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

ADJUST DOSE: Coadministration with potent CYP450 3A4 inhibitors may significantly increase the plasma concentrations and effects of mavorixafor, which is primarily metabolized by the isoenzyme. When a single dose of mavorixafor (200 mg) was coadministered with the strong CYP450 3A4 and P-glycoprotein (P-gp) inhibitor itraconazole (200 mg at steady state), mavorixafor's systemic exposure (AUC) increased approximately 2-fold. The resulting AUC was similar to that expected from a single dose of 400 mg given alone to healthy subjects. Mavorixafor is also a substrate of P-gp, so itraconazole's ability to inhibit this efflux transporter may have contributed to the increase in AUC. Clinical data with potent CYP450 3A4 inhibitors that do not also inhibit P-gp are not available. As mavorixafor causes concentration-dependent QT interval prolongation, an increase in its AUC may increase the risk of experiencing this adverse effect. Likewise, this risk may be further increased if the CYP450 3A4 inhibitor being used also carries a risk of QT prolongation (e.g., adagrasib, ceritinib, clarithromycin, ketoconazole, levoketoconazole, mifepristone, posaconazole, saquinavir, telithromycin, voriconazole).

MANAGEMENT: If mavorixafor must be used concurrently with a potent CYP450 3A4 inhibitor, the daily dose should be reduced to 200 mg. Close monitoring for an increase in adverse effects, such as QT prolongation, is also advised. Any modifiable risk factors for QT prolongation, such as electrolyte abnormalities, should be corrected. The QTc (QT interval corrected for heart rate) should be assessed at baseline and as clinically indicated during concomitant therapy. In addition, the labeling for each medication should be consulted as changes in the QTc interval may require dose adjustments or discontinuation of the drug(s) suspected to be at fault.

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.

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.

MONITOR: Coadministration with mavorixafor may increase the plasma concentrations of drugs that are substrates of the isoenzyme CYP450 2D6, isoenzyme CYP450 3A4, and/or the efflux transporter P-glycoprotein (P-gp). It is important to determine if the isoenzyme in question is responsible for drug clearance or drug activation as these situations may result in either a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 2D6 substrate dextromethorphan in healthy subjects, dextromethorphan's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 6- and 9-fold, respectively. On the other hand, when mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, the Cmax and AUC increased by only 1.1- and 1.7-fold, respectively. Likewise, when a single dose of a transporter cocktail containing P-gp substrate digoxin (0.25 mg) was administered to healthy subjects on mavorixafor (400 mg/day at steady state), digoxin's Cmax and AUC increased by 1.5- and 1.6-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if mavorixafor is used concurrently with medications that are substrates of the P-gp efflux transporter and/or undergo metabolism via CYP450 2D6 and/or 3A4. This may be particularly important in cases where minimal concentration changes may result in serious adverse reactions from the substrate(s) in question. Dose adjustments and/or increased monitoring may be required. For example, digoxin's serum concentrations should be measured before initiating concomitant use with mavorixafor and as clinically indicated during coadministration. The labeling for the substrate(s) in question should be consulted for more specific recommendations.