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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 79-84

Assessment of drug–drug interactions between chemotherapeutic and chronically used medications at Khartoum Oncology Hospital


1 Department of Clinical Pharmacy, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
2 Department of Clinical Pharmacy, Khartoum Oncology Hospital, Khartoum, Sudan
3 Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan

Date of Submission21-May-2020
Date of Decision03-Jun-2020
Date of Acceptance09-Jun-2020
Date of Web Publication14-Jul-2020

Correspondence Address:
Dr. Bashir Alsiddig Yousef
Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Al-Qasr Ave., Khartoum 11111
Sudan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MTSM.MTSM_17_20

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  Abstract 


Background: Drug–drug interactions (DDIs) in oncology are significantly crucial because chemotherapeutic drugs usually have a narrow therapeutic index. Many DDIs are expected to be present between chemotherapeutic agents and chronically used medications as the number of DDIs increases in parallel with the number of drugs taken. Because of the limited literature about this area in Sudan. Thus, this study was conducted to assess the DDIs between chemotherapeutic and chronically used medications in Sudanese patients.Methods: This study was carried out in Khartoum Oncology Hospital from March to May 2019. The data were collected using data collection sheets that were filled from patient records and direct interviews with the patients. The presence of DDIs was detected by Lexicomp® drug interaction software. Results: A total of 117 patients have been involved in this study. The main DDIs between chemotherapeutic and chronically used medications were identified in 20.5% of patients, which represented 8% of the total DDIs between all drugs. Of these, 76% of the DDIs were pharmacodynamic (PD), 20% were pharmacokinetic (PK), and 4% were both PD and PK. The majority (92%) of these DDIs have been moderate in severity and had the risk rate of C (84%). 12.5% of these patients experienced clinical consequences for which they were admitted to the emergency department. DDIs between antihypertensive medications and paclitaxel were the most common (68%). There was a significant association between the age and the presence of DDIs (P = 0.017). Conclusion: DDIs between chemotherapeutic and chronically used medications represented 8% of the total identified DDIs in the study patients.

Keywords: Adverse drug reaction, chemotherapy, drug–drug interactions, Khartoum Oncology Hospital


How to cite this article:
Osman MA, Abdalla MA, Mohamed AA, Yousef BA. Assessment of drug–drug interactions between chemotherapeutic and chronically used medications at Khartoum Oncology Hospital. Matrix Sci Med 2020;4:79-84

How to cite this URL:
Osman MA, Abdalla MA, Mohamed AA, Yousef BA. Assessment of drug–drug interactions between chemotherapeutic and chronically used medications at Khartoum Oncology Hospital. Matrix Sci Med [serial online] 2020 [cited 2020 Oct 24];4:79-84. Available from: https://www.matrixscimed.org/text.asp?2020/4/3/79/289735




  Introduction Top


Cancer is a main disease problem facing the world. Globally, cancer problem has increased to 18.1 million new cases and 9.6 million deaths in 2018, according to GLOBOCAN 2018 estimates of cancer.[1] Approximately, one in 5 men and one in 6 women worldwide have cancer during their lifetime, and one in 8 men and one in 11 women die from the disease.[1],[2] In Sudan, 25,746 new cases and 17,160 deaths happened in 2018.[3] Cancer can be managed through one or more approaches including surgery, radiation therapy, chemotherapy, hormone therapy, stem cell transplant, immunotherapy, targeted therapy, and personalized medicine.[4],[5],[6],[7] Among them, chemotherapy is commonly used as it can completely cure some types of cancer, decrease the tumor size, and increase the life expectancy of other types of cancer.[4] Chemotherapy can be categorized into four types according to the goal that will be achieved, which are curative chemotherapy, adjuvant chemotherapy, neoadjuvant chemotherapy, and palliative chemotherapy.[8]

Drug–drug interactions (DDIs) contribute to the majority of adverse drug reactions, and about 70% of interactions are clinically relevant. The main three types of DDIs are pharmaceutical, pharmacodynamic (PD), and pharmacokinetic (PK) DDIs. Furthermore, DDIs are also classified according to the severity and the risk rate of the interaction.[9],[10],[11] DDIs in oncology are significantly important because the existence of DDIs in oncology is conceived to be more than in most other conditions, but the exact data are not available, and because chemotherapeutic drugs usually have a narrow therapeutic index, making any DDI extremely important.[9],[12],[13],[14] Moreover, DDIs can lead to death, as according to a study by Buajordet et al., about four cases of cancer-associated deaths were because of drug interactions unrelatedly of cancer-specific therapy.[15],[16]

Therefore, the importance of drug interactions in oncology should be stressed more. Comprehensive knowledge of possible interactions and drug monitoring can significantly help in reducing the occurrence of adverse effects, increasing the efficacy of the regimen, and minimizing treatment costs.[15] Many DDIs are expected to be present between chemotherapeutic agents and chronically used medications as the number of DDIs increases in parallel with the number of drugs taken.[15] As there is limited documented information about DDIs with chemotherapeutic agents in Sudan. Thus, conducting such a study at Khartoum Oncology Hospital to assess the DDIs between chemotherapeutic and chronically used medications will help a lot in reducing the adverse effects, and clinical consequences form these DDIs.


  Methods Top


Study design and settings

This is a descriptive cross-sectional hospital-based study through direct interviews with patients and secondary use of data from patients' records. The study was conducted at the daycare unit, Khartoum Oncology Hospital, during the period of March to May 2019.

Patient selection

A total coverage sampling technique was used in this study. All cancer patients who received chemotherapy and came to the daycare unit at Khartoum Oncology Hospital during the study period were recruited in this study. In addition, patients with age of 18 years or above were included in the study, whereas patients who could not account for their chronically used medications were excluded from this study. The total number of recruited included patients was 117 patients. All their medical records were also reviewed.

Data collection methods

The data were collected using data collection sheets that were verified using a pilot study consisting of 10 initial data collection sheets. The data collection sheets were filled from patient records and direct interviews with the patient. The presence of DDI was detected by Lexicomp® drug interaction software (version 1.9.1; Lexi-Comp Inc., Hudson, OH, USA).[17]

Classification of drug–drug interactions

DDIs were classified according to the type into PD or PK. They were classified as PK interactions when one medication changes the absorption, distribution, metabolism, or excretion of another and PD when one drug has an antagonistic, additive, or synergistic effect on another drug.[9],[10],[11] DDIs were also classified according to the severity into major, moderate, or minor. The severity of a DDI is considered a major if the effects are potentially life-threatening or capable of causing permanent damage; moderate, when the effects may cause a decline in a patient's clinical status or if additional treatment, hospitalization, or an extended hospital stay may be required; or minor, if the effects are usually mild and should not significantly affect the therapeutic outcome.[18] DDIs also were classified according to the risk rate. Risk rating is a rapid indicator about how to respond to the interaction data. Each interact monograph in Lexicomp is given a risk rating of A, B, C, D, or X. The progression from A to X is accompanied by increased urgency for responding to the data. A means that there is no interaction, B means that there is interaction, but no action is needed, C means that therapy must be monitored, D means that the regimen must be modified, whereas X means that the combination must be avoided.[17]

Statistical analysis

The data were analyzed using descriptive statistics by the Statistical Package for the Social Sciences (SPSS v. 23) Version 23.0 software; Armonk, NY: IBM Corp). Chi-square test was performed to identify whether there is a significant association between DDIs and demographic characteristics. P < 0.05 was considered statistically significant.

Ethical considerations

An ethical clearance (FPEC-02-2019) to carry out the research was obtained from the Ethical Committee of the Faculty of Pharmacy, University of Khartoum. Additional approval for checking the medical records was obtained from Khartoum Oncology Hospital. Informed written consent of the interviewed individuals was obtained after a clear explanation of the study purposes.


  Results Top


A total of 117 patients have met the inclusion criteria and involved in the study. [Table 1] shows the gender, age, and other clinical data of the patients. The majority of the study patients were females (79.5%), and more than half of the study patients (59.8%) were of the age group of 50–70 years. Breast cancer was the most common cancer type (41%), followed by gynecological cancer (28.20%) and gastrointestinal tract cancer (9.40%) [Table 1].
Table 1: Demographic and clinical characteristics of patients (n=117)

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Regarding the used chemotherapeutic medications, more than half of the patients (59.8%) were using chemotherapeutic regimens composed of two medications. AAmong these regimens, paclitaxel plus carboplatin was used in 23.9% of the study patients. Moreover, only 27 patients were used a one-medication chemotherapeutic regimen. Among these regimens, gemcitabine was the most common as it was used by 7.70% of the study patients [Table 2]. We found that gemcitabine was the most common as it was used by 7.70% of the study patients [Table 2]. Furthermore, 18 patients were using a chemotherapeutic regimen composed of three medications. Among these regimens, epirubicin plus cyclophosphamide plus 5-fluorouracil was the most common used by 5.10% of the study patients [Table 2], whereas only two patients were found to use four medications' chemotherapeutic regimen (vinblastine, doxorubicin, bleomycin, and dacarbazine) [Table 2].
Table 2: Patients' distribution according to used chemotherapeutic medications

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On the other hand, we found more than half of the study patients used two types of supportive care medications (59%). Only one patient used one supportive care medication (0.9%) [Table 3]. Moreover, as shown in [Table 3], dexamethasone plus ondansetron was included in the supportive care regimen of 99.9% of the study patients. Dexamethasone plus ondansetron only was used by 59% of the study patients.
Table 3: Patients' distribution according to used supportive medications

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Regarding the comorbidities, 78.6% of the patients had one comorbidity, whereas the remaining have more than one chronic disease [Table 4]. Hypertension was the most common comorbidity in the study patients (56.40%), followed by diabetes mellitus (45.30%). Thus, antihypertensive drugs most commonly used medications by the patients (38.9%), followed by antidiabetic drugs (35.10%) [Table 4].
Table 4: Distribution of patients with accompanying chronic diseases and medications used to treat these comorbidities

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After analysis of DDIs using Lexicomp® software, 110 patients (94%) had DDIs, whereas 7 patients (6%) had no DDI. The number of patients who had main DDIs between chemotherapeutic and chronically used medications was 24 patients (20.5%), the number of those who had other DDIs was 109 patients (93.2%), whereas the number of those who had both types of DDIs was 23 patients (19.7%) [Table 5]. Furthermore, DDIs between chemotherapeutic and chronically used medications represented 8% of the total DDIs of the study patients. DDIs between supportive care and chronically used medications were the most common DDIs in the study patients as they represented 38.9% of the total DDIs [Table 5].
Table 5: Patients' distribution according to the drug-drug interactions

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According to different categorizations, 70.4% of the DDIs had the risk rate C, and 66.6% of the DDIs were PD, and 62.1% were moderate in severity. DDIs included either antihypertensives (76%), methotrexate (12%), or warfarin (12%) [Table 6]. 76% of these DDIs were PD, 20% were PKs, and 4% were of both PD and PK types. 84% had the risk rate C, and the rest (16%) had the risk rate D. 92% were moderate in severity, and 8% were major [Table 6]. Among these patients, three (12.5%) had experienced clinical consequences for which they were admitted to the emergency department. Hypotension and fatigability were experienced by a patient (4.2%) who was taking amlodipine and paclitaxel, febrile neutropenia was experienced by a patient (4.2%) who was taking methotrexate and furosemide, and rectal bleeding was experienced by a patient (4.2%) who was taking warfarin and fluorouracil.
Table 6: Medications that involved in the drug-drug interactions between chemotherapeutic and chronically used medications (25 drug-drug interactions, 24 patients)

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Regarding other DDIs, ondansetron and cyclophosphamide interaction was the most common DDI (30:62) between chemotherapeutic and supportive care medications, whereas carboplatin and taxane interaction was showed the highest frequency (27:68) among DDI between chemotherapeutic medications. On the other hand, dexamethasone and antidiabetic interaction was the most common interaction (54:122) between chronically used and supportive care medications.

Chi-square test showed that there was a significant association between the age and the main DDIs between chemotherapeutic and chronically used medications (P = 0.017). There was no significant association between gender and these DDIs. Concerning other DDIs, there was no significant association neither with age nor with gender.


  Discussion Top


DDI is one of the most common problems facing the treatment of cancer patients by anticancer drugs because these drugs have a narrow therapeutic index.[19] The risk of DDIs in cancer patients increases in the elderly, mainly due to the physiological changes and the presence of comorbid conditions.[9],[20] In the current study, we assessed the DDIs between chemotherapeutic and chronically used medications and other DDIs in the daycare unit of Khartoum Oncology Hospital. The majority of the studied patients were females (79.5%), which agrees with statistics of GLOBOCAN 2018 report that an estimated 60.3% of the newly diagnosed cancer patients in Sudan were females.[3] Similarly, breast cancer was the most commonly diagnosed cancer (41%) in this study, which is also follow the GLOOBOCAN statistics.[3] Other studies also show high percentages of breast cancer among the studied patients.[15],[21],[22] Often, in cancer therapy, more than one chemotherapeutic agent is used to increase the therapeutic effect and save normal cells. In this study, about 59.8% of the patients used two types of chemotherapeutic medications. Taxane-platinum based was the most common chemotherapeutic regimen used, and this may be because this regimen is included in the therapy of many cancer types, especially breast and gynecological cancers.

Most of the DDIs occurred in the age group of 50–70 years, and this may be because most of the study patients were in this age group (59.8%) and also may be due to the fact that this age group has many comorbidities for which they are taking many medications. This, to some extent, is in accordance with other studies that also indicate the high DDIs among this age group.[21],[22] Furthermore, there is a significant association between the age and the DDIs between chemotherapeutic and chronically used medications (P = 0.017). This is because the elderly have variable physiological changes, and they are exposed to polypharmacy due to the multiple comorbidities that increase the risk of DDIs with the chemotherapy drugs.[19],[23] This, in line with a study conducted in geriatric cases, showed that patients were taking an average of 9.1 drugs per prescription with a high frequency of DDIs.[24]

The most common comorbidities were hypertension and diabetes mellitus, which represented 56.4% and 45.3% of the study patients, respectively. These percentages are much higher than other studies done in other populations.[20],[21] This may be due to the Sudanese unhealthy sedentary lifestyle. Accordingly, antihypertensive and antidiabetic medications were the most commonly prescribed drugs in this study. Moreover, almost all patients (99.1%) were used supportive care drugs such as dexamethasone and ondansetron in order to treat or limit the complications and side effects of cancer and chemotherapy.[25],[26]

In total, 314 DDIs were found in 117 patients, and the majority of these interactions have been moderate in severity (62.1%), which is in accordance with other studies.[15],[22],[27] Furthermore, the majority of the interactions in this study have been of the PD type (66.6%), which agrees with van Leeuwen et al. study in which a PD DDI was found in 86% of all cases[22] and disagrees with Ramos-Esquivel et al. report that found that 86.1% of the DDIs were of the PK type. This difference may be due to the different therapeutic regimens used in different hospitals.[21] Furthermore, more than half of the interactions in this study have involved supportive care agent; this finding substantiates the observation that anticancer chemotherapeutic agents were not the only culprit in DDIs; rather, medications received for comorbidities and supportive treatment also had a main part in the observed DDIs in their study.[9]

Major DDIs between chemotherapeutic and chronically used medications were identified in 24 patients and most commonly with antihypertensive drugs. The majority of these DDIs have been moderate in severity (92%) and had the risk rate C (84%). Clinically, three patients (2.6%) were experienced clinical consequences for which they were admitted to the emergency department. This result is in parallel with a study that retrospectively described 2.0% of the patients with cancer requiring hospital admission because of real DDIs.[28] However, no actions were taken by health-care providers to avoid the clinical consequences of DDIs, even with the risk rate D that requires therapy modification. Furthermore, in patients who actually experienced DDIs clinical consequences, no actions were taken about the DDIs. The only action that had been taken was for a patient who came with rectal bleeding as a consequence of taking warfarin and fluorouracil concomitantly. For this patient, warfarin had been stopped and replaced with heparin.

The current study has some limitations. First, the study is observational with no causality associations, and therefore, there is no certainty that these clinical consequences had occurred due to the DDIs. In addition, it only covers the consequences that had occurred for patients who admitted to the emergency ward, so late-onset consequences of DDIs were not detected. Second, the duration of data collection was short, and consequently, the sample size was limited. Despite these limitations, this study is novel, as it is the first report about DDIs of chemotherapeutic agents among Sudanese cancer patients. Thus, further comprehensive analytical studies with a larger population, and longer duration and personal follow-up, are strongly recommended.


  Conclusion Top


The study revealed that DDIs between chemotherapeutic and chronically used medications represented 8% of the total identified DDIs in the study patients. Most of these DDIs were moderate, PD, and had the risk rate C. It found that there was a significant association between the age and these DDIs, indicating that most of these DDIs occur in the age group of 50–70 years.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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