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

GENERALLY AVOID: Coadministration of pexidartinib with strong CYP450 3A4 inhibitors and/or uridine diphosphate glucuronosyltransferase (UGT) inhibitors may significantly increase the plasma concentrations and the incidence and severity of adverse effects of pexidartinib, including potentially fatal hepatotoxicity. The proposed mechanism is inhibition of CYP450 3A4 and/or UGT, the primary isoenzymes responsible for the metabolic clearance of pexidartinib. Concomitant administration of itraconazole, a strong CYP450 3A4 inhibitor, increased pexidartinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 70%, respectively. Coadministration with probenecid, a UGT inhibitor, increased pexidartinib Cmax and AUC by 5% and 60%, respectively.

MANAGEMENT: The use of pexidartinib with strong CYP450 3A4 inhibitors and/or UGT inhibitors should generally be avoided. If concomitant use is required, the dose of pexidartinib should be reduced according to the manufacturer's recommendations. If concomitant use of a strong CYP450 3A4 inhibitor or UGT inhibitor is discontinued, the dose of pexidartinib may be increased, after 3 plasma half-lives of the strong CYP450 3A4 inhibitor or UGT inhibitor, to the dose that was used prior to starting the strong CYP450 3A4 inhibitor or UGT inhibitor.

GENERALLY AVOID: Serious cases of hepatotoxicity, some fatal, have occurred in patients treated with pexidartinib. Concomitant use of other potentially hepatotoxic agents may potentiate the risk of liver injury. The mechanism of hepatotoxicity is unknown, its occurrence cannot be predicted, and it is unknown whether liver injury occurs in the absence of increased transaminases. In one study, 5% of patients who received pexidartinib developed signs of serious liver injury (elevated serum transaminases greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times ULN). In these patients, peak ALT ranged from 6 to 9 times ULN, peak total bilirubin ranged from 2.5 to 15 times ULN, and ALP was greater than 2 times ULN. Liver transaminases and total bilirubin improved to less than 2 times ULN in these patients 1 to 7 months after discontinuing pexidartinib.

MANAGEMENT: The use of pexidartinib with other potentially hepatotoxic agents should be avoided. Patients treated with pexidartinib should have liver function tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT), prior to initiation of pexidartinib, weekly for the first 8 weeks, every 2 weeks for the next month, and every 3 months thereafter. Pexidartinib therapy may require a dosage reduction, to be withheld, or permanently discontinued based on the severity of the hepatotoxicity. A recurrence of increased serum transaminases, bilirubin, or ALP may occur upon rechallenge with a reduced dose of pexidartinib. Liver function tests should be performed weekly for the first month after rechallenge. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

GENERALLY AVOID: Serious cases of hepatotoxicity, some fatal, have occurred in patients treated with pexidartinib. Concomitant use of other potentially hepatotoxic agents may potentiate the risk of liver injury. The mechanism of hepatotoxicity is unknown, its occurrence cannot be predicted, and it is unknown whether liver injury occurs in the absence of increased transaminases. In one study, 5% of patients who received pexidartinib developed signs of serious liver injury (elevated serum transaminases greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times ULN). In these patients, peak ALT ranged from 6 to 9 times ULN, peak total bilirubin ranged from 2.5 to 15 times ULN, and ALP was greater than 2 times ULN. Liver transaminases and total bilirubin improved to less than 2 times ULN in these patients 1 to 7 months after discontinuing pexidartinib.

MANAGEMENT: The use of pexidartinib with other potentially hepatotoxic agents should be avoided. Patients treated with pexidartinib should have liver function tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT), prior to initiation of pexidartinib, weekly for the first 8 weeks, every 2 weeks for the next month, and every 3 months thereafter. Pexidartinib therapy may require a dosage reduction, to be withheld, or permanently discontinued based on the severity of the hepatotoxicity. A recurrence of increased serum transaminases, bilirubin, or ALP may occur upon rechallenge with a reduced dose of pexidartinib. Liver function tests should be performed weekly for the first month after rechallenge. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

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.

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.

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 through 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. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

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. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.