Table 3.
Novel or tested pharmacogenetics hypotheses related to CYP3A and CYP2D6 genes
| Gene | Substrate (S) | Inhibitors (I) | DDI dosing recommendations in drug labels (S/I) | Adverse drug events | Novel genetic hypotheses | PMIDs for tested hypotheses |
|---|---|---|---|---|---|---|
| CYP3A | Alprazolam | Nefazodone/Fluoxetine/Ritonavir | n/a | Sedation | Yes | - |
| Amprenavir | Ritonavir | 1200 mg/200 mg o.d, 600 mg/100 mg b.i.d | Diarrhea | Yes | - | |
| Hyperlipidemia | Yes | - | ||||
| Nausea | Yes | - | ||||
| Oral paresthesias | Yes | - | ||||
| Rash | Yes | - | ||||
| Vomiting | Yes | - | ||||
| Atazanavir | Ritonavir | 300 mg/100 mg o.d, 400 mg/100 mg o.d if given with other HIV drugs | Cholelithiasis | Yes | - | |
| Diarrhea | Yes | - | ||||
| Hyperlipidemia | Yes | - | ||||
| Increase in total and subcutaneous fat | Yes | - | ||||
| Metabolic syndrome | Yes | - | ||||
| Upper respiratory tract infection | Yes | - | ||||
| Vomiting | Yes | - | ||||
| Hyperbilirubinemia | No | 28599374 | ||||
| Nephrolithiasis | No | 25151207 | ||||
| Atorvastatin | Itraconazole/Ticagrelor/Ritonavir | >20 mg atorvastatin to be given with caution; no adjustment with Ticagrelor; minimum required dose with ritonavir | Rhabdomyolysis | Yes | ||
| Atorvastatin | Itraconazole/Ritonavir | >20 mg atorvastatin to be given with caution; minimum required dose with ritonavir | Myopathy | No | 28812116, 17289397, 15900215 | |
| Carbamazepine | Ritonavir | n/a | Ataxia | Yes | - | |
| Cerivastatin | Cyclosporine | n/a | Myopathy | Yes | - | |
| Rhabdomyolysis | Yes | - | ||||
| Cisapride | Ketoconazole/Clarithromycin/Diltiazem | Contraindicated; n/a for diltiazem | QTc prolongation | Yes | - | |
| Cisapride | Clarithromycin/Diltiazem | Contraindicated; n/a for diltiazem | Syncope | Yes | - | |
| Cisapride | Ketoconazole/Clarithromycin | Contraindicated | Ventricular arrythmias | Yes | - | |
| Colchicine | Clarithromycin | 0.3 or 0.6 mg colchicine; dose and frequency depend on the condition treated | Death | Yes | - | |
| Gi toxicity | Yes | - | ||||
| Multiorgan failure | Yes | - | ||||
| Myelosuppression | Yes | - | ||||
| Pancytopenia | Yes | - | ||||
| Cyclosporine | Telaprevir | n/a | Cytomegalovirus reactivation | Yes | - | |
| Acute rejection | No | 27653228, 18444945, 29043387 | ||||
| Cyclosporine | Ketoconazole/Nefazodone | n/a | Nephrotoxicity | No | 22388796 | |
| Darunavir | Ritonavir | 800 mg/100 mg o.d, 600 mg/100 mg b.i.d | Diarrhea | Yes | - | |
| Headache | Yes | - | ||||
| Hyperlipidemia | Yes | - | ||||
| Increase in alt | Yes | - | ||||
| Increase in total and subcutaneous fat | Yes | - | ||||
| Lipoma | Yes | - | ||||
| Metabolic syndrome | Yes | - | ||||
| Nasopharyngitis | Yes | - | ||||
| Nausea | Yes | - | ||||
| Upper respiratory tract infection | Yes | - | ||||
| Diazepam | Cimetidine | n/a | Sedation | Yes | - | |
| Docetaxel | Ketoconazole | n/a | Less febrile neutropenia | Yes | - | |
| Less neutrophil suppression | Yes | - | ||||
| Anemia | No | 25495407, 17410042 | ||||
| Diarrhea | No | 25495407, 17410042 | ||||
| Edema | No | 19332043 | ||||
| Fatigue | No | 21468756, 17410042 | ||||
| Increase in liver function tests | No | 25495407 | ||||
| Myelosuppression | No | 25495407, 17545536, 19332043, 16765145, 17410042 | ||||
| Nausea | No | 25495407, 17410042 | ||||
| Neuropathy | No | 27574448, 17410042 | ||||
| Everolimus | Voriconazole | Avoid voriconazole | Pneumonia | Yes | ||
| Fentanyl | Fluconazole/Voriconazole | n/a | Respiratory depression | No | 21223952 | |
| Imatinib | Docetaxel | n/a | Diarrhea | Yes | - | |
| Nausea | Yes | - | ||||
| Vomiting | Yes | - | ||||
| Indinavir | Ritonavir | 800 mg/100 mg b.i.d, 800 mg/200 mg b.i.d | Alopecia | Yes | - | |
| Flank pain | Yes | - | ||||
| Hematuria | Yes | - | ||||
| Hyperlipidemia | Yes | - | ||||
| Nausea | Yes | - | ||||
| Nephrolithiasis | Yes | - | ||||
| Vomiting | Yes | - | ||||
| Levomethadyl acetate | Ketoconazole | n/a | Prolongation of miosis | Yes | - | |
| Lopinavir | Ritonavir | 800 mg/200 mg o.d, 400 mg/100 mg b.i.d, 600 mg/150 mg If given with other HIV drugs | Asthenia | Yes | - | |
| Diarrhea | Yes | - | ||||
| Gastritis | Yes | - | ||||
| Headache | Yes | - | ||||
| Hyperglycemia | Yes | - | ||||
| Hyperinsulinemia | Yes | - | ||||
| Hyperlipidemia | Yes | - | ||||
| Lipoma | Yes | - | ||||
| Rash | Yes | - | ||||
| Lovastatin | Ritonavir/Telaprevir/Boceprevir | Contraindicated | Myalgia | Yes | - | |
| Lovastatin | Itraconazole/Ritonavir | Contraindicated | Myopathy | Yes | - | |
| Lovastatin | Itraconazole/Cyclosporine/Ritonavir | Contraindicated; avoid cyclosporine | Rhabdomyolysis | Yes | - | |
| Methadone | Fluvoxamine | n/a | Opioid withdrawal | No | 21902501 | |
| Midazolam | Ketoconazole/Saquinavir | Avoid ketoconazole; n/a for saquinavir | Cognitive impairment | Yes | - | |
| Midazolam | Posaconazole | Avoid posaconazole | Diarrhea | Yes | - | |
| Midazolam | Ketoconazole/Ritonavir/Diltiazem/Verapamil/Ranitidine/Erythromycin | Avoid ketoconazole/diltiazem/verapamil/erythromycin; n/a for ranitidine; ritonavir contraindicated | Sedation | No | 17786417 | |
| Nelfinavir | Ritonavir | n/a | Diarrhea | Yes | - | |
| Nausea | Yes | - | ||||
| Rash | Yes | - | ||||
| Paclitaxel | Cyclosporine | n/a | Nail changes | Yes | - | |
| Neurotoxicity | No | 23640974, 20212519 | ||||
| Vomiting | No | 15901749 | ||||
| Paclitaxel | Cyclosporine/Pazopanib | n/a | Diarrhea | Yes | - | |
| Nausea | No | 15901749 | ||||
| Paclitaxel | Cyclosporine/Pazopanib/Verapamil | n/a | Neutropenia | No | 12454106, 26179145, 15901749 | |
| Paclitaxel | Pazopanib | n/a | Abscess | Yes | - | |
| Dysgeusia | Yes | - | ||||
| Fatigue | Yes | - | ||||
| Gastrointestinal perforations | Yes | - | ||||
| Hair color changes | Yes | - | ||||
| Hepatotoxicity | Yes | - | ||||
| Hyperbilirubinemia | Yes | - | ||||
| Hypertension | Yes | - | ||||
| Myalgia | Yes | - | ||||
| Alopecia | No | 24025145 | ||||
| Myelosuppression | No | 26179145, 21702053, 15901749 | ||||
| Neuropathy | No | 25398452 | ||||
| Paclitaxel | Pazopanib/Verapamil | n/a | Thrombocytopenia | No | 15901749 | |
| Pimozide | Clarithromycin | Contraindicated | QTc prolongation | Yes | - | |
| Quetiapine | Ritonavir/Atazanavir | 1/6th the usual dose | Delirium | Yes | - | |
| Sedation | Yes | - | ||||
| Weight gain | Yes | - | ||||
| Quinidine | Cimetidine | n/a | QT, QTc, QRS AND RR prolongation | Yes | - | |
| Saquinavir | Ritonavir/Nelfinavir | 1000 mg/100 mg b.i.d; n/a for nelfinavir | Abdominal discomfort | Yes | - | |
| Diarrhea | Yes | - | ||||
| Dysphagia | Yes | - | ||||
| Headache | Yes | - | ||||
| Nausea | Yes | - | ||||
| Saquinavir | Ritonavir | 1000 mg/100 mg b.i.d, | Asthenia | Yes | - | |
| Hyperlipidemia | Yes | - | ||||
| Increase in liver function tests | Yes | - | ||||
| Paresthesias | Yes | - | ||||
| QTc prolongation | Yes | - | ||||
| Simvastatin | Amiodarone | <20 mg/day | Acute renal failure | Yes | - | |
| Azotemia | Yes | - | ||||
| Simvastatin | Diltiazem | n/a | Hepatitis | Yes | - | |
| Simvastatin | Amiodarone/Diltiazem | <20 mg/day; n/a for diltiazem | Hepatotoxicity | Yes | - | |
| Simvastatin | Clarithromycin/Amiodarone/Ritonavir/Itraconazole/Cyclosporine/Verapamil | Avoid clarithromycin/itraconazole; <20 mg/day with amiodarone and verapamil; <10 mg/day with cyclosporine; ritonavir contraindicated | Rhabdomyolysis | Yes | - | |
| Simvastatin | Ritonavir/Telaprevir/Boceprevir | Contraindicated | Myalgia | No | 16321621 | |
| Simvastatin | Diltiazem/Clarithromycin/ Ritonavir/ Amiodarone/Itraconazole/Cyclosporine/Verapamil | Avoid clarithromycin/itraconazole; <20 mg/day with amiodarone and verapamil; <10 mg/day with cyclosporine; n/a for diltiazem; ritonavir contraindicated | Myopathy | No | 17289397, 22122820 | |
| Sirolimus | Cyclosporine | 2 mg or 5 mg per day maintenance based on immunologic risk | Hypertension | Yes | - | |
| Hypertriglyceridemia | Yes | - | ||||
| Myelosuppression | Yes | - | ||||
| Nephrotoxicity | Yes | - | ||||
| Diabetes mellitus | No | 28245187 | ||||
| Hypercholesterolemia | No | 21441846 | ||||
| Tacrolimus | Fluconazole/Voriconazole | 1/3rd the usual dose followed by adjustments based on blood concentration levels | Hepatotoxicity | No | 24438215 | |
| Hyperglycemia | No | 25966085 | ||||
| Nephrotoxicity | No | 17495880, 20526235, 23574377, 19644155, 19067682, 21677300, 25201288, 26856709, 27977332, 27217047, 29539600 | ||||
| Terfenadine | Nefazodone/Ketoconazole/Itraconazole | n/a | QTc prolongation | Yes | - | |
| Torsades de pointes | Yes | - | ||||
| Tipranavir | Ritonavir | 500 mg/200 mg b.i.d | Diarrhea | Yes | - | |
| Headache | Yes | - | ||||
| Hepatotoxicity | Yes | - | ||||
| Hyperlipidemia | Yes | - | ||||
| Nausea | Yes | - | ||||
| Trazodone | Ritonavir | n/a | Dizziness | Yes | - | |
| Fatigue | Yes | - | ||||
| Hypotension | Yes | - | ||||
| Nausea | Yes | - | ||||
| Sedation | Yes | - | ||||
| Syncope | Yes | - | ||||
| Triazolam | Nefazodone/Ritonavir | Contraindicated | Sedation | Yes | - | |
| Verapamil | Cimetidine | n/a | Increase in negative dromotropic effect | Yes | - | |
| CYP2D6 | Codeine | Quinidine | n/a | Psychomotor effects | Yes | - |
| Pupillary effects | Yes | - | ||||
| Respiratory depression | No | 22492761, 18713907 |
||||
| Dextromethorphan | Quinidine | 20 mg/10 mg o.d for 7 days and then b.i.d | Diarrhea | Yes | - | |
| Falls | Yes | - | ||||
| QTc prolongation | Yes | - | ||||
| Urinary tract infection | Yes | - | ||||
| Imipramine | Fluoxetine | n/a | QTc prolongation | Yes | - | |
| Lidocaine | Propafenone | n/a | Negative inotropic effect | Yes | - | |
| Central nervous system side effects | Yes | - | ||||
| Metoprolol | Cimetidine | n/a | Fatigue | No | 2049246, 24637943 | |
| Anxiety | Yes | - | ||||
| Asthenia | Yes | - | ||||
| Sweating | Yes | - | ||||
| Metoprolol | Diphenhydramine | n/a | Systolic blood pressure | No | 24637943 | |
| Metoprolol | Diphenhydramine/Verapamil | n/a | Heart rate reduction | No | 19037197, 18784654, 24637943, 24193112, 29095089 | |
| Metoprolol | Propafenone | n/a | Nightmares | Yes | - | |
| Left ventricular failure | Yes | - | ||||
| Metoprolol | Verapamil | n/a | Atrioventricular block | No | 3437726 | |
| Systemic arterial pressure | No | 19037197, 24637943 | ||||
| Mexiletine | Quinidine | n/a | Prolongation of refractory period and conduction | Yes | - | |
| Propafenone | Quinidine | Avoid quinidine | Heart rate reduction | No | 7595187 | |
| Propranolol | Cimetidine | n/a | Heart rate reduction | No | 9399616, 12728976 | |
| Risperidone | Ritonavir | n/a | Dystonia | No | 20599499 | |
| Parkinsonism | No | 20599499 | ||||
| Coma | Yes | - | ||||
| Akathisia | Yes | - | ||||
| Timolol | Paroxetine | n/a | Heart rate reduction | No | 7474246, 20925579 | |
| Venlafaxine | Fluoxetine | n/a | Serotonin syndrome | No | 19822698, 23799451, 16958828, 10780263 | |
| Zuclopenthixol | Fluoxetine | n/a | Extrapyramidal side effects | No | 12107620 | |
| Dystonia | Yes | - |
DDI: drug-drug interactions, PMID: PubMed ids for journal articles, n/a: not available, o.d: once a day, b.i.d: twice a day