Drug Interactions between betiatide and cobicistat / darunavir / emtricitabine / tenofovir alafenamide

MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration 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 is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. 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: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, 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.

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.

MONITOR: Coadministration of the radiopharmaceutical technetium (Tc99m) mertiatide with another drug that is also eliminated by active tubular secretion may result in increased plasma concentrations of one or both drugs. The exact mechanism has not been fully described but may involve competition in binding to organic anion transporter 1 (OAT1) in the proximal tubule of the kidney, which is involved in moving some drugs from the blood into the urine. The risk and significance of this interaction may vary. Some sources state that the risk is expected with diuretics like hydrochlorothiazide, but only theoretical with others (e.g., nonsteroidal anti-inflammatory drugs). Delayed excretion of Tc99m mertiatide may affect the efficacy of the diagnostic procedure. However, clinical data are limited. One crossover study conducted in 12 healthy male volunteers (22-25 years old), reviewed the differences in scans using Tc99m mertiatide injection alone to those obtained when subjects received either a selective OAT1 substrate (10% sodium p-aminohippurate (PAH) given via intravenous infusion at 120 mg/min 10 minutes prior to and during the scan) or a potent OAT1 inhibitor (probenecid 750 mg 1 hour prior to the scan). PAH appeared to have a greater impact than probenecid, increasing the late phase (30-60 minutes post radiopharmaceutical injection) plasma clearance half-life of Tc99m mertiatide from approximately 27.7 minutes to 54.9 minutes. However, in some circumstances, the administration of an NSAID or other medication that affects the secretion of Tc99m mertiatide may be clinically indicated. For example, there are some protocols that utilize aspirin to enhance Tc99m mertiatide renography for the investigation/diagnosis of renal artery stenosis.

MANAGEMENT: Caution is recommended with the concomitant administration of technetium (Tc99m) mertiatide with drugs that are secreted in the proximal tubule due to the potential to affect the efficacy of the diagnostic procedure. Likewise, since Tc99m mertiatide may also delay the excretion of other drugs eliminated via this route, monitoring for excessive pharmacologic effects of both drugs should be considered. Current clinical guidelines and/or manufacturer's labeling should be consulted for more specific information and guidance. Dehydration and acidosis can also impact kidney function and prolong renal drug elimination. Refer to the product labeling or local protocols for guidelines on patient hydration prior to testing with Tc99m mertiatide.

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.