Comorbidities and pharmacotherapies in patients with Gaucher ...

Molecular Genetics and Metabolism 117 (2016) 172–178

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Comorbidities and pharmacotherapies in patients with Gaucher disease type 1: The potential for drug–drug interactions Jeanine Utz a,⁎, Chester B. Whitley b, Paul L.M. van Giersbergen c, Stefan A. Kolb d a

University of Minnesota Medical Center, Fairview, Minneapolis, MN, USA University of Minnesota, Minneapolis, MN, USA Van Giersbergen Consulting, Wuenheim, France d Actelion Pharmaceuticals Ltd., Allschwil, Switzerland b c

a r t i c l e

i n f o

Article history: Received 4 November 2015 Received in revised form 1 December 2015 Accepted 1 December 2015 Available online 2 December 2015 Keywords: Gaucher disease type 1 Comorbidity Pharmacotherapy Drug–drug interactions Treatment decisions Clinical decisions

a b s t r a c t Purpose: Clinical care for patients with rare diseases may be complicated by comorbidities. Administration of medications to treat comorbidities may elicit potentially harmful drug–drug interactions (DDIs). Genetic background may also influence DDI occurrence. We investigated the range of comorbid conditions in patients with Gaucher disease type I (GD1), the pharmacotherapies prescribed and the potential for DDI with enzyme replacement and substrate reduction therapies and additional medications, specifically cytochrome P450 (CYP) metabolizing medications. Methods: A literature review examined comorbid conditions and pharmacotherapies reported in GD1. Analysis of two national databases reported real-world prescription practices in patients with GD1 (Germany, N = 87; US, N = 374). Prescribed drugs were assessed for known interactions with isoenzymes from the hepatic CYP enzyme family. Results: The literature reported GD1 symptomatology and comorbid conditions in broad agreement with the known clinical picture. German patients received 86 different medications whereas US patients received 329 different medications. An average of 3.2 medications (Germany) and 7 medications (US) per patient were prescribed. Moderate/strong inhibitors of CYP isoenzymes were prescribed to 20% and 57% of patients in the US and Germany, respectively. Conclusion: This study describes the extensive number of comorbid conditions and drugs prescribed to patients with GD1, and the importance of determining CYP isoenzyme interaction to reduce DDI risk. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction Gaucher disease (GD) is caused by an inherited deficiency in the lysosomal enzyme glucocerebrosidase, resulting from mutations in the gene GBA. Subsequently, glucosylceramide accumulates in the lysosomes of macrophages throughout the body. This affects a number of tissues, including the spleen, liver and bone, and in certain GD subtypes, the brain [1,2]. Tissues of the lung, heart, skin and conjunctiva may also be affected, albeit to a lesser extent, in some patients [3]. GD is the most common inborn lysosomal disease [2]. It exists in three distinct types: type 1, type 2 and type 3. GD type 1 (GD1) has historically been described as non-neuronopathic, although a neurological component of GD1, including increased risk of Parkinson's disease and increased prevalence of peripheral neuropathies has been recognized ⁎ Corresponding author at: University of Minnesota Medical Center, Fairview, MN 55455, USA. E-mail address: [email protected] (J. Utz).

in recent years [4–6]. GD type 2 and type 3 are described as neuronopathic due to central nervous system involvement [1,3]. GD1 accounts for over 90% of cases [2]. In Western countries, the prevalence of GD1 is 1/75,000; however, in individuals of Ashkenazi Jewish heritage, the occurrence is markedly higher (around 1/600) [2]. Classical clinical manifestations of GD1 include hepatosplenomegaly and bone disease [1]. The latter can manifest as osteopenia, osteoporosis, chronic and acute bone pain, pathological fractures, avascular necrosis, and necrosis of the humeral or femoral heads [7]. Compromised bone marrow function often results in cytopenias, with thrombocytopenia and anemia commonly present [3]. An increased prevalence of specific comorbid conditions, including Parkinsonism and multiple myeloma, has also been reported [8–10]. Two approved treatment types exist for patients with GD1: enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Both treatments aim to relieve symptoms, prevent irreversible bone changes and improve patient quality of life [2]. ERT is considered standard of care for patients with GD1, and is administered via periodic intravenous

http://dx.doi.org/10.1016/j.ymgme.2015.12.001 1096-7192/Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

J. Utz et al. / Molecular Genetics and Metabolism 117 (2016) 172–178

infusion [2]. The majority of GD1 patients receive ERT; most patients receive imiglucerase (FDA approved in 1994), with fewer patients receiving the recently approved ERTs velaglucerase alfa and taliglucerase (FDA approved in 2010 and 2012, respectively). The SRT miglustat was FDA approved in 2003 for the treatment of patients with mild or moderate GD1 who are unable to receive ERT [2]. A second oral SRT, eliglustat, was FDA approved in 2014 both as an alternative to ERT and as first-line therapy for the treatment of GD1 [11]. In addition to GD1-specific therapy, patients may need additional medications for symptomatic management or treatment of comorbidities. It is therefore likely that many patients will receive additional drugs along with their primary GD1 therapy, which may increase the potential for drug–drug interactions (DDIs). There is consequently a need for increased vigilance in clinical monitoring for this patient population [12,13]. Clinical assessment for the potential of DDIs focuses largely on hepatic drug metabolism, which relies heavily on the cytochrome P450 (CYP) family of enzymes. The CYP1, CYP2, and CYP3 families have been reported to metabolize around 95% of all pharmacological therapies [11,14]. Notable CYP isoenzymes with high involvement in hepatic drug metabolism include CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 [14,15]. CYP2D6 is responsible for metabolizing approximately 25% of available medications [16]. The CYP3A sub-family, of which CYP3A4 is the major liver enzyme, is involved in the metabolism of approximately 30–35% of all marketed drugs [5]. Variations in the influence of CYP enzymes in determining systemic exposure of drugs is best exemplified by the effect of genetic factors [16]. CYP gene polymorphisms, resulting in faster or slower rates of metabolic activity, can have profound effects on systemic drug exposure, in some cases necessitating genetic analysis prior to therapy initiation [14,17]. It should be noted that in addition to CYP enzymes, several other proteins may impact systemic drug exposure. For example, p-glycoprotein (P-gp) regulates the transport of molecules across intracellular and extracellular membranes throughout the body and acts as an efflux pump for many molecules, preventing access to the central nervous system at the blood–brain barrier junction, and restricting uptake of some drugs from the gastrointestinal tract [18–20]. Where two or more drugs are prescribed to an individual patient, there is a potential for unwanted DDIs. Enzyme inducers or inhibitors of metabolic enzymes may change the rate at which other substrate drugs are metabolized, thereby altering systemic exposure. When drugs with a narrow window of safety or efficacy are administered along with another substrate that is an inhibitor or inducer of the proteins that determine exposure, systemic concentrations may fall below or exceed doses that are efficacious and tolerable, leading to inadvertent under- or over-dosing and their inherent dangers. The present study combined the results of a literature review and an analysis of prescription data for patients with GD1 receiving ERT, representing the majority of GD1 patients, to identify comorbidities and pharmacotherapies associated with patients with GD1, and to assess the potential for DDIs in this patient population. It was anticipated that the present study will help physicians to understand the real-world risk of DDIs and to facilitate clinical decision-making when treating patients with GD1. 2. Materials and methods 2.1. Literature review strategy and data collection A PubMed literature search was conducted to identify reported symptoms, comorbid conditions and pharmacotherapies associated with GD1. The search was limited to articles in the English language published over the 10-year period between November 2003 and November 2013. “Gaucher disease type 1 OR Gaucher's disease type 1” was used as the search term with no further limitations to avoid the exclusion of potentially relevant articles. 1101 articles were initially retrieved and subsequently screened for relevance by title and abstract

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content, excluding articles that did not report GD1 comorbidities. The remaining 285 articles were analyzed for details of comorbid conditions and reported treatment interventions. 2.2. Patient prescription database analyses Two anonymized patient databases obtained from IMS Health were analyzed. The first comprised a list of co-prescribed substances received by 87 German patients who were treated with ERT (imiglucerase) from July 2012 to June 2013. The second comprised a list of co-prescribed substances received by 374 patients in the US who were treated with ERT (imiglucerase or velaglucerase alfa) from January 2012 to December 2013. All reports that did not relate to prescribed agents with systemic exposure, and reports of vitamins, water for injection and vaccines were omitted from the analysis. This included all non-drug prescriptions (e.g., needles) and locally applied drugs that were not expected to have significant systemic exposure. Records of the same active ingredient under different names were combined, combination prescriptions were separated into respective active drug agents, and therapies were categorized by drug class and summarized descriptively. Medications prescribed to patients with GD1 were then assessed to determine if they were a substrate of CYP isoenzymes CYP1A2, CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Prescribing information, product information and summary of product characteristics were consulted for each drug to determine CYP metabolism. In the absence of information within these documents, a PubMed literature search was performed, followed by a Google search if necessary. For the US dataset, only drugs prescribed to ≥5 patients were included in the final analysis. The US Food and Drug Administration guideline regarding DDIs was consulted to determine if a drug was an inhibitor or inducer of a CYP isoenzyme [21]. For this, all drugs were screened, i.e., there was no patient number limit. However, weak inhibitors/inducers were not included as the risk of these drugs causing clinically relevant DDIs secondary to a CYP drug metabolism process was deemed to be low. 3. Results 3.1. Literature review The literature review reported GD1 symptomatology as characterized by visceral disorders (hepatomegaly and splenomegaly), hematological disorders (pancytopenia, neutropenia, leukopenia, thrombocytopenia, anemia, and blood clotting disorders), skeletal

Table 1 GD1 comorbidities reported in the literature. Physiological system

Presentation/symptom

References

Malignancies/cancer

Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, myeloma, solid tumors (e.g., kidney, liver) Parkinson's disease, atypical Parkinson's/Parkinson's-like disorders, Lewy body disease, epilepsy, cognitive impairment, neuropathy, depression Hypermetabolism, insulin resistance, type I and type II diabetes Hypertension, heart failure, valvular heart disease, cardiomegaly Acute rheumatic fever, repeat infections, anaphylaxis/allergic responses Atrophic gastritis, Ménétrier's disease

[23,38]

Neuropsychiatric disorders

Metabolic disorders Cardiovascular disorders Immunological disorders Gastrointestinal disorders Clinical procedures involved with treatment

[39,40]

[41,42] [43–45] [46,47] [48,49]

[50–52] Surgical anesthesia, allogeneic bone marrow transplant, hematopoietic stem cell transplant

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disorders (bone/joint pain, skeletal malformations, osteopenia, and osteoporosis) and pulmonary disorders. The literature search also uncovered a variety of comorbidities reported in patients with GD1, which are summarized in Table 1. These included neurological disorders such as Parkinson's disease and epilepsy, immunological disorders, such as acute rheumatic fever, and anaphylaxis, and metabolic disorders such as type I and type II diabetes. Malignancies were also reported, particularly hematological cancers (Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, myeloma), as well as solid tumors of the kidney and liver. Cardiovascular disorders such as hypertension, valvular heart disease, cardiomegaly, and heart failure were also noted. Of the articles examined, a total of 35 reported the medications prescribed to patients with GD1 to treat their comorbidities, representing a wide range of pharmacotherapies used to treat comorbidities in patients with GD1. These included a large number of therapies for cancer, Parkinson disease, and cardiovascular diseases. These are outlined fully in Table S1. 3.2. Patient prescription database analyses Two national patient prescription databases were analyzed. The German database contained records for 87 patients, and the US database contained records for 374 patients. 3.3. Analysis of co-prescribed medications In Germany, 86 drugs were co-prescribed alongside ERT to patients with GD1; in the US, 329 drugs were co-prescribed, with 129 of these being prescribed to more than 5 patients. The average number of comedications prescribed to patients was lower for Germany (3.2 drugs per patient) compared to the US (7.0 drugs per patient). In both the German and US databases, analgesics, antibiotics and hypertension/cardiovascular drugs were amongst the most frequently prescribed medications (Fig. 1). Amongst the top 10 medications prescribed in Germany [including number of prescriptions reported] were 2 medications in the hypertension and cardiovascular drug category (ramipril, 8; simvastatin, 7), 2 analgesics (ibuprofen, 21; metamizole, 7), 2 antibiotics (cefuroxime axetil, 10; amoxicillin, 9), 2 gastrointestinal drugs (pantoprazole, 13; omeprazole, 7), and one each from the endocrinological therapy category

(levothyroxine, 9) and glucocorticoids (prednisolone, 8). A full list of drugs prescribed in Germany is detailed in Table S2. In the US the top 10 prescribed drugs [including number of prescriptions reported] comprised 3 analgesics (acetaminophen, 135; oxycodone, 60; hydrocodone, 89), 4 antibiotics (azithromycin, 88; ciprofloxacin, 47; clavulanate, 38; amoxicillin, 71), the oral contraceptive ethinyl estradiol, 59, the corticosteroid prednisone, 39 and the bronchodilator fluticasone, 42. A full list of drugs prescribed in the US is detailed in Table S3. In Germany, a greater proportion of hypertension/cardiovascular (Germany, 20.8% vs. US, 8.2%), anticoagulants (Germany, 4.3% vs. US, 0.7%), and gastrointestinal medications (Germany, 11.5% vs. US, 2.3%) were co-prescribed compared with the US (Fig. 1). In contrast, analgesics (Germany, 19.4% vs. US, 25.0%), glucocorticoids (Germany, 3.9% vs. US, 8.0%), and antibiotics (Germany, 17.6% vs. US, 24.0%) represented a lower proportion of the medications co-prescribed in Germany, as compared with those prescribed in the US (Fig. 1). The increased coprescription of medications in the miscellaneous category in the US (6.8% in Germany vs. 14.0% in the US) was, in part, due to the coprescription of oral contraceptives (23.2% of miscellaneous coprescribed medications or 4.3% of total co-prescribed medications in the US). A large number of the co-prescribed medications reported in Germany and the US were substrates of the assessed CYP isoenzymes (Fig. 2). In both Germany and the US, a greater proportion of coprescribed medications were found to be substrates of CYP3A4 than of any other isoenzyme included in the study analysis (Fig. 2). 3.4. Analysis of patients receiving co-prescribed medications In Germany, 17 (20%) patients were co-prescribed a moderate/ strong inhibitor of any of the investigated CYP isoenzymes, compared with 215 (57%) patients in the US. The moderate/strong inhibitors (and the CYP isoform affected) received by German patients were ciprofloxacin (CYP1A2 and CYP3A4, [n = 6]), omeprazole, and esomeprazole (CYP2C19, [n = 7 and n = 2, respectively]), duloxetine (CYP2D6, [n = 1]), and clarithromycin (CYP3A4, [n = 1]). The moderate/ strong inhibitors prescribed to US patients were ciprofloxacin (CYP1A2 and CYP3A4, [n = 47]), oral contraceptives (CYP1A2, [n = 59]), gemfibrozil (CYP2C8, [n = 1]), fluconazole (CYP2C9, [n = 22]), fluoxetine, omeprazole, and esomeprazole (CYP2C19, [n = 11, n = 16, and n = 7, respectively]), bupropion, duloxetine,

Fig. 1. Proportion of total prescriptions by drug class given to German and US patients with GD1.


Fig. 2. Percentage of co-prescribed drugs that are substrates of CYP isoenzymes by country.

fluoxetine, paroxetine and terbinafine (CYP2D6, [n = 13, n = 7, n = 11, n = 8, and n = 4, respectively]), and aprepitant, ciprofloxacin, diltiazem, clarithromycin, erythromycin, fluconazole, ketoconazole and verapamil (CYP3A4, [n = 3, n = 47, n = 5, n = 3, n = 7, n = 22, n = 1, and n = 2, respectively) (Fig. 3). Patients were rarely prescribed inducers for CYP3A4 and CYP2C9 (data not shown). Carbamazepine was the only inducer (CYP3A4), prescribed to 1 patient (1.1%) in Germany and to 3 patients (0.8%) in the US. 4. Discussion The present study combines the results of a literature review and patient prescription database analyses to highlight the large variety of comorbid conditions experienced by patients with GD1, and the diverse range of the pharmacotherapies prescribed for these conditions, in the context of potential DDIs. 4.1. Symptomology and comorbid conditions in GD1 The comorbidities reported in patients with GD1 by the literature search can be grouped into the following: coincidental comorbidities, comorbidities with a higher incidence in GD1, and those related to the core features of GD1. For example, cardiovascular diseases, heart failure and gastrointestinal diseases usually have no known etiological link to GD1 and most likely occur coincidentally with GD1. Certain neurological disorders have a proven genetic link with GD1, with some specific mutations in GBA associated with an increased risk of developing Parkinson disease [22]. Whilst GD1 pathophysiology may not directly cause

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certain comorbidities, it may manifest secondarily to GD1. For example, bone marrow dysfunction may indirectly contribute to the higher incidence of hematological cancers observed in patients with GD1 [23]. Metabolic disorders, such as insulin resistance and diabetes, may also arise more frequently in patients with GD1 due to defects in sphingolipid metabolism [24]. GD1 symptomology reported in the literature review is supported by data from the International Collaborative Gaucher Group Gaucher Disease Registry, which reports the incidence of each symptom as follows: splenomegaly, 85%; hepatomegaly, 63%; anemia, 34%; thrombocytopenia, 68%; osteopenia, 55%; fractures, 7%; bone crises, 7%; bone pain, 33%; growth retardation, 36% [2]. The comorbid conditions of patients receiving SRT as reported as part of the post-authorization safety surveillance program for miglustat were also in agreement with the output of the literature search [25,26]. Reported conditions included: bone disease, 55.6% (including osteopenia, 44.6%; bone pain, 27.4%; avascular necrosis, 17.1%; bone crisis, 6.9%; osteolysis, 16.9%; recent pathological fractures, 3.9%); neurological manifestations, 28.6% (including Parkinson disease/Parkinsonism, 4.5%; epilepsy, 1.8%); malignancy, 6.4%; monoclonal gammopathy, 5.6%; and diabetes, 6.4% [25,26]. 4.2. Pharmacotherapies There were some notable similarities in the range of pharmacotherapies reported by each data resource evaluated in this study, for example, drugs used to treat cardiovascular diseases such as hypertension. Antibiotics were commonly reported in both the literature review and co-prescription analysis. Cancer and Parkinson disease therapies were reported in the literature review but were not reported in the coprescription analysis, whereas antidepressants and analgesics were reported in the co-prescription analysis but not the literature review. The discrepancies between reported pharmacotherapies can be explained by the differing focuses of the two sources. The literature more commonly reports cases of novel and noteworthy comorbidities (commonly reporting the co-incidence of cancer and neurological symptoms) and their associated pharmacotherapies. When drugs commonly prescribed for the general population are reported in the literature, they are often grouped together (e.g., ‘broad-spectrum antibiotics’). By contrast, the patient prescription database records all of the individual therapies prescribed to patients, including the more commonly used therapies such as analgesics and antibiotics. Interestingly, the average number of co-medications prescribed to individual patients throughout the duration of the study was lower in Germany (3.2 drugs per patient) than in the US (7.0 drugs per patient). The relatively large average number of drugs received by patients with GD1 reinforces the requirement for careful consideration of medications to reduce the risk of DDI occurrence. 4.3. Hepatic metabolism of drugs co-prescribed to GD1 patients who receive ERT

Fig. 3. Percentage of patients who were prescribed a moderate or strong inducer of CYP isoenzymes by country (patients can be prescribed inhibitors or inducers of more than one CYP isoenzyme).

In patients with GD1, the percentage of drugs metabolized by the investigated CYP isoenzymes reflected that which is seen in the general population. It should be noted that a higher proportion of German patients were prescribed drugs metabolized by CYP2C19, compared with patients in the US (11.6% vs. 5.4%, respectively). There were no further notable differences between Germany and the US. A high proportion of patients with GD1 in both countries received moderate or strong inhibitors of one of the assessed CYP450 isoenzymes, increasing the risk of DDIs. This could result in increased systemic exposure of other substrates of the affected CYP450 isoenzymes, potentially leading to an increase in the frequency or intensity of associated adverse events. For each of the CYP isoenzymes assessed in the present study, the proportion of patients who received medications classed as inhibitors was lower in Germany than in the US (Fig. 3).

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The largest disparity between countries was seen for the proportion of patients who received medications that were CYP1A2 inhibitors (Germany, 6.9%; US, 28.1%). This is due to the prescription of oral contraceptives which were captured in the US but not the German prescription database. CYP isoenzyme inhibitors reported in the co-prescription analysis (Table S4) included drugs used to treat cardiovascular and gastrointestinal diseases; antibiotic, antifungal and antidepressant drugs were particularly well represented. Anti-depressive medication therapies for patients with GD1 may have clinical importance as co-therapies that deserve further study, as it has been noted that depression commonly occurs in patients with GD1 in clinical practice [27]. However, it should be noted that the present study did not allow for the analysis of the clinical relevance of these co-prescribed medications. As few inducers of the assessed CYP isoforms were prescribed, the risk of inadvertently increasing the rate of drug metabolism leading to lower systemic exposures and lack of efficacy is relatively low. 4.4. Cytochrome P450 polymorphisms The systemic exposure of a drug, and the subsequent potential for DDIs to occur, may also be influenced by the alleles of certain CYP450 isoenzymes. In particular, genetic polymorphisms in the isoenzymes CYP2D6 and CYP2C19 have been associated with efficacy outcomes and/or adverse effects of many medications, including medications used to treat cancer, psychiatric disorders and cardiovascular diseases [14]. For example, genetic polymorphisms in the CYP2C9 isoenzyme have been associated with increased sensitivity to the anti-thrombotic agent warfarin (prescribed to 8 patients in the US dataset) [28]. Furthermore, the CYP1A2 polymorphism 1545C NT (rs2470890) is associated with a significantly greater occurrence of more severe adverse events following administration of clozapine, an antipsychotic medication [29]. Additionally, CYP2C8 is estimated to metabolize around 5% of therapeutically prescribed drugs, and is the main CYP isoenzyme responsible for the metabolism of paclitaxel, a frequently used chemotherapy drug [30]. The CYP2C8*3 polymorphism has also been reportedly associated with reduced metabolism of paclitaxel [15]. The aforementioned influence of certain CYP polymorphisms on the extent of systemic drug exposure may require close monitoring of CYP substrate drugs in patients who harbor a known CYP polymorphism. Additionally, prior to initiation of therapy with a known CYP isoenzyme substrate, there may be occasions when genotyping of the patient is required, to allow prediction of correct dosing. In most circumstances this will lead to additional costs associated with genetic testing and may lead to delays in therapy initiation. 4.5. Factors affecting choice of GD1 therapy ERT is considered the standard of care for treatment of GD1. ERT is given by slow intravenous infusion once every two weeks. This particular route and method of administration can have a significant impact on patient quality of life due to disruption to everyday activities. SRT is administered orally and therefore offers a convenient alternative for patients who have difficulties finding time for ERT infusions, or patients who may have a history of difficulties tolerating infusions (e.g., history of infusion reactions). SRT may not be suitable for those patients who do not want the added burden of multiple daily doses. When considering the optimal therapeutic regimen for any patient, the potential for DDIs should be considered when polypharmacy is required. Currently, the majority of patients receiving therapy for GD1 receive ERT. To date, there are no known drug interactions with the available ERTs, and ERTs do not interact with CYP450 isoenzymes. Thus the risk of drug interactions between ERT and other medications is considered to be very low to negligible. A more prominent concern with ERT therapies is the development of immunological responses and hypersensitivity reactions [31].

Along with miglustat, the emergence of eliglustat is likely to increase the profile and general awareness of oral SRT therapies, potentially increasing SRT use amongst patients, particularly those who are dissatisfied with their current ERT. The impact of SRTs on concomitant therapies should be assessed prior to initiation of therapy. Miglustat has been shown to be excreted largely unchanged in the urine and is not known to interact with any CYP isoenzymes. It is therefore not thought likely to cause DDIs [32]. Miglustat inhibits disaccharidase activity in the gastrointestinal tract. As a result, patients taking miglustat are advised to eat a diet relatively low in carbohydrates [33]. Eliglustat does, however, have known DDIs. The metabolism of eliglustat is mediated by both CYP2D6 and to a lesser extent CYP3A4 [34], with no known involvement of other CYP isoenzymes. This is reflected in eliglustat's label, which requires genetic phenotyping of CYP2D6 prior to initiation of therapy, setting out separate dosing regimens depending on the anticipated metabolic rate. Polypharmacy with CYP2D6 and CYP3A4 substrates is also addressed, and is contraindicated for certain combinations of genetic polymorphisms with a moderate or strong CYP3A4 inhibitor [11]. Grapefruit and grapefruit juice should be avoided with eliglustat, which inhibits CYP3A4 in the gastrointestinal tract and may increase systemic exposure to eliglustat [11,34, 35]. 4.6. Other considerations Transporter proteins, such as P-gp, play an important role in regulating access of small molecule drugs to certain physiological compartments and pumping small molecule substrates out of cells [19]. Neither ERT therapies nor miglustat interact with P-gp; however, eliglustat is a known inhibitor [11]. Co-administration of eliglustat with a P-gp substrate, particularly those with a narrow therapeutic window (e.g., digoxin, used by 3 US patients in the present study) [36], may necessitate more frequent monitoring and could increase the risk of associated adverse events. Drug–disease interactions should also be taken into consideration when evaluating concomitant medications. Common comorbidities of GD1 include hematological complications, osteopenia, and osteoporosis [2]. Some patients with GD1 are also at increased risk for avascular necrosis of the bone/osteonecrosis [7]. Corticosteroids may increase the risk of osteopenia, osteoporosis [37], and osteonecrosis. Bisphosphonates are sometimes prescribed to increase bone mass in patients with GD1, but may also increase the risk of osteonecrosis [7]. The literature review included an initial screening of all articles on GD1 published between November 2003 and November 2013 (n = 1101). Many of these articles were case studies and provided highly detailed reports of the precise comorbidities and medications that patients were prescribed. These cases were often reported due to their unusual/noteworthy aspects; this may lead to an overrepresentation of rare, or an under-representation of common, comorbid conditions and complications. For example, psychiatric disorders, such as depression and anxiety, have been observed in patients with GD1 in clinical practice [27], but were not reported by the present literature search. The principal strength of the patient prescription database analyses is that it reports real-world prescription data, giving an accurate representation of the actual medications prescribed to the majority of patients with GD1. Limitations of the database analysis include a lack of information on dose scheduling and treatment duration of medications. Additionally, the patient prescription database analyses did not consider polypharmacy; many patients who were prescribed N1 pharmacotherapy were entered as single entities. The patient prescription database does not account for any over-the-counter/non-prescription drugs taken by these patients. In conclusion, this study highlights the diverse range of symptoms and comorbidities experienced by patients with GD1, and the wide variety of therapeutic agents used to treat the various conditions. The


potential impact of concomitant medications on hepatic drug metabolism pathways may complicate clinical decision-making; GD1 therapy should be optimized for each patient based on their individual circumstances. Concomitant medications and routine monitoring of DDIs and adverse effects associated with polypharmacy should be considered on an ongoing basis. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ymgme.2015.12.001. Conflicts of interests SA Kolb is an employee of Actelion Pharmaceuticals Ltd. PLM van Giersbergen is a paid consultant for Actelion Pharmaceuticals Ltd. J Utz is the Specialty Therapy Management Provider at the University of Minnesota, Fairview, the Director of a Pharmacotherapy of Inherited Metabolic Disorders (PIMD) 2-year PharmD Post-Doctoral training program (funded by Genzyme), and a participant on Speakers Bureau for Actelion, Pfizer, Genzyme. CB Whitley has nothing to disclose. Acknowledgments Writing and editorial assistance in the preparation of this manuscript were provided by Katie Bickford and Andrew Smith PhD of Fishawack Communications GmbH, Basel, Switzerland. This support was funded by Actelion Pharmaceuticals Ltd. Prescription data were obtained from IMS Health and paid for by Actelion Pharmaceuticals Ltd. References [1] E. Beutler, Enzyme replacement in Gaucher disease, PLoS Med. 1 (2) (2004), e21. [2] B.E. Rosenbloom, N.J. Weinreb, Gaucher disease: a comprehensive review, Crit. Rev. Oncog. 18 (3) (2013) 163–175. [3] A. Nagral, Gaucher disease, J. Clin. Exp. Hepatol. 4 (1) (2014) 37–50. [4] A. Halperin, D. Elstein, A. Zimran, Are symptoms of peripheral neuropathy more prevalent in patients with Gaucher disease? Acta Neurol. Scand. 115 (4) (2007) 275–278. [5] T.M. Cox, B.E. Rosenbloom, R.A. Barker, Gaucher disease and comorbidities: B-cell malignancy and parkinsonism, Am. J. Hematol. 90 (Suppl. 1) (2015) S25–S28. [6] M. Biegstraaten, E. Mengel, L. Marodi, M. Petakov, C. Niederau, P. Giraldo, et al., Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study, Brain 133 (10) (2010) 2909–2919. [7] G. Giuffrida, M.R. Cingari, N. Parrinello, A. Romano, A. Triolo, M. Franceschino, et al., Bone turnover markers in patients with type 1 Gaucher disease, Hematology Reports 4 (4) (2012), e21. [8] B.E. Rosenbloom, N.J. Weinreb, A. Zimran, K.A. Kacena, J. Charrow, E. Ward, Gaucher disease and cancer incidence: a study from the Gaucher Registry, Blood 105 (12) (2005) 4569–4572. [9] J.L. Capablo, A. Saenz de Cabezon, J. Fraile, P. Alfonso, M. Pocovi, P. Giraldo, Neurological evaluation of patients with Gaucher disease diagnosed as type 1, J. Neurol. Neurosurg. Psychiatry 79 (2) (2008) 219–222. [10] O. Goker-Alpan, R. Schiffmann, M.E. LaMarca, R.L. Nussbaum, A. McInerney-Leo, E. Sidransky, Parkinsonism among Gaucher disease carriers, J. Med. Genet. 41 (12) (2004) 937–940. [11] FDA, CERDELGA™ (Eliglustat) Capsules: Full Prescribing Information, August 2014. [12] D. Hughes, M.D. Cappellini, M. Berger, J. Van Droogenbroeck, M. de Fost, D. Janic, et al., Recommendations for the management of the haematological and oncohaematological aspects of Gaucher disease, Br. J. Haematol. 138 (6) (2007) 676–686. [13] G.M. Pastores, D.A. Hughes, Gaucher disease, in: R.A. Pagon, M.P. Adam, H.H. Ardinger, S.E. Wallace, A. Amemiya, L.J.H. Bean, et al., (Eds.), GeneReviews®, 1993 Seattle (WA). [14] X. Yang, B. Zhang, C. Molony, E. Chudin, K. Hao, J. Zhu, et al., Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver, Genome Res. 20 (8) (2010) 1020–1036. [15] Y. Mukai, A. Senda, T. Toda, T. Hayakawa, E. Eliasson, A. Rane, et al., Drug–drug interaction between Losartan and Paclitaxel in human liver microsomes with different CYP2C8 genotypes, Basic Clin. Pharmacol. Toxicol. 116 (6) (2015) 493–498. [16] S. Bernard, K.A. Neville, A.T. Nguyen, D.A. Flockhart, Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications, Oncologist 11 (2) (2006) 126–135. [17] C.F. Samer, K.I. Lorenzini, V. Rollason, Y. Daali, J.A. Desmeules, Applications of CYP450 testing in the clinical setting, Molecular Diagnosis & Therapy 17 (3) (2013) 165–184.

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