Drug Interactions between lopinavir / ritonavir and quetiapine

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of quetiapine, which is primarily metabolized by the isoenzyme. In 12 healthy volunteers, administration of a single 25 mg dose of quetiapine with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 4 days) increased mean quetiapine peak plasma concentration (Cmax) and systemic exposure (AUC) by 3.4- and 6.2-fold, respectively, and decreased mean oral clearance by 84%. High plasma levels of quetiapine may increase the risk and/or severity of serious adverse effects such as extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases (in children and adolescents), priapism, QT prolongation, cognitive and motor impairment, dysphagia, and heat-related illnesses due to disruption of body temperature regulation. A case report describes a patient treated with quetiapine 700 mg/day who developed severely impaired consciousness and respiratory depression requiring intensive care surveillance following two 500 mg doses of clarithromycin, another potent CYP450 3A4 inhibitor. Quetiapine plasma level was found to be nearly 5 times the high end of the recommended therapeutic range. The patient recovered a week after quetiapine was withdrawn. The interaction was also suspected in a case report of two patients receiving quetiapine with ritonavir-boosted atazanavir. One patient experienced significant increases in appetite and serum glucose and a weight gain of more than 22 kg over six months. The patient's weight returned to baseline five months after stopping both treatments. The second patient had increased sedation and mental confusion, which resolved several days following self-discontinuation of quetiapine. In another report, a patient receiving HIV antiretroviral therapy containing lopinavir-ritonavir developed priapism several hours after starting quetiapine and perphenazine for a schizoaffective disorder. Inhibition of CYP450 3A4 and 2D6 by lopinavir-ritonavir is thought to be involved, resulting in elevated levels of both quetiapine and perphenazine.

MANAGEMENT: The dosage of quetiapine should be reduced when prescribed with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. The product labeling recommends a reduction to one-sixth of the original dosage. Following discontinuation of the CYP450 3A4 inhibitor, the dosage of quetiapine should be increased by 6-fold.

GENERALLY AVOID: Lopinavir in combination with ritonavir may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, the maximum mean time-matched difference in QTcF interval from placebo (after baseline correction) was 5.3 msec for the lower dosage and 15.2 msec for the supratherapeutic dosage in the 12 hours post-dose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. No subject experienced an increase in QTcF greater than 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. There have been cases of QT interval prolongation and torsade de pointes arrhythmia during postmarketing use of lopinavir-ritonavir, although causality could not be established. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of lopinavir-ritonavir with other drugs that can prolong the QT interval should generally be avoided. Patients treated with any medication that can cause QT prolongation should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.