acid, galantamine, gemfibrozil, hydroxyzine, isosorbide dinititrate/mononitrate, labetalol, levetiracetam, losartan, lovastatin, magnesium sulphate, mebendazole, mefloquine, melarsoprol, meperidine, metoprolol, midazolam, moxifloxacin, naproxen, neomycin, nicotinic acid/niacin, nimodipine, nisoldipine, nitroglycerin, norethisterone, ondansetron, oxytetracycline, peginterferon alfa-2a and 2b, pentazocine, pilocarpine, pravastatin, praziquantel, prazosin, propafenone, propylthiouracil, pyrantel pamoate, quetiapine, quinidine, quinine, roxithromycin, sertraline, sildenafil, sirolimus, solifenacin, spiramycin, sulfadoxine, suramin, telmisartan, terbinafine, testosterone, tetracycline, thiopental, ticlopidine, tirofiban, torasemide, vardenafil, venlafaxin and zaleplon.

As mentioned in the article published by Periáñez-Párraga (1), lack of information and clinical trials in patients with hepatic insufficiency make it difficult to recommend specific dosage adjustments leading to a lack of consistency in dosage adjustment recommendations. Dosage recommendations and pharmacokinetic parameters are not coincident in different scientific sources, as it is shown in the differences between both reviews.

 

Núria Padullés-Zamora, Elisabet Leiva-Badosa and Ramón Jodar-Masanes
Department of Pharmacy. Hospital Universitari de Bellvitge. IDIBELL. Hospitalet de Llobregat, Barcelona. Spain

 

References

1. Periáñez-Párraga L, Martínez-López I, Ventayol-Bosch P, Puigventós-Latorre F, Delgado-Sánchez O. Drug dosage recommendations in patients with chronic liver disease. Rev Esp Enferm Dig 2012;104:165-84.         [ Links ]

2. Delcò F, Tchambaz L, Schienger R, Drewe J, Krahenbuhl S. Dose adjustment in patients with liver disease. Drug Saf 2005;28:529-45.         [ Links ]

3. Drug Evaluation Monograph. En: Drugdex^® Information System. Micromedex Inc. Engleewood: Staff; 2011. (fecha última consulta 19 de agosto de 2011).         [ Links ]

4. American Pharmacists Association. Lexi-Comp's drug reference handbooks. 17th ed. Ohio, 2008.         [ Links ]

5. British national formulary. BMJ Group and RPS Publishing. Germany, 2009.         [ Links ]

6. FDA (2003). Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labelling. Available at: http://www.fda.gov/cber/gdlns/imphep.pdf.         [ Links ]

7. EMEA (2005). Guidance in the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. Available at: http://www.emea.europa.eu/pdfs/human/ewp/23390.         [ Links ]

8. 15th WHO Model List of Essential Medicines. Available at: http://www.who.int/selection_medicines/list/WMF2008.pdf.         [ Links ]