ORIGINAL PAPERS

 

Drug dosage recommendations in patients with chronic liver disease

Recomendaciones para la dosificación de medicamentos en pacientes con insuficiencia hepática crónica

 

 

Leonor Periáñez-Párraga, Iciar Martínez-López, Pere Ventayol-Bosch, Francesc Puigventós-Latorre and Olga Delgado-Sánchez

Department of Pharmacy. Hospital Universitari Son Espases. Palma de Mallorca-Illes Balears, Spain

This work has been funded by the Joaquim Bonal 2009 grant from the "Societat Catalana de Farmacia Clínica".

Correspondence

 

 

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ABSTRACT

Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens.
A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet.
Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs.
The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%).
In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.

Key words: Liver disease. Liver dysfunction. Prescription drugs. Hepatic impairment. Dose-response relationship.

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RESUMEN

La insuficiencia hepática crónica produce alteraciones que afectan a la cinética de los medicamentos y a pesar de que su ajuste se basa en el índice Child-Pugh, no se disponen de recomendaciones y/o algoritmos de referencia que faciliten su dosificación.
Se realizó una revisión bibliográfica de la dosificación en insuficiencia hepática crónica de los medicamentos de la guía del hospital incluidos en el listado de fármacos que la OMS recomienda no utilizar o utilizar con precaución en pacientes con enfermedad hepática, añadiendo las novedades terapéuticas de los últimos años. Para ello se revisaron las fichas técnicas, base DrugDex-Micromedex, recomendaciones de la OMS y artículos de revisión de los últimos 10 años en Medline; además, se calcularon los parámetros cinéticos de cada fármaco con el objeto de establecer una recomendación teórica basada en la propuesta de Delcò y Huet.
Se presentan recomendaciones para 186 medicamentos, según lo indicado en la ficha técnica (49,5%), DrugDex-Micromedex (26,3%) y OMS (18,8%); 6 recomendaciones se realizaron en base a publicaciones específicas y en 4 fármacos se propuso la recomendación teórica basada en los parámetros farmacocinéticos.
Las recomendaciones finales para el manejo clínico fueron de: modificación de dosis (26,9%), monitorización hepática/analítica del paciente (8,6%), contraindicación (18,8%), emplear con precaución (19,3%) y no requerir ajuste (26,3%).
En esta revisión se presentan recomendaciones específicas para el manejo práctico del paciente con insuficiencia hepática crónica, obtenida mediante una síntesis de la bibliografía publicada y completada con aplicación de una metodología teórica.

Palabras clave: Enfermedad hepática. Disfunción hepática. Prescripción farmacológica. Insuficiencia hepática. Relación dosis-respuesta.

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Introduction

The liver plays a fundamental role in the metabolism of most drugs because hepatic and biliary excretion processes determine the rate of their elimination from the body, while bioavailability is affected by first-pass mechanisms.

Alterations affecting the kinetics of drugs in chronic liver disease (CLD) are mainly due to three mechanisms: reduction of portal blood flow which affects the pre-systemic elimination of high extraction drugs; decreased synthesis of transport proteins, mainly albumin and alpha-glycoprotein, which affect the bioavailability of drugs highly bound to plasma proteins; reduced drug-metabolizing hepatic enzymes, which affects the amount of plasma active metabolite, thus, the effectiveness and toxicity (1).

Chronic liver disease is assessed through Child-Pugh score system which is based on five variables: the presence of ascites and encephalopathy, plasma concentrations of bilirubin and albumin and prothrombin time. The Child-Pugh score indicates the level of chronic hepatic damage: score 5-6 is class A (mild); 7-9 corresponds to class B (moderate); and 10-15 is class C (severe) (2,3).

Another classification scheme such as MELD (Model for End stage Liver Disease) is based on serum bilirubin concentration, serum creatinine, the international normalized ratio (INR) of prothrombin time, and the underlying cause of liver disease (4). The MELD score was designed to predict 3-month mortality among patients on a liver- transplant waiting list and has been adopted to use for allocating priorities in patients awaiting liver transplantation (5). However, unlike in renal patients, where estimates of glomerular filtration rate (creatinine clearance, inulin clearance) correlate with kinetic parameters of drug elimination such as renal clearance, these classification schemes lack the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. That is why it is not a frequently used classification scheme for pharmacological adjustment.

The recommendations for drug dosage adjustment in patients with CLD are based on Child-Pugh scores. Since 2003 and 2005 respectively, the regulating agencies Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require the performance of kinetic studies previous to the authorization of new drugs in patients with CLD in order to provide future dose adjustment recommendations (6,7). This information reflected in the summary of product characteristics (SPC) is highly useful. However, a great amount of drugs lack of this specific information because patients recruited in clinical trials show a good hepatic function (Child-Pug class A) and do not have an advanced liver dysfunction (Child-Pugh class C).

The complexity of hepatic metabolism has limited the development of tools allowing predictions of drug behavior in patients with chronic liver disease. Unlike in renal insufficiency, there are no guidelines and algorithms of reference to facilitate drug dosage in these patients. In this context, there is a growing need to check and expand the available information in the SPC. The review of recommendations from other sources and the application of calculation procedures based on the kinetic parameters of the drug are needed to establish practical dose recommendations in CLD for the frequently used drugs in the care environment.

The aim of this article is to provide dose adjustment recommendations for the most commonly used drugs in the hospital in patients with chronic liver disease.

 

Materials and methods

Drugs were selected from the list of medicines WHO recommends to avoid or to use with caution in patients with liver disease (8), selecting those included in the hospital Pharmacotherapeutic Guide (PG). The therapeutic novelties from over the last few years were also included.

A literature review about dosage recommendations in chronic liver disease was carried out for the selected drugs from the following sources: a) SPC; b) DrugDex Micromedex (9); c) WHO recommendations (8); and d) review articles published in the last 10 years in the Medline database with the following search strategy: "Hepatic"[Ti] OR "liver"[Ti]) AND ("Dose-Response Relationship, Drug"[Mesh]) AND (Review[ptyp] AND (English[lang] OR Spanish[lang]) AND "2001/02/27"[PDat]: "2011/02/24"[PDat]). The following search engines were used: "Scholar-google" and "Alquimia" (10) with the aim of finding bulletins published by centers of reference which include drug dosage recommendations in chronic liver disease.

The final dosage recommendations have been based on the SPC information and on the rest of the bibliography defined in the search strategy. In case they were not coincident, the most restrictive proposal was taken.

When no information was found, the adjustment recommendations were given according to the process defined by Delcò et al. (1), based on the method established by Huet et al. (11) and Krähenbühl et al. (12). This method classifies each drug according to three parameters: hepatic extraction ratio (E_H) -classified in 3 categories (high ≥ 60%, intermediate 30-60% and low ≤ 30%), bioavailability (F) and plasma protein binding (PB) (Table I). For the drugs with no E_H available information, E_H was calculated using the formula defined by Westphal et al. (11): [E_H = (Q₀ x CL_syst)/Q_H]. Q₀ values (extra renal drug moiety) and CL_syst (systemic or total clearance) were obtained from the literature, assuming a hepatic blood flow (Q_H) of 1.5 L/min.

In order to have supplementary information to the bibliography, the following parameters were registered for all drugs: E_H, bioavailability, plasma protein binding and the corresponding category according to the Huet classification (11).

 

Results

The information of 191 drugs was reviewed: 56 of oncology therapy, 84 anti-infective agents [antibiotics (35), anti-tuberculosis drugs (5), antifungal (15) and antiretroviral agents (29)], 13 of cardiovascular therapy and 38 of other pharmacological groups.

The final recommendation was established for 186 reviewed drugs and was defined according to the SPC in 92 (49.5%), 49 in DrugDex Micromedex (26.3%) and 35 in WHO (18.8%); the recommendations of 6 drugs (3.2%) were based on the publications of Azanza et al. (14), for the group of antimicrobials. In four drugs (2.2%) (dacarbazine, leuprorelin, maraviroc and zidovudine) no information in the previously mentioned databases was found nor in further bibliography searches. That is why a theoretical adjustment recommendation based on the proposal defined by Delcò et al. (1) and Huet et al. (11) was given. In five drugs (buserelin, dactinomycin, enfuvirtide, megestrol and trastuzumab) no information was found about dosage adjustment due to lack of data.

Depending on the type of recommendation the following was obtained: 48 drugs (25.8%) needed quantitative adjustment; 88 drugs (47.3%) had to follow qualitative recommendations divided into: 37 caution of use, 16 monitoring the patient and 35 contraindication; and 50 drugs (26.9%) did not require dosage adjustment, being 72% of them of low E_H (< 0.3).

Regarding the reviewed drugs, the established classification by Huet et al. (11) was the following respectively: 19 (10.2%) class 1; 28 (15.1%) class 2; 77 (41.4%) class 3 and 62 (33.3%) class 4.

From the 191 reviewed drugs, E_H was calculated with the Westphal et al. formula (13) in 103 drugs (53.9%); in 66 drugs (34.6%) it was not obtained due to lack of data; in 22 drugs (11.5%) E_H was obtained through the bibliography.

Some other registered parameters to justify dosage adjustment were: PB ≥ 90% in 66 drugs (34.6%), < 90% in 102 drugs (53.4%) and no data was obtained in 23 drugs (12.0%). The hepatic/biliary metabolism predominance with a score of Q₀ > 0.4 was found in 65 drugs (34.0%), it was less than 0.4 in 35 drugs (18.3%) and it could not be obtained in 91 (47.6%), which indicates that most of the drugs in which Q₀ was obtained are highly metabolized and/or are excreted through bile.

The dosage adjustment recommendation is shown in table II, it indicates the final recommendation in drugs requiring adjustment in chronic liver disease, drugs in which hepatic or analytic monitorization is recommended, contraindicated drugs in chronic liver disease, drugs used with caution and drugs not requiring adjustment in chronic liver disease. The category Huet and Krähenbühl and the E_H of every drug is also found in table II.

 

Discussion

In this review, a dosage adjustment for 186 frequently used drugs in hospitals in patients with chronic liver disease is proposed.

There is not an established method available to assess hepatic failure which correlates with the hepatic clearance of drugs. Besides, the semiquantitive scale of Child-Pugh is not precise and it does not always quantify the specific capacity of the liver to metabolize different drugs. Drug adjustment to the hepatic function of the patient by using the Child-Pugh score has limitations because it was initially designed to stratify the risk of anastomosis or portocaval shunt in cirrhotic patients. However, it has been demonstrated that the Child-Pugh score shows also some relation with survival and with the development of complications in cirrhosis. The Child-Pugh score requires quantification of subjective variables such as ascites and encephalopathy, which vary among different observers and can be modified by medical interventions such as the lactulose and/or diuretics prescription in encephalopathy and ascites.

The Child-Pugh score is mostly used in the review articles which include drug dosage recommendations in patients with chronic liver disease through the application of an explicit methodological procedure (8,15-19). The bulletin written by Shapiro (20) compared the Child-Pugh scores with the Cockcroft-Gault equation used in the adjustment for renal insufficiency. In some studies, the adjustment based on the E_H with supplementary information such as plasma protein binding, hepatic cytochrome metabolism or transaminases among others (1,17,19) is proposed. However, general recommendations are proposed for most of the drugs.

To define the drugs that have to be adjusted in patients with chronic liver disease, the main parameter proposed by different authors is E_H. Kim et al. (21) proposes to establish three categories to adjust drugs depending on E_H in the hepatic first-pass effect, being those of high extraction the adjusted ones.

The recommendations of the Drug Information Service (22) propose that in the case of a severe liver dysfunction (albumin < 30 g/dL, INR > 1.2), drugs with a high EH are still the ones which should have a higher adjustment despite it includes the possibility of dose reduction in the low extraction ones. Accordingly, Shlatter et al. (16) agree in the dosage recommendations based on E_H and/or pharmacological bioavailability, justifying adjustments of initial doses and maintenance.

The established recommendations about the possible dose adjustment in patients with hepatic insufficiency by Verbeeck et al. (19) are very similar to the ones by Delcò et al. (1) and Klotz (23). Both characterize the drugs depending on the hepatic extraction rate, plasma protein binding and their hydrophilicity. The difference with the previous authors is that the latest propose an initial and maintenance dose adjustment (1,19) of the drugs with a low level of extraction and a narrow therapeutic range. Pirmohamed (17) proposes to select those with a wide therapeutic range to ensure a lower hepatotoxicity. Some other authors such as Sloss et al. (18) establish the avoidance of use or the increase of administration intervals in drugs with a low therapeutic margin and high-medium EH as measures to reduce the dose. Besides monitoring carefully the adverse effects and analyzing the possible pharmacological interactions. Finally, the article published by Azanza et al. (14) summarizes in tables the adjustments in the presence of renal insufficiency and/or of hepatic function failure from the antimicrobials according to the Child-Pugh score published in the literature. Drugs classified as "use with caution" are also another aspect to evaluate. The use of them should assess the balance of benefit/risk for each case because in all of them the adverse reactions in the hepatic level have been described, which could make the pathology worse in these subpopulation of patients. In the review, the lack of information and clinical studies with many drugs becomes clear. This is because until recent years, patients with Child-Pugh C were excluded in the development of new drugs for ethical reasons. Despite regulating agencies EMA and FDA recommend to study the research drugs in order to predict their behavior in patients with hepatic insufficiency and to being able to recommend dose adjustment, according to a recent survey, the number of drugs with specific adjustment recommendations based on the hepatic function with Child-Pugh scores is still very limited (24), probably due to hepatic insufficiency as exclusion criteria in most of the clinical trials. This would explain the lack of data in many cases in the SPC about dosage adjustment in moderate-severe hepatic insufficiency.

Moreover, there is a confirmed lack of consistency in the different consulted sources. This situation is also found in the general dosage recommendations as well as in the available kinetic data of drugs, mainly in the E_H, as it happens in the adjustment for renal insufficiency (25).

In view of the discrepancies highlighted above, the more conservative model is followed; despite it has the risk of an under-dosage, in some cases. Moreover, no guidelines in case of concomitant renal insufficiency or hepato-renal syndrome have been developed which could show one of its own limitations. Despite the existence of theoretical general recommendations in the medical literature about drug dosage in patients with hepatic insufficiency taking into account the pharmacokinetic parameters of E_H, plasma protein binding and bioavailability (1,15-19,21,22), it has been considered more useful to individualize the recommendations for each drug and adjust them to adult patients with liver diseases. We wonder if the recommendations can be applied to all patients with hepatic disease or if, on the contrary, a limit between acute, chronic or multiorganic failure hepatic diseases should be established.

In clinical practice, patients should be carefully analyzed to determine the risks and benefits, taking many factors into account such as the severity of the disease, the consequences of not using the drug and the existence of equivalences or alternatives of different available treatments. When having the chance to choose among many drugs to treat the same disease, the less hepatotoxic should be selected through published reviews which would help to take the right one (26) and with a wide therapeutic range. In case of hepatic insufficiency, caution to manage the treatment is imposed as well as an effective follow-up to determine the intensity and duration of the desirable and undesirable effects, mainly if repeated or continuous administrations exist.

In conclusion, nowadays there are significant gaps in the necessary data for the safety in drug administration in patients with hepatic function failure. That is why in this review a contribution to the practical management of drugs to facilitate dosage recommendations to doctors/caregivers in patients with chronic liver disease is presented. It has been obtained through a synthesis of the published bibliography and completed by applying a theoretical methodology.

 

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Correspondence:
Leonor Periáñez-Párraga.
Department of Pharmacy.
Hospital Universitari Son Espases.
Carretera Valldemosa, 79.
07010 Palma de Mallorca, Spain.
e-mail: leonord.perianez@ssib.es

Received: 28-09-11.
Accepted: 23-11-11.