Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and dabrafenib

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or 2C8 may increase the plasma concentrations of dabrafenib and its active metabolites. In vitro studies have shown that dabrafenib is a substrate of CYP450 3A4 and 2C8, while hydroxy-dabrafenib and desmethyl-dabrafenib are substrates of CYP450 3A4. In a pharmacokinetic study, administration of dabrafenib 75 mg twice daily in combination with the potent CYP450 3A4 inhibitor ketoconazole 400 mg once daily for 4 days increased dabrafenib systemic exposure (AUC) by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. When dabrafenib was given similarly with the potent CYP450 2C8 inhibitor gemfibrozil 600 mg twice daily for 4 days, dabrafenib AUC increased by 47%, but AUC of the metabolites did not change.

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are substrates of CYP450 3A4, including many of the known inhibitors of the isoenzyme such as conivaptan, delavirdine, nefazodone, telithromycin, and most azole antifungal agents, macrolide antibiotics, and protease inhibitors. Dabrafenib has been found in vitro to be a dose-dependent inducer of CYP450 3A4. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of CYP450 3A4 may be observed during the first few days of treatment. In 12 study subjects, administration of the CYP450 3A4 probe substrate midazolam following repeat doses of dabrafenib 150 mg twice daily for 15 days reduced midazolam peak plasma concentration (Cmax) by 61% and systemic exposure (AUC) by 74%.

MANAGEMENT: The use of dabrafenib with potent CYP450 2C8 inhibitors such as gemfibrozil or potent CYP450 3A4 inhibitors such as ceritinib, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, telithromycin, and most protease inhibitors and azole antifungal agents should generally be avoided if possible. Some authorities recommend avoiding concomitant use of dabrafenib during and for 2 weeks after treatment with itraconazole. Otherwise, patients should be closely monitored for development of adverse effects such as febrile reactions (high fever or fever accompanied by rigors, hypotension, dehydration, or renal failure), hyperglycemia, uveitis, and cutaneous malignancies (e.g., squamous cell carcinoma, keratoacanthoma, melanoma). During coadministration of dabrafenib with a CYP450 3A4 inhibitor, the potential for diminished therapeutic effects of the inhibitor should also be considered.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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MONITOR: Coadministration of lopinavir-ritonavir with inducers of CYP450 3A4 may decrease the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. Clinical studies have shown that potent CYP450 3A4 inducers such as rifampin and phenytoin can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the inhibiting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 20 days) with rifampin (600 mg once daily for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively. In another study of 12 healthy volunteers, coadministration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) and phenytoin (300 mg once daily on days 11 thru 22) resulted in decreases in Cmax, AUC and Cmin of lopinavir by 24%, 33% and 46%, respectively. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant. The extent to which other, less potent inducers of CYP450 3A4 may interact with lopinavir-ritonavir is unknown.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with CYP450 3A4 inducers. Close clinical and laboratory monitoring of antiretroviral response is recommended.

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