Maribavir

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Clinical Pharmacology
Maribavir is a benzimidazole riboside antiviral agent that competitively inhibits the protein kinase activity of human CMV enzyme pUL97, which results in inhibition of the phosphorylation of proteins. 1,9 In dose-ranging studies, no exposure-response relationship was observed for viral load or probability of achieving unquantifiable plasma CMV DNA. 1 Maribavir has also been shown to inhibit Epstein-Barr virus replication. 10,11 When maribavir was tested in combination with ganciclovir, strong antagonism of ganciclovir antiviral activity was observed; the pUL97 kinase activity inhibited by maribavir is necessary for the activation of ganciclovir and valganciclovir. 1,12,13 No antagonism was observed with cidofovir, foscarnet, letermovir, or rapamycin. Maribavir showed additive activity with cidofovir, foscarnet, letermovir, and GW275175X (a benzimidazole) when tested against wild-type and mutant CMV virus. Strong synergy has been reported with rapamycin. 12,13 Maribavir-resistant virus was selected in cell culture. Substitutions in pUL97 that conferred reduced susceptibility, ranging from 3.5-fold to greater than 200-fold, included L337M, V353A, L397R, T409M, and H411L/N/Y. Substitutions that conferred reduced susceptibility ranging from 1.7fold to 4.8-fold were identified in pUL27:R233S, W362R, W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301-311del. 1 Among patients with virologic failure in a phase 2 maribavir clinical trial, 25 patients had treatment-emergent maribavir resistance-associated substitutions in pUL97 F342Y (4.5-fold reduction in susceptibility), T409M (78-fold reduction), H411L/Y (69-fold and 12-fold reduction), and/or C480F (224-fold reduction). The shortest maribavir exposure associated with a resistance mutation was 6 weeks. 1,14 In a phase 2 trial, a patient with the F342Y substitution detected at baseline did not achieve CMV DNA viral clearance after 12 weeks of maribavir therapy, and subsequently developed an additional substitution (H411Y) known to confer resistance. 15 In a phase 3 study, treatmentemergent pUL97 substitutions F342Y (4.5-fold reduced susceptibility), T409M (78-fold reduction), H411L/N/Y (69-fold, 9-fold, and 12-fold reductions, respectively), and/ or C480F (224-fold reduction) were detected in 58 subjects; treatment failed in 47 patients and relapse occurred in 11 patients. One subject with the pUL27 L193F substitution (2.6-fold reduced susceptibility) at baseline did not achieve the primary end point. 1 Case reports have also described treatment-resistant mutations emerging during maribavir treatment in patients with CMV infection after solid organ transplant and HSCT. Substitution in pUL97 C480F conferred the highest level of maribavir resistance and ganciclovir cross-resistance in these patients. 16 Phenotyping has also suggested improved maribavir sensitivity among some ganciclovir-resistant mutations (E362D, V345I, M460V, M460I), possibly due to increased affinity of drug binding. 17 Cross-resistance has been observed between maribavir and ganciclovir/valganciclovir in cell culture and in clinical studies. The pUL97 ganciclovir/valganciclovir resistanceassociated substitutions F342S/Y, K355del, V356G, D456N, V466G, C480R, P521L, and Y617del reduce susceptibility to maribavir by more than 4.5-fold. The pUL54 DNA polymerase substitutions conferring resistance to ganciclovir/valganciclovir, cidofovir, or foscarnet remained susceptible to maribavir. Other ganciclovir/valganciclovir resistance pathways have not been assessed for their impact on maribavir susceptibility. The pUL97 F342Y and C480F maribavir treatment-emergent resistance-associated substitutions confer greater than 1.5-fold reduced susceptibility to ganciclovir/valganciclovir. Maribavir-resistant virus has remained susceptible to cidofovir and foscarnet. 1 As a postmarketing commitment, the FDA is requiring the manufacturer to conduct phenotypic analysis of maribavir against human CMV. Substitutions designated as a high priority for analysis are pUL97 M460I/T, A594E/P/T/V, L595F/W, and C603R/W/Y. Substitutions designated as medium priority are pUL97 A440V, V466M, A591V, E596G, K599E, and C607F/Y. Substitutions designated as low priority are pUL97 P132L, L405P, C518Y, I610T, and A613V; pUL27 P10L, N289D, H29Y, D298G, N300G, P307L, V310A, D351N, and I367V; and pUL54 S290R and K475S. 18 Maribavir does not prolong the QT interval to a clinically important extent. 1,19 Pharmacokinetics Following oral administration, median T max is 1 to 3 hours. 1,19,20 Plasma exposure (C max and AUC) increased approximately dose proportionally following a single dose of 50 to 1600 mg and multiple doses of up to 2400 mg/day. 1,20 Compared with administration in the fasted state, administration with a moderate-fat meal resulted in a small reduction in AUC 0-∞ (geometric mean ratio, 0.864; 90% CI, 0.804-0.929) and C max (0.722; 90% CI, 0.656-0.793). Steady state is reached within 2 days with twice-daily dosing. 1 Mean steady-state volume of distribution is 27.3 L. Maribavir is 98% plasma protein bound. The blood-to-plasma ratio is 1.37. 1,20 Maribavir does not appear to cross the blood-brain barrier. 9 Maribavir, the parent drug, is responsible for the pharmacologic activity. Mean maribavir half-life is 4.32 hours in transplant recipients. 1 A half-life of 3 to 5 hours has been reported in healthy subjects and patients with HIV infection. 20 Maribavir is primarily eliminated by hepatic metabolism via CYP3A4 (major) and CYP1A2 (minor). An N-dealkylated metabolite (VP 44469) is the major circulating inactive metabolite; metabolite levels peak at 2 to 4 hours after maribavir administration. 1,19 The majority of the maribavir dose is excreted in the urine (61%, with less than 2% as unchanged drug); 14% of the dose is excreted in the feces (5.7% as unchanged drug). 1,20 No clinically important differences in maribavir pharmacokinetics were observed based on age (18-79 years), sex, race (White, Black, Asian, or other), ethnicity (Hispanic/ Latino or non-Hispanic/Latino), body weight (36-141 kg), mild to severe renal impairment (creatinine clearance 12-70 mL/minute), or mild to moderate hepatic impairment (Child-Pugh class A or B). Maribavir has not been studied in patients with end-stage renal disease, including patients on dialysis, or in patients with severe hepatic impairment. 1,21 The pharmacokinetics of maribavir have not been evaluated in patients younger than 18 years. Modeling suggests that the recommended dosing regimen is expected to result in maribavir plasma exposures in patients 12 years and older and weighing at least 35 kg that are comparable to those observed in adults. 1 The metabolism of maribavir is not mediated by CYP2B6, 2C8, 2C9, 2C19, or 3A5 or by UGT1A4, UGT1A6, UGT1A10, or UGT2B15. The transport of maribavir is not mediated by OATP1B1, OATP1B3, or BSEP. 1

Guideline: Cytomegalovirus in solid organ transplant recipients-guidelines of the American Society of Transplantation Infectious Diseases Community of Practice
Reference: American Society of Transplantation Infectious Diseases Community of Practice, 2019 2 Comments: Preemptive therapy may be used for the prevention of CMV disease in solid organ transplant recipients. Specific preemptive therapy recommendations vary depending on donor and recipient CMV status and transplant type. The recommended antiviral drugs for preemptive therapy are valganciclovir or IV ganciclovir, adjusted based on renal function. Therapy is continued until CMV DNA is no longer detectable or has declined to levels below a predefined threshold for at least 2 weeks. First-line antiviral drugs for the treatment of CMV disease are IV ganciclovir and oral valganciclovir. IV ganciclovir is recommended initial treatment for severe or life-threatening CMV disease, for those with very high viral load, and for those with potentially impaired GI absorption. Oral valganciclovir and IV ganciclovir are equally effective initial therapy for mild to moderate CMV disease. Foscarnet and cidofovir are considered second-line agents due to nephrotoxicity risk. Letermovir has also been used in select patients but is not recommended in solid organ transplant recipients until clinical trials prove efficacy and safety. The duration of antiviral therapy should be individualized based on resolution of clinical symptoms and virologic clearance. Patients initially treated with IV ganciclovir may be switched to oral valganciclovir once there is adequate clinical and virologic control. The addition of IV immunoglobulin or CMV immunoglobulin to antiviral therapy for CMV disease may be considered for patients with life-threatening disease, CMV pneumonitis and other forms of severe disease, drug-resistant virus, or hypogammaglobulinemia. Patients who develop refractory CMV infection or disease after prolonged antiviral exposure or who fail to respond to at least 2 weeks of antiviral therapy should be suspected of having drug-resistant virus. Genotypic assays should be performed to assess resistance mutations. Definitive antiviral therapy should be guided by results of genotypic testing. Options may include foscarnet, high-dose IV ganciclovir, cidofovir, maribavir, or letermovir. CMV immunoglobulin or IV immunoglobulin may be used as an adjunct to antiviral drugs in transplant recipients with resistant CMV disease. Patients: Three hundred fifty-two HSCT or solid organ transplant recipients (at least 12 years of age) with CMV infections refractory to the most recent treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections with or without a confirmed genetic mutation conferring resistance to 1 or more of the 4 potential investigator-assigned treatments (IATs). CMV viremia had to be documented, with a CMV DNA screening value of at least 910 units/mL on 2 consecutive tests separated by at least one day. Exclusion criteria included CMV disease with CNS involvement or retinitis, and resistant or refractory CMV infection due to inadequate adherence to the prior treatment regimen.

Studies
Median patient age was 57 years in the maribavir group (range, 19-79 years) and 54 years in the IAT group (range, 19-77 years); most were male (63% in the maribavir group and 55.6% in the IAT group), White (76% and 74.4%, respectively), and not Hispanic/Latino (83%); 40.1% had undergone HSCT (39.6% in the maribavir group and 41% in the IAT group) and 59.9% had undergone solid organ transplant (60.4% in the maribavir group and 59% in the IAT group). Median CMV DNA levels were 3377 units/mL in the maribavir group and 2869 units/mL in the IAT group; 65.1% and 72.6%, respectively, had levels categorized as "low" at baseline, while only 6% in each group had levels categorized as "high." Disease was categorized as refractory with resistance in 51.5% of patients in the maribavir group and in 59% in the IAT group. The most common recent anti-CMV agent prior to randomization was ganciclovir/valganciclovir in both groups (86.8% of patients in the maribavir group and 83.8% in the IAT group), followed by foscarnet (11.5% and 15.4%, respectively).
Intervention: Following stratification by transplant type (HSCT or solid organ transplant) and screening for CMV DNA levels (high: 91 000 units/mL or greater; intermediate: 9100 to less than 91000 units/mL; or low: less than 9100 units/mL), patients were randomized 2:1 to receive either maribavir 400 mg orally twice daily or IAT (ganciclovir, valganciclovir, foscarnet, or cidofovir as monotherapy or a combination regimen) for 8 weeks. After completion of the treatment phase, patients entered a 12-week follow-up phase. The most common IAT was foscarnet (41% of patients), followed by ganciclovir or valganciclovir (each used in 24% of patients); cidofovir was administered in 6 patients, the combination of foscarnet and valganciclovir was administered in 4 patients, and the combination of foscarnet and ganciclovir was administered in 3 patients. Median duration of study drug exposure was 57 days (range, 2-64 days) in the maribavir group and 34 days (range, 4-64 days) in the IAT group. A maribavir rescue arm was available for patients originally assigned IAT after at least 3 weeks of treatment and upon confirmation of meeting prespecified criteria. Patients who received maribavir rescue or alternative CMV treatment before the end of week 8 were considered nonresponders.  18 A phase 2, randomized, double-blind study of 120 HSCT or solid organ transplant recipients with CMV infection refractory or resistant to at least one antiviral agent evaluated maribavir 400, 800, and 1200 mg doses administered twice daily for up to 24 weeks. Undetectable CMV DNA was reached within 6 weeks of treatment initiation in 80 of 120 patients (67%; 95% CI, 57% to 75%), with rates of 70% for maribavir 400 mg, 63% for maribavir 800 mg, and 68% for maribavir 120 mg. 22 Another phase 2, randomized, open-label study of 161 HSCT or solid organ transplant recipients with CMV reactivation (but not refractory or resistant CMV) evaluated maribavir 400, 800, and 1200 mg doses administered twice daily compared with valganciclovir for up to 12 weeks. Undetectable CMV DNA in plasma was achieved within 3 weeks of treatment initiation in 62% of patients treated with maribavir and 56% treated with valganciclovir, and within 6 weeks in 79% and 67%, respectively. Serious adverse events and adverse events prompting discontinuation of treatment were more common in the maribavir group. 23 Experience in a small number of patients treated with maribavir under individual emergency investigational New Drug Applications has also been described, with 4 of 6 patients achieving undetectable CMV DNA levels within 6 weeks of starting maribavir therapy. 24 Results of a phase 2 CMV prophylaxis study suggested efficacy with maribavir compared with placebo in CMVseropositive allogeneic stem cell transplant recipients. However, in phase 3 CMV prophylaxis trials evaluating lowdose maribavir (100 mg twice daily) in HSCT and liver transplant recipients, maribavir did not demonstrate efficacy compared with placebo. [25][26][27] Limitations: SOLSTICE was an open-label study. No pediatric patients were enrolled. Patients were not stratified by refractory or resistant CMV; more patients with refractory-only CMV were included in the maribavir group.

Contraindications
The maribavir prescribing information states there are no contraindications to its use. 1 Though not stated in the product labeling, a potential contraindication is hypersensitivity to maribavir or any of its inactive ingredients (ie, FD&C Blue No. 1, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, titanium dioxide, talc). 1

Warnings and Precautions
Maribavir may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting CMV pUL97 kinase, which is required for the activation/phosphorylation of these antiviral agents. Coadministration of maribavir with ganciclovir or valganciclovir is not recommended. 1 Virologic failure due to resistance can occur during or after therapy with maribavir. Virologic relapse during the posttreatment period has generally occurred within 4 to 8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer crossresistance to ganciclovir and valganciclovir. If a patient relapses or is not responding to treatment, monitor CMV DNA levels and check for maribavir resistance. 1 Drug interactions may result in reduced therapeutic effect of maribavir or adverse reactions of concomitant drugs. Concomitant medication must be reviewed during therapy, and dosing recommendations must be followed to prevent or manage potential drug interactions (see Drug Interactions section). Maribavir is primarily metabolized by CYP3A4. Drugs that are strong inducers of CYP3A4 are expected to decrease maribavir concentrations and result in reduced virologic response. Coadministration with strong inducers should be avoided, except for select anticonvulsants for which dosing recommendations are available. 1 Maribavir has the potential to increase the concentrations of immunosuppressant drugs that are CYP3A4 and/or P-gp substrates (eg, tacrolimus, cyclosporine, sirolimus, everolimus) for which minimal concentration changes could lead to serious adverse events. Immunosuppressant drug levels should be monitored frequently during maribavir therapy, especially during initiation and after discontinuation of maribavir, and immunosuppressant doses should be adjusted as needed. 1,28 There are no adequate and well-controlled studies of maribavir use during pregnancy. In some animal reproduction studies, embryo-fetal survival was decreased at maribavir exposures less than those observed in humans at the recommended human dose. 1 Caution should be used when administering maribavir to a breastfeeding patient. No studies have been conducted to assess the presence of maribavir or its metabolites in human milk or their effects on breastfeeding infants or milk production. 1 Safety and effectiveness of maribavir have not been established in pediatric patients younger than 12 years. The recommended dosing regimen in pediatric patients 12 years and older and weighing at least 35 kg is the same as that for adults, based on evidence from controlled trials in adults and population pharmacokinetic modeling and simulation demonstrating that age and body weight had no clinically meaningful impact on plasma exposure to maribavir. Maribavir exposure is expected to be similar between adults and the approved pediatric population, and the course of CMV disease is similar between adults and pediatric patients, allowing extrapolation of data in adults to pediatric patients. 1

Adverse Reactions
The most common adverse events (incidence at least 10%) in patients treated with maribavir were taste disturbance, nausea, diarrhea, vomiting, and fatigue. See Table 2 for the incidence of adverse events in patients treated with maribavir compared with IAT (consisting of monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir). Taste disturbance occurred in 46% of patients treated with maribavir. Taste disturbance resolved during therapy in 37% of these patients (median duration, 43 days; range, 7-59 days). For the patients with ongoing taste disturbance after maribavir discontinuation, resolution occurred in 89%; median duration of symptoms after discontinuation was 6 days (range, 2-85 days). 1 Serious adverse events occurred in 38% of patients in the maribavir group and in 37% of the IAT group. The most common serious adverse events in both groups were infections, with CMV infection and disease being most common. A higher proportion of patients discontinued study medication due to an adverse event in the IAT group than in the maribavir group. The most common adverse events prompting discontinuation were neutropenia (9%) and acute kidney injury (5%) in the IAT group and dysgeusia, diarrhea, nausea, and recurrence of underlying disease (each reported at 1%) in the maribavir group. 1 Laboratory abnormalities, including reductions in neutrophils, hemoglobin, and platelets and increases in creatinine, occurred with a similar frequency in the maribavir and IAT groups. 1

Drug Interactions
Maribavir may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting CMV pUL97 kinase, which is required for the activation/phosphorylation of these antiviral agents. Coadministration of maribavir with ganciclovir or valganciclovir is not recommended. 1 Maribavir is a CYP3A4 substrate. Drugs that are strong inducers of CYP3A4 are expected to decrease maribavir  29 Maribavir is a weak inhibitor of CYP3A4 and an inhibitor of P-gp and BCRP. Coadministration of maribavir with drugs that are sensitive substrates of CYP3A, P-gp, and BCRP may result in a clinically relevant increase in plasma concentrations of these substrates. Table 3 summarizes clinically important drug interactions and monitoring and dosing recommendations. 1,28,30 Clinically significant drug interactions were not observed with ketoconazole, antacid, caffeine, S-warfarin, voriconazole, dextromethorphan, or midazolam. 1,[29][30][31] At clinically relevant concentrations, clinically significant interactions are not expected when maribavir is administered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, or 3A4; UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7; P-gp; BSEP; MATE1/2K; OAT1 or OAT3; OCT1 or OCT2; or OATP1B1 or OATP1B3. In a clinical drug-drug interaction cocktail study, coadministration with maribavir had no effect on substrates of CYP1A2, 2C9, 2C19, 2D6, and 3A4. 1,30,31

Recommended Monitoring
Patients should be carefully evaluated for potential drug interactions prior to initiating therapy. 1 Quantitative CMV DNA or RNA or pp65 antigenemia should be performed once weekly to assess virologic response to treatment. The same assay type and sample type (plasma or whole blood) should be used to assess virologic response over the course of CMV disease. 2 If a patient relapses or is not responding to treatment, monitor CMV DNA levels and check for maribavir resistance phenotypes. 1,16,17 A 1-log decline in CMV viral load is the anticipated outcome after at least 2 weeks of antiviral therapy. CMV infection is considered refractory if CMV DNA levels increase after at least 2 weeks of therapy. 2 CMV treatment guidelines recommend that complete blood count and serum creatinine be monitored once weekly during antiviral therapy. 2 Immunosuppressant drug levels should be monitored throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir. 1

Dosing
The recommended maribavir dosage is 400 mg (two 200 mg tablets) taken orally twice daily with or without food. 1 If coadministered with carbamazepine, the maribavir dose should be increased to 800 mg twice daily. 1 If coadministered with phenytoin or phenobarbital, the maribavir dose should be increased to 1200 mg twice daily. 1 No dosage adjustment is necessary in patients older than 65 years; in patients with mild, moderate, or severe renal impairment; or in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Administration of maribavir has not been studied in patients with end-stage renal disease, including patients on dialysis, or in patients with severe hepatic impairment. 1

Product Availability and Storage
Maribavir was approved by the FDA on November 23, 2021.18 Maribavir is available as 200 mg tablets in bottles of 28 and 56. 1 Store maribavir tablets at 20°C to 25°C (68°F-77°F); brief exposure to 15°C to 30°C (59°F-86°F) is permitted. 1

Drug Safety/REMS
No REMS is required for maribavir. 18

Conclusion
Maribavir, a benzimidazole antiviral, is indicated for the treatment of patients 12 years and older and weighing at least 35 kg with posttransplant CMV infection/disease that is refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir (with or without genotypic resistance). Maribavir offers an oral treatment alternative with a unique mechanism of antiviral activity; however, cross-resistance may occur, and phenotyping is advised for patients who do not respond or who relapse during treatment. Screening for potential drug interactions is important before initiating therapy. The most common adverse event associated with maribavir is taste disturbance; neutropenia and renal toxicity occurred more frequently with comparator agents.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.