key: cord-0742386-nq5eo1u5 authors: Biswas, Mohitosh; Roy, Debendra Nath title: Potential clinically significant drug‐drug interactions of hydroxychloroquine used in the treatment of COVID‐19 date: 2021-08-16 journal: Int J Clin Pract DOI: 10.1111/ijcp.14710 sha: 83f60883c293a731cb4d27151a757e126511b7a9 doc_id: 742386 cord_uid: nq5eo1u5 AIMS: Hydroxychloroquine (HCQ) is using as a repurposed drug in considerable proportion of COVID‐19 patients. However, being a substrate of cytochrome P450 (CYP) enzymes of CYP3A4/5, CYP2C8 and CYP2D6, the safety and efficacy of this drug may be affected by the coadministration of respective CYP inhibitors, substrates or inducer drugs. It was aimed to identify potential clinically significant drug‐drug interaction (DDI) pairs of HCQ. METHODS: Inhibitors, substrates and inducer drugs lists of CYP enzymes of interest from international well‐recognised evidence‐based drug interaction resources were used to identify potential clinically significant pharmacokinetic DDI pairs of HCQ. RESULTS: Among 329 identified interacting drugs that predicted to cause clinically significant DDIs of HCQ, 45 (13.7%), 43 (13.1%) and 123 (37.4%) unique DDI pairs were identified from the FDA, Stockley's and Flockhart lists, respectively. Of interest, 55 (16.7%) DDI pairs were recognised by all three resources. At least, 29 (8.8%) severe DDI pairs were identified predicted to cause severe toxicity of HCQ in patients with COVID‐19. When comparing these interactions with Liverpool DDI lists, it was found that out of 423 total interactions, 238 (56.3%) and 94 (22.2%) unique DDI pairs were identified from all three resources and Liverpool DDI lists, respectively. Of interest, only three (0.7%) DDI pairs were recognised by both the three international resources and Liverpool DDI lists of HCQ. CONCLUSION: Using HCQ has clinical debate whether it should or should not continue in COVID‐19 patients, however, potential clinically significant DDIs identified in this study may optimise safety or efficacy of HCQ in considerable proportion of patients. trigger the higher concentration of HCQ active metabolite which may, in turn, increase the risk of HCQ-induced toxicity. This predictive DDIs is plausible for COVID-19 patients taking HCQ since many patients with COVID-19 had multiple comorbidities and are vulnerable to polypharmacy. 7, 8 Some patients responded well to the HCQ therapy and getting improved while the clinical conditions of many others were deteriorating and even many patients were died. 2, 5, 9, 10 Although many factors, for example age, sex, comorbidities, hypoxia, organ dysfunction, etc might trigger the clinical outcomes; however, one of the other predisposing factors of these may be partly because of the DDIs associated with the patients of COVID-19 taking multiple medications. It had well-evidenced in numerous studies with other classes of diseases especially in older people that polypharmacy was a known risk factor for the development of clinically significant DDIs and was provoking ADRs and drug toxicities as well. [11] [12] [13] [14] It is therefore predicted that similar effects may also exist for COVID-19 patients treated with HCQ. Being a substrate of CYP2C8, CYP3A4/5 and CYP2D6, its pharmacokinetics (PK) effects may be affected by either the inhibitor or substrate or inducer drugs of the respective CYP enzymes and are predicted to cause potential clinically significant DDIs. It is important to recognise that the Liverpool interactions group has provided prescribing resources where they categorised the interactions of experimental COVID-19 antiviral therapies as "contraindicated medications," "potential interactions requiring dose adjustment/close monitoring," "potential interactions of weak intensity" or "no clinically significant interactions." 15 However, the lists of interacting drugs provided by the Liverpool drug interaction prescribing resource may not be comprehensive since it might miss some of the important interacting drugs. For example, in the detailed recommendations for interactions with experimental COVID-19 antiviral therapies, this COVID-19 drug interaction resource enlisted ~15 contraindicated medications for HCQ but interestingly no drugs were found to interact with HCQ that were causing toxicity of HCQ. Of these 15 contraindicated medications, 08 drugs were predicted to increase their exposure by interaction with HCQ, that is increase toxicity of comedications and only seven drugs were predicted to decrease the exposure of HCQ, that is decrease efficacy/therapeutic failure of HCQ but no drugs were enlisted that can possibly increase the exposure of HCQ and toxicity as well. This may indicate that these lists of drugs may not cover all possible interacting drugs of HCQ. Amid this emergency situation, details of the treatment provided in COVID-19 patients were not available and was therefore unable to assess the potential clinically significant DDIs of the patients with COVID-19. However, the present study was aimed to predictively identify potential clinically significant DDIs pairs from the international resources so as to aware clinicians regarding the probability and severity of these interactions. This is a predictive original research aimed to identify potential clinically significant DDI pairs, this study used the US Food and Drug Administration (FDA) clinical table of CYP enzyme of interest for strong, moderate or weak inhibitors. This is because the FDA is a reputable internationally recognised body that provides clinical tables of CYPs that are evidence-based and systematically categorise the inhibitor drugs according to their strength and are updated on a regular basis. 16 The tables classify "strong," "moderate" or "weak" inhibitors which give an indication of the severity of putative interactions leading to safety or efficacy concerns greater than those present when the drugs are administered alone. For example, "strong, moderate and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively." Secondly, this study used clinical tables of Flockhart CYP DDI interactions in which inhibitors were also categorised as strong, moderate and weak as done by the FDA CYP clinical tables. 17 For this reason, the present study has predictively categorised the potential interactions of HCQ as identified from the FDA and Flockhart lists as severe, moderate or weak interactions in which HCQ was predictively paired with strong, moderate or weak inhibitor drugs, respectively. Thirdly, potential clinically significant DDI pairs were also identified from the Stockley's drug interactions since this is also an internationally well recognised evidence-based drug interactions resource. 18 Finally, the identified potential clinically significant DDIs were compared with the lists of interacting drugs of HCQ as provided by the Liverpool COVID-19 drug interaction resource. Liverpool interactions group had provided prescribing resources where they categorised the interactions of experimental COVID-19 antiviral therapies as "contraindicated medications," "potential interactions requiring dose adjustment/close monitoring," "potential interactions of weak intensity" or "no clinically significant interactions." 15 The list of interacting drugs of HCQ was extracted from this prescribing resource and compared with the lists of drugs identified from the FDA, Stockley's drug interactions and Flockhart lists. As shown in Figure Table 1 . This showed that at least 55 DDI pairs should be taken into clinical considerations to optimise safety or efficacy of HCQ since these drugs were recognised from all three internationally renowned drug interaction resources. As discussed in the "Method" section and as shown in Table 2, there were 29 (8.8% of total interactions identified) severe DDI pairs were identified from the FDA and Flockhart lists involving strong inhibitors of CYP3A4/5, CYP2C8 and CYP2D6 and were predicted to cause drug toxicity of HCQ. Patients with COVID-19 taking HCQ with any of these 29 drugs need special monitoring as these drugs may increase the blood concentrations of HCQ substantially and may therefore be vulnerable to severe drug toxicity. Since clinicians sometimes become fatigue to DDI alerts functional in some developed countries whereas in many countries computerised DDI alert systems may not exist, hence severe DDI pairs may be useful to them for taking precautions in advance regarding these severe DDIs as shown in Table 2 Since chloroquine (CQ) has comparable PK properties with HCQ and is also metabolised by CYP2C8, CYP3A4/5 and CYP2D6 enzymes, 6 therefore the potential clinically significant DDIs identified for HCQ may also generally be applicable to CQ. In summary, at least 29 DDI pairs should be taken into clinical considerations to optimise safety of HCQ since these drugs were predicted to cause clinically significant severe DDIs. As HCQ is using in many countries for combating COVID-19, it is inevitably important to aware clinicians regarding the potential ADRs [29] [30] [31] Aside from the considerations of potential DDIs, patients treated with HCQ and had liver and kidney failure should also give an important clinical consideration. Unlikely, HCQ is a very slow-acting drug and has a prolonged half-life for blood clearance. Patients with kidney failure will not able to clear the HCQ from the blood at the rate as it is desired and eventually decreased clearance rate may increase the bioavailability of this drug and may cause drug toxicity. 6 As known, ~40 of HCQ is metabolised in the liver and subsequently excreted from the body. 6 The clinician should consideration all resources for checking DDIs of HCQ since there was disagreement for enlisting interacting drugs. The lead author is greatly acknowledging the professional support from Dr Mamunur Rashid, Professor, Department of Pharmacy, University of Rajshahi, Bangladesh. No conflict of interest to declare. The lead author contributed 90% of this manuscript while the second author contributed 10%. 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