Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open‐Label, Randomized, Crossover Studies

The effect of food composition, tablet crushing, and antacid coadministration on maribavir pharmacokinetics was assessed in 2 Phase 1 studies in healthy adults. In the first, a single maribavir 400‐mg dose was administered under fasting conditions, with a low‐fat/low‐calorie or a high‐fat/high‐calorie meal. In the second, a single maribavir 100‐mg dose was administered under fasting conditions, as a crushed tablet, or as a whole tablet alone or with an antacid. The 90% confidence intervals of the geometric mean ratios were within 80%‐125% for area under the concentration‐time curve (AUC), but not for maximum plasma concentration (Cmax) for low‐fat/low‐calorie and high‐fat/high‐calorie meals versus fasting or for whole tablet with antacid versus whole tablet alone. The 90% confidence intervals of the geometric mean ratios for AUC and Cmax were within 80%‐125% for crushed versus whole tablet. Maribavir median time to Cmax value in plasma under fed conditions was delayed versus fasting conditions, but there was no statistical difference for crushed versus whole tablet or with versus without antacid. As the antiviral efficacy of maribavir is driven by AUC but not Cmax, findings suggest that maribavir can be administered with food or antacids or as a crushed tablet.

adult patients (and pediatric patients in the United States) with posttransplant CMV infection/disease, with or without resistance, that is refractory (or intolerant in Australia) to treatment. 5,6Following oral administration, maribavir is rapidly absorbed, achieves peak plasma concentrations at 1-3 hours after dosing, and demonstrates dose-proportional pharmacokinetics (PK) up to 1600 mg. 6The maribavir indication was expanded in the United States to include adolescents aged 12 years and older weighing 35 kg or greater after population PK modeling and simulations to predict PK dosing in adolescents indicated similar maribavir disposition, efficacy, and safety profiles to those in adult patients with CMV. 7 It is metabolized primarily in the liver through cytochrome P450 (CYP) 3A4 (70%-85% of hepatic microsomal CYP pathways) and CYP1A2 (15%-30%) pathways, with the formation of the primary metabolite VP44469, which is pharmacologically inactive against CMV. 6,8,9ccordingly, coadministration with oral ketoconazole, a strong inhibitor of CYP3A4, moderately reduced the oral clearance of maribavir by 35% and VP44469 by 13% in healthy adults, whereas coadministration with rifampin, a potent CYP3A4 inducer, increased oral clearance by 2.5-fold. 10,11A physiologically based PK model also predicted a clinically significant impact of strong or moderate CYP3A4 inducers but not CYP3A4 inhibitors on maribavir, suggesting that no dose adjustment of maribavir is necessary when coadministered with CYP3A4 inhibitors, whereas a maribavir dosing increase in line with local regulations may be required when coadministered with CYP3A4 inducers. 10,11Maribavir is also metabolized by hepatic uridine diphosphate-glucuronosyltransferases (minor clearance pathway). 12The structures of maribavir and VP44469 have been previously published. 13dditional maribavir studies have shown that its invitro permeability across a cultured Caco-2 cell monolayer is considered high (5.9 × 10 -6 cm/s in an apical-tobasolateral direction and 33.7 × 10 -6 in a basolateral-toapical direction). 13Its solubility is pH dependent, with a profile of 34 mg/mL at pH 3, 0.67 mg/mL at pH 6.6, and 0.8 mg/mL in water. 13In a study of maribavir PK in healthy Japanese and matched non-Hispanic White participants, maribavir was found to have higher systemic exposure and similar safety outcomes in Japanese versus White participants; however, this was not considered clinically important, and the same maribavir dose could be considered for Japanese populations as is approved in White populations. 14Studies of maribavir PK in participants with mild-to-severe renal impairment or moderate hepatic impairment have also suggested that no dose adjustment is required for such patients. 15,16In addition, maribavir does not prolong the cardiac QT interval to any clinically relevant extent at 3 times the recommended dose in healthy participants, nor does it result in any clinically meaningful changes in heart rate or systolic blood pressure. 17he PK of orally administered drugs can be affected by several factors, including formulation and coadministration with food or other drugs.Many transplant recipients have specific caloric dietary requirements.In parallel with increased obesity prevalence, there has been an increase in patients with obesity requiring transplants. 18Furthermore, immunosuppressive drugs used to prevent transplant rejection can stimulate appetite and cause weight gain. 18Therefore, some transplant recipients may require a low-calorie (LC) diet.Other transplant recipients, such as those with a pancreatic transplant, are more likely to lose weight posttransplant. 18Patients who have undergone HSCT for hematological malignancies may have weight loss due to HSCT nutrition-related adverse events (AEs). 19uch patients may strive for a high-calorie (HC) diet.
Heart and/or lung transplant recipients with dysphagia (ie, difficulty in swallowing) 20 may need to have medications administered as crushed tablets or by nasogastric or orogastric tube.Transplant recipients who experience gastric disturbances in the postoperative period may receive antacids.The solubility of maribavir increases with decreasing pH, 13 and changes in the stomach pH with antacids can potentially affect maribavir bioavailability, as it is administered orally.Neither the PK of maribavir administered with high-or low-calorie meals nor the effects of crushing the tablet and antacid coadministration on maribavir PK have been reported previously in a peer-reviewed journal.
Given the importance of understanding whether the PK of maribavir may be affected by the different diets of transplant recipients, a food effect (FE) study (NCT05382104) was undertaken.The key objective of this study was to determine the relative bioavailability of a single oral dose of 400-mg maribavir commercial tablet formulation administered with a low-fat (LF)/LC meal or a high-fat (HF)/HC meal, versus administration under fasting conditions.
To determine the impact of crushing tablets or antacid coadministration on oral absorption of maribavir, a crushed tablet coadministered with antacid (CT/CA) study was conducted.The key objectives of this study were to determine the relative bioavailability of a single dose of 100-mg maribavir administered as a crushed versus a whole tablet, and the effect of concurrent administration of an antacid containing aluminum and magnesium on the PK of a single dose of 100-mg maribavir administered as a whole tablet.

Study Designs
Both the FE and CT/CA studies were Phase 1 singlecenter, open-label, randomized, single-dose, 3-period, multiple sequence, crossover studies in healthy adult participants (Figure S1 and Table S1).The For the FE study, maribavir as a single 400-mg dose (2 × 200-mg tablets) was administered orally to each participant under 3 treatment conditions (Treatment A, fasting; Treatment B, LF/LC meal; Treatment C, HF/HC meal), within 3 treatment periods.The LF/LC meal comprised 400-500 kcal in total (27% protein, 47% carbohydrate, and 25% fat; eg, breakfast: 8 oz of 1% fat milk, 1 boiled egg, and 1 packet of flavored instant oatmeal made with water).The HF/HC meal comprised 800-1000 kcal in total (19% protein, 31% carbohydrate, and 50% fat; eg, breakfast: 8 oz of whole milk, 2 eggs fried in butter, 2 bacon strips, 2 slices of toast with butter, and 4 oz of hash brown potatoes).Each treatment period was 2 days long, and after Treatment Periods 1 and 2, there was a 3-day (72-hours) washout period.Before maribavir dosing, all participants fasted overnight for 10 hours or longer.For Treatments B and C, the meal was provided and consumed within 30 minutes before maribavir dosing.All participants fasted for 4 hours after dosing.Water (except that provided with each maribavir dose) was restricted 1 hour before and 1 hour after dosing but was allowed ad libitum at all other times.Maribavir was administered at approximately the same time in each treatment period.Participants were randomized to one of 6 treatment sequences: ABC, ACB, BAC, BCA, CAB, or CBA (Figure S1).
For the CT/CA study, maribavir as a single 100-mg dose (1 × 100-mg tablet) was administered orally within 3 treatment periods under 3 different treatment conditions.This 100-mg dose was based on completed Phase 3 CMV prophylaxis studies.Treatments were administered in the following manner under fasting conditions: Treatment A as a crushed tablet diluted with 60 mL of water (see Supplemental Methods for further details), Treatment B as a whole tablet with 240 mL of water, and Treatment C as a whole tablet with 240 mL of water, 10 minutes after administration of a 20-mL antacid suspension comprising aluminum hydroxide and magnesium hydroxide (each 200 mg/5 mL).All participants began overnight fasting at 11:00 p.m., were administered maribavir in the morning, and fasted for a further 4 hours after dosing.Treatment periods were 3 days with a minimum 7-day washout period after Treatment Periods 1 and 2. Participants were randomized to one of 3 treatment sequences: ABC, BCA, or CAB (Figure S1).

Study Populations
Both the FE and CT/CA studies were conducted in healthy volunteers, who had provided informed written consent to participate.The determination of health status was based on medical history, a physical examination, clinical laboratory test results, vital signs, and a 12-lead electrocardiogram (ECG).Key inclusion and exclusion criteria were broadly similar for both studies, as shown in Table S1.

Study Assessments
Blood samples for PK assessments were taken before the maribavir dose and up to either 24 hours (CT/CA study) or 36 hours (FE study) after the maribavir dose for Treatment Periods 1, 2, and 3 (Table S1).
Safety and tolerability were assessed throughout the studies by acquiring data on treatment-emergent AEs (TEAEs), AEs of special interest, vital signs, laboratory parameters, ECGs, and physical examinations.

Bioanalytical Methodology
For the FE study, plasma maribavir concentrations were determined by a validated analytical method using high-performance liquid chromatography (HPLC) equipped with a triple quadrupole mass spectrometer.Plasma samples were processed by liquid-liquid extraction.The validated calibration range for maribavir was 0.2-100 μg/mL.The internal standard for the assay was d7-maribavir.The samples were separated by an Advanced Chromatography Technologies Ltd. (Aberdeen, UK) ACE C18 column (ACE-121-0502, 50 × 2.1 mm, 5 μm, 100Å) at ambient temperature.The mobile phase A (MPA) was 4:6:90:0.1 ACN:MeOH:H2O:HCOOH, and the mobile phase B (MPB) was 40:60:0.1 ACN:MeOH:HCOOH.A gradient HPLC elution method was used.The gradient started from 63% MPA% with 0.4 mL/min flow rate for 1 minute; MPA% then was decreased to 10% over 0.5 minute and maintained for another 0.5 minute with 1.0 mL/min flow rate; MPA% was then returned to 63% in 0.1 minute with 0.4 mL/min flow rate.The total run time was 2.1 minute.The mass spectrometer was operated in electrospray ionization negative iron mode, monitoring transitions 374.0-242.0m/z (for maribavir) and 381.0-249.0m/z (for the internal standard).The intraday and interday coefficient of variation (CV%) ranged from 0.6% to 5.1% and 2.4% to 5.8%, respectively.The intraday and interday relative error (RE%) ranged from −7.5% to 7.5% and −3.1% to 1.5%, respectively.
For the CT/CA study, plasma maribavir and VP44469 concentrations were quantified using a validated tandem liquid chromatography and mass spectrometric detection method.Plasma samples were processed by solid phase extraction.The validated calibration range for maribavir and VP44469 was 0.2-40 μg/mL.The internal standard for the assay, for both plasma maribavir and VP44469, was VP20510.The samples were separated by Phenomenex Luna Synergi Hydro-RP column (4 μm, 2 mm × 50 mm).An HPLC elution gradient started with 20% MPB% for 1.5 min; MPB% was increased to 100% over 0.5 minutes and maintained at 100% for another 1 minute; MPA% was returned to 20% in 0.1 minute.The total run time was 3.1 minutes.The flow rate was 0.5 mL/min.The mobile phase A was water:formic acid/100:0.l(v:v), and the mobile phase B was methanol.The mass spectrometer was operated in atmospheric pressure chemical ionization negative iron mode, monitoring transitions 374-242 m/z (for maribavir), 332-200 m/z (for VP44469), and 400-268 m/z (for the internal standard).The intrarun precision CV% and accuracy RE% for maribavir ranged from 1.9% to 2.5% and −1.7% to 5.7%.The intrarun precision CV% and accuracy RE% for VP44469 ranged from 2.1% to 4.5% and −2.7% to 4.4%.
The lower limit of quantification for maribavir (FE and CT/CA study) and for the metabolite (CT/CA study) was 0.2 μg/mL.

Study End Points
PK end points for the FE and CT/CA studies are listed in Table S1.Safety end points for both studies included incidence, severity, seriousness (FE study only) and causality of TEAEs, and changes from baseline in vital signs, laboratory parameters, ECGs, and physical examinations.

Statistical Analyses
PK and safety assessments were summarized using descriptive statistics.For demographics and safety, continuous variables were summarized using n, mean, standard deviation, median, and range, and categorical data were reported as frequency and percentages.Data analyses for PK and safety were conducted using SAS Version 9.4 for the FE study and SAS Version 8 (SAS Institute) for the CT/CA study.
Study Analysis Populations.Participants who met the following criteria were included in the noncompartmental PK analysis in both studies: for the FE study, all participants who received at least 1 dose of maribavir, did not vomit or have diarrhea within 4 hours dosing, and had 5 or more postdose time points with evaluable postdose maribavir concentration values; for the CT/CA study, all participants who completed any dosing periods and had plasma samples assayed.For both studies, participants who received at least 1 dose of maribavir were included in the safety analyses.
Pharmacokinetic Analysis: FE Study.The arithmetic mean profiles of the plasma maribavir concentrationtime data were plotted by treatment on linear and semilog scales using nominal PK sampling times.The PK parameters were calculated from concentrationtime profiles using noncompartmental analysis methods and summarized by treatment using descriptive statistics (n, mean, standard deviation, CV%, median, range, geometric mean, and geometric CV%).
FE estimates were derived from a linear mixedeffects model applied to natural logarithmictransformed maximum measured plasma concentration (C max ), and the area under the concentration-time curve (AUC), from time 0 to the last quantifiable concentration (AUC last ) or infinity (AUC ∞ ) with treatment, period, and sequence as fixed effects, and participant within sequence as a random effect.The degrees of freedom were estimated using the Kenward-Roger approximation. 21Point estimates and their associated 90% CIs were constructed for differences between Treatment B (LF/LC meal) minus Treatment A (fasting), and Treatment C (HF/HC meal) minus Treatment A (fasting).Point estimates and their associated 90% CIs were then back-transformed to provide point estimates and 90% CIs for the GMRs of Treatment B versus A and Treatment C versus A. An absence of FE was defined as the 90% CIs for the test-to-treatment ratios for AUC last , AUC ∞ , and C max being fully contained within the acceptance range of 80%-125%.
Analysis of time to C max (t max ) and lag time to first quantifiable concentration in plasma (t lag ) was performed by nonparametric Wilcoxon signed-rank test; median difference (treatment effect) and corresponding 90% CI were estimated using the Hodges-Lehmann method.3][24] Note that t max and t lag parameters were not natural logarithmic-transformed. Treatment comparisons were as per linear mixed-effects model applied to AUC last and AUC ∞ end points.
Pharmacokinetic Analysis: CT/CA Study.A linear mixedeffects model for a 3-period crossover design was applied to all natural logarithmic-transformed PK parameters, apart from t max , with treatment, sequence, and period as fixed effects.A compound variancecovariance matrix was assumed for the repeated structure of participant within sequence.The degrees of freedom were estimated using Satterthwaite's approximation.The Satterthwaite approximation and the Kenward-Roger approximation employed in the FE study exhibit remarkably similar performance and are deemed highly robust, particularly for smaller sample sizes. 21stimates of the difference between the treatment least-squares means and their standard errors were obtained for the PK end points indicated in Table S1, except for t max .The results were back-transformed to provide point estimates and 90% CIs for the GMRs of Treatment A relative to reference Treatment B, and of Treatment C relative to reference Treatment B. For all parameters, except t max , the treatments were considered as bioequivalent with respect to a parameter if the 90% CI was fully contained within the acceptance range of 80%-125%.
The ranked values of t max were analyzed with the ANOVA model.Statistical tests for t max were at the 0.05 level of significance.Treatment comparisons were as per other PK end points.

Sample Size Calculations
For the FE study, assuming an intraparticipant CV of 0.166 and 0.218, respectively, for AUC ∞ and C max , the point estimate of GMR between treatments at 0.90, and the 90% CI of the GMR being within the range of 80%-125%, a total of 24 participants were required to complete all treatment periods of the study, based on sample size calculation.To account for possible dropouts, a total of 30 participants was planned.
For the CT/CA study, sample size calculations were based on using a 2-sided paired t-test, with the type I error rate set to 5% and the power set to 80%.Assuming an intraparticipant CV for AUC of 30%, a total of 13 participants was required to detect a 25% increase in AUC of maribavir.Hence, a target enrollment of 15 participants was sufficient to provide 13 participants who ultimately completed the study.

Patient Disposition and Baseline Demographics
FE Study.In total, 31 participants were randomized to one of 6 treatment sequences.Their mean age was 35.2 years, and 21 (68%) were men.Demographics and other characteristics of the participants at baseline are shown in Table S2.Thirty participants completed the study.One participant, who was randomized to sequence ACB, was withdrawn from the study on Day 3 of Treatment Period 2, due to a positive COVID-19 test.This participant was included in the PK and safety analyses for the first 2 treatment periods (Treatment A and Treatment C) but was missing for Treatment Period 3 (Treatment B).A replacement participant was dosed with the same sequence and completed all 3 periods of the study.One participant, randomized to sequence ACB, was excluded from the PK analysis, as for all time points following all treatments, the participant had postdose maribavir plasma concentrations below the level of quantification.
CT/CA Study.In total, 15 participants were randomized to one of 3 treatment sequences, completed the study, and were included in the PK analysis.The mean age of participants was 32 years, and 8 (53%) were men.Participant demographics and other characteristics at baseline are shown in Table S2.

Pharmacokinetics
FE Study.Overall, mean maribavir plasma concentrations were comparable for fasting conditions (Treatment A), following an LF/LC meal (Treatment B), and following an HF/HC meal (Treatment C) from 3 hours after dosing through to 36 hours after dosing.As shown in the linear mean plasma maribavir concentration-time curve in Figure 1, peak mean maribavir C max was highest under fasting conditions at 18.4 μg/mL (reached at 1 hour after dosing) versus 13.8 μg/mL (at 3 hours after dosing) following an LF/LC meal and 13.0 μg/mL (at 3 hours after dosing) following an HF/HC meal.The semilog mean plasma maribavir concentrationtime curve is shown in Figure S2.
PK parameters following a single oral dose of maribavir 400 mg for Treatments A, B, and C are summarized in Table 1.The geometric least squares mean plasma maribavir C max , AUC last , and AUC ∞ were similar for both meal conditions (Table 2).The GMRs for C max , AUC last , and AUC ∞ for maribavir in plasma after a LF/LC meal (Treatment B) versus under fasting conditions (Treatment A) were 76.6%, 84.1%, and 84.7%, respectively, after an HF/HC meal (Treatment C) versus under fasting conditions (Treatment A) were 71.6%, 87.4%, and 87.8%, respectively.For both food conditions the 90% CIs of the GMRs were within the 80%-125% reference interval for AUC last and AUC ∞ but not for C max for maribavir in plasma (Table 2).The projected trough concentrations at 12 hours following twice-daily dosing of maribavir and concentration at nominally 12 hours after dosing, which are indicators for antiviral efficacy, were also numerically similar among the 3 conditions (Table 1).
The median t max values for maribavir in plasma were similar following an LF/LC meal (Treatment B) and an HF/HC meal (Treatment C) at approximately 3 hours after dosing but were delayed compared with a median t max value of approximately 1 hour under fasting conditions (Treatment A).Nonparametric analysis of t max and t lag for plasma maribavir concentrations suggested significant median differences for both LF/LC and HF/HC meals (Treatments B and C) versus fasting  CT/CA Study.Mean plasma concentrations of maribavir were nearly identical following oral administration of maribavir for whole or crushed tablets (Figure 2; Figure S3).The 90% CI of the GMRs for the crushed tablet relative to the whole tablet was within the equiv-alence interval of 80%-125% for all PK parameters, except t max (Table 3).For t max , the test for treatment effects was not statistically significant (P = .142).None of the tests for sequence or period effects were statistically significant at the 0.05 level (Table 3).
Mean plasma maribavir concentrations following administration of a maribavir whole tablet with antacid tended to be slightly lower than following administration of a maribavir whole tablet alone (Figure 2).For maribavir, the C max was approximately 16% lower for the whole tablet with antacid relative to the whole tablet alone, and the 90% CI of the GMR was not within AUC, area under the concentration-time curve; AUC 12h , AUC, from time 0 to 12 hours after dosing; AUC ∞ , AUC from time 0 to infinity; AUC last , AUC from time 0 to the last quantifiable concentration; C 12h , concentration at nominally 12 hours after dosing; C τ , projected trough concentration at 12 hours following twice-daily dosing of maribavir; C max , maximum measured plasma concentration; CL/F, apparent plasma clearance; FE, food effect; GCV, geometric coefficient of variation; GM, geometric mean; PK, pharmacokinetic; SD, standard deviation; t max , time to C max ; t 1 2 z , terminal disposition phase half-life; t lag , lag time to first quantifiable concentration in plasma.a n = 28 for these parameters.
the 80%-125% reference interval (Table 4).AUC values were approximately 12% lower when the whole tablet was coadministered with antacid, but were considered equivalent because the 90% CIs of GMRs were within the equivalence interval (Table 4).The mean half-life was approximately 4 hours for maribavir with no significant treatment difference.For t max , the test for treatment effects was not statistically significant (P = .142).PK parameter data for the main metabolite of maribavir, VP44469, are provided in Figure S4 and Tables S3  and S4.

Safety/Tolerability
No participants experienced serious AEs.There were no treatment-related trends noted in vital signs, ECGs, or laboratory data in either study.One participant discontinued from the FE study due to a TEAE of COVID-19.No participants discontinued from the CT/CA study.Safety data from both studies are summarized in Table S5.
In the FE study, the proportion of participants who experienced TEAEs was similar under fasting conditions (n = 11; 35%) or following an LF/LC meal (n = 10; 33%) but were lower with an HF/HC meal (n = 7; 23%).In the CT/CA study, the proportion of participants with TEAEs was 40% (n = 6) with the crushed tablet, 47% (n = 7) with the whole tablet, and 53% (n = 8) with coadministration with antacid.

Discussion
We conducted 2 single-dose Phase 1 studies (FE and CT/CA studies) of maribavir in healthy participants to gain an understanding of how the PK of maribavir is influenced by food intake, crushing the tablet, and coadministration with antacid.Results from the FE study indicate that fasting or fed conditions and meal compositions (LF/LC and HF/HC) did not have a relevant effect on overall exposure to maribavir.This was demonstrated by 90% CIs of the GMRs for AUCs within the bioequivalence interval for fed versus fasted conditions, and the comparability of AUCs, concentration at nominally 12 hours after dosing, and projected trough concentrations at 12 hours values after an LF/LC meal or an HF/HC meal to those under fasted conditions.These data suggest that maribavir can be administered with an LF/LC or HF/HC meal.As AUC has previously been reported to be the best predictor of efficacy for other anti-CMV drugs, 25 the slightly reduced C max at fed state or with antacid, as well as slightly delayed absorption under fed condition, compared with the fasted state, would be expected to have little clinical significance on maribavir antiviral activity.Mechanistically, the slightly reduced C max and prolonged absorption of maribavir at fed states, regardless of the type of meal, likely was a result of increased pH in the stomach with the presence of food and decreased solubility.The observed food effects on maribavir PK were consistent with other compounds with similar physicochemical properties. 26Although maribavir peak concentrations were slightly lower for HF/HC meals than for LF/LC meals, the composition of the meals themselves did not affect overall maribavir exposure or time to peak exposure.Therefore, the type of meal consumed could be expected to have little relevance on the PK of maribavir.
Results from the CT/CA study showed that the whole tablet and crushed tablet of maribavir were  bioequivalent, indicating that maribavir absorption was unaffected by crushing the tablet.Concomitant administration of maribavir with aluminum-and magnesiumcontaining antacid had no clinically meaningful effect on maribavir absorption and bioavailability.These results add to data from a population PK analysis of transplant recipients in which the bioavailability of maribavir was not affected by proton pump inhibitors or histamine 2 blockers. 27Taken together, these data suggest that maribavir absorption and bioavailability may not be affected by increased gastric pH resulting from antacids, proton pump inhibitors, or histamine 2 blockers.This finding is of clinical relevance given that patients undergoing transplant surgery frequently experience gastric disturbances in the postoperative period and thus may receive these products.
There were no new safety signals raised in these 2 Phase 1 studies.Dysgeusia was the most frequently reported TEAE, which is consistent with other Phase 1, 2, and 3 clinical studies conducted with maribavir. 6,28,29ne limitation of these studies was that the study populations included healthy individuals and not transplant recipients.However, steady-state exposure of maribavir 400 mg twice daily has been shown to be similar between transplant recipients and healthy individuals, with C max and AUC over the dosing interval being 17.2 μg/mL and 128 μg•h/mL in transplant recipients and 17.6 μg/mL and 91.5 μg•h/mL in healthy individuals. 9,30These data provide support that the FE and CT/CA characterization of maribavir in healthy participants is relevant to transplant recipients under similar conditions of food intake, crushed tablets, and coadministration with antacids.Furthermore, different doses were used across the 2 studies (100 mg in CT/CA based on evaluated dosing in Phase 3 prophylaxis clinical trials versus 400 mg based on current recommended dosing for maribavir treatment).However, previous data demonstrating dose proportionality of maribavir PK exposure within a wide range of dosage (50-1600 mg) suggest that the results based on a 100-mg dose can be extrapolated to 400 mg. 6The 2 studies also employed different sample size calculations.The sample size calculation for the FE study relied on a CI precision and was not conducted with considerations of power.In contrast, the sample size calculation for the CT/CA study was based on a 2-sided paired t-test with 80% power and 5% type I error.The calculation relies on 2 main assumptions: the absence of a period effect and the absence of a treatment-by-period interaction.These assumptions should be tested using the methods outlined in Pocock. 31It is important to note, however, that the CT/CA study was conducted by the previous sponsor and the authors are unable to confirm whether these assumptions were tested, as this information is no longer available.According to statistical analysis results, the period effect is not deemed significant to AUC.Unfortunately, there is no documentation of testing for the treatment-by-period interaction.While the authors acknowledge this as a limitation, its impact on the interpretation of results is considered limited, as only the interaction was not tested.
In conclusion, findings from these 2 Phase 1 studies suggest that a maribavir tablet can be administered without dose adjustment with food or antacids, or as a crushed tablet.
FE study was conducted by Celerion (Lincoln, NE [Institutional Review Board (IRB): Advarra, Columbia, MD] and the CT/CA study at Prism Research [St.Paul, MN [IRB: RCRC IRB, West Austin, TX]).The studies were conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonisation Tripartite Guideline for Good Clinical Practice.

Figure 2 .
Figure 2. Mean maribavir plasma concentration-time on a linear scale following a single oral dose of maribavir 100 mg administered crushed (Treatment A), administered whole (Treatment B), and coadministered whole with an antacid (Treatment C) (CT/CA study).CT/CA, crushed tablet/coadministration with antacid.

Table 1 .
Summary of PK Parameters Following a Single Oral Dose of Maribavir 400 mg Under Fasting Conditions (Treatment A), Following a Low-Fat/Low-Calorie Meal (Treatment B) and Following a High-Fat/High-Calorie Meal (Treatment C) (FE Study)

Table 2 .
Assessment of Food Effect on Maribavir PK Parameters Following a Low-Fat/Low-Calorie Meal (Treatment B) Versus Under Fasting Conditions (Treatment A) and Following a High-Fat/High-Calorie Meal (Treatment C) Versus Under Fasting Conditions (Treatment A) (FE Study) One patient did not have 5 or more postdose time points with evaluable postdose maribavir concentration values following all treatments that enable noncompartmental analysis, and thus was excluded from the PK set, concentration summary statistics, and PK analysis.b One patient, was dropped from the study in period 2 prior to Treatment B due to a positive COVID-19 result.

Table 3 .
Summary of Maribavir PK Parameters and Ratios of Geometric Means (90% CI) for Crushed Tablet (Treatment A) Versus Whole Tablet (Treatment B) Administered Under Fasting Conditions (CT/CA Study)Treatment A: maribavir 100-mg tablet crushed and administered as a single oral dose under fasted conditions; Treatment B: maribavir 100-mg tablet administered as a single oral dose under fasted conditions.ANOVA,analysis of variance;AUC,area under the concentration-time curve;AUC 0-t ,AUC from time 0 to the time of the last measurable concentration; AUC ∞ , AUC from time 0 to infinity; CI, confidence interval; C max , maximum measured plasma concentration; CL/F, apparent plasma clearance; CT/CA, crushed tablet/coadministration with antacid;GMR,geometric mean ratio;PK,pharmacokinetic;SD,standard deviation;t max ,time to maximum measured plasma concentration; t 1 Ranked values of t max were analyzed with the ANOVA model (P = .142).

Table 4 .
Summary of Maribavir PK Parameters and Ratios of Geometric Means (90% CI) for Whole Tablet Alone (Treatment B) Versus Coadministration with Antacid (Treatment C) Under Fasting Conditions (CT/CA Study) Ranked values of t max were analyzed with the ANOVA model (P = .142).
Treatment B: maribavir 100-mg tablet administered as a single oral dose under fasted conditions; Treatment C: maribavir 100-mg tablet administered as a single oral dose under fasted conditions 10 minutes after antacid -a 20-mL oral suspension of aluminum hydroxide and magnesium hydroxide.ANOVA,analysis of variance;AUC,area under the concentration-time curve;AUC 0-t ,AUC from time 0 to the time of the last measurable concentration; AUC ∞ , AUC from time 0 to infinity; CI, confidence interval; C max , maximum measured plasma concentration; CL/F, apparent plasma clearance; CT/CA, crushed tablet/coadministration with antacid;GMR,geometric mean ratio;PK,pharmacokinetic;SD,standard deviation;t max ,time to a