Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide and Kitabis Pak

GENERALLY AVOID: Coadministration of tenofovir with other nephrotoxic agents may increase the risk of renal impairment due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of tenofovir, which is primarily eliminated by a combination of glomerular filtration and active tubular secretion. The use of tenofovir has been associated with dose-related nephrotoxicity including acute renal failure and Fanconi syndrome characterized by renal tubular injury with severe hypophosphatemia, possibly as a result of mitochondrial toxicity. Cases of acute renal failure after initiation of high-dose or multiple nonsteroidal anti-inflammatory agents have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir therapy. Some patients required hospitalization and renal replacement therapy. Available clinical data seem to suggest a lower risk of nephrotoxicity with tenofovir alafenamide fumarate (TAF) than with tenofovir disoproxil fumarate (TDF), presumably due to lower tenofovir systemic exposure following administration of TAF relative to TDF. Whereas TDF is metabolized in plasma to tenofovir and phosphorylated intracellularly to the active moiety tenofovir diphosphate, TAF is largely metabolized and phosphorylated intracellularly, resulting in substantially higher intracellular concentrations of tenofovir diphosphate and lower plasma levels of tenofovir at the therapeutic dose of 25 mg compared to TDF 300 mg. It has been further reported that tenofovir is actively transported into the proximal renal tubular cell by organic anion transporters (OAT) 1 and 3, but that TAF is not a substrate for these transporters and thus less likely to cause tubular injury. There have been no cases of Fanconi syndrome or proximal renal tubulopathy in clinical trials of various TAF-containing products according to the manufacturers.

MANAGEMENT: The use of tenofovir in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and ganciclovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine) should be avoided if possible. Renal function tests including serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein should be performed prior to and during therapy with tenofovir. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

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MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

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GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

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