A Multipart Phase 1 Study to Assess Safety and Pharmacokinetics of Ibuzatrelvir in Healthy Participants and Dose Selection for a Dose‐Ranging Study

ABSTRACT

COVID‐19 continues to be a threat to global health and a burden on healthcare systems. There is an ongoing need for COVID‐19 antiviral therapies that are safe and effective across broad patient populations. Ibuzatrelvir is a potent, selective inhibitor of the SARS‐CoV‐2 main protease and demonstrated favorable properties for clinical development. We report safety, tolerability, and pharmacokinetic data for ibuzatrelvir from a phase 1 first‐in‐human study in healthy adults. Study parts evaluated ibuzatrelvir as single or multiple ascending doses, including analysis of participants in fasted and fed states, pharmacokinetics in Chinese and Japanese participants, relative bioavailability of crystalline tablet formulations, and dose selection for patients with COVID‐19. Oral administration of ibuzatrelvir led to rapid absorption after all doses, and steady‐state plasma concentrations were achieved by Day 2 for all doses. High‐fat meals decreased maximum plasma concentration and area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration, but the concentration at 12 h postdose was comparable when administered without food. Exposures of ibuzatrelvir were similar between Chinese and non‐Chinese participants, as well as between Japanese and non‐Japanese participants. Ibuzatrelvir was safe and well‐tolerated, with no serious or severe adverse events reported and no participants discontinuing. In conclusion, pharmacokinetics and safety were established for single‐agent oral ibuzatrelvir, supporting the design and dose selection for further phase 2 trials and the continued development of ibuzatrelvir (NCT05580003).

Study Highlights

What Is the Current Knowledge on the Topic?

Ibuzatrelvir has shown potent antiviral activity against multiple SARS‐CoV‐2 variants, has low potential to affect the pharmacokinetics (PK) of coadministered drugs, and is more metabolically stable than nirmatrelvir, demonstrating its potential as a monotherapeutic agent for COVID‐19.

What Question Did This Study Address?

This first‐in‐human phase I study evaluated the safety, tolerability, and PK of ibuzatrelvir after single and multiple ascending doses in healthy adults, the PK in Chinese and Japanese participants, as well as the relative bioavailability of crystalline and spray‐dried dispersion tablet formulations, and dose selection for a dose‐ranging study in patients with COVID‐19.

What Does This Study Add to Our Knowledge?

In healthy adults, ibuzatrelvir was rapidly absorbed, with comparable exposures across Japanese and Chinese participants, and was safe and well‐tolerated after single or multiple doses.

How Might This Change Clinical Pharmacology or Translational Science?

Results support the continued clinical development of ibuzatrelvir as a potential monotherapy for COVID‐19.

1. Introduction

In May of 2023, the World Health Organization declared that COVID‐19 would remain a global health threat with ongoing waves of new variants, cases, and deaths [1]. Consistent with this warning, new variants have emerged over time that evade the immune response [2, 3], causing symptomatic disease and a continuing burden of COVID‐19 on global healthcare systems [4, 5].

Nirmatrelvir/ritonavir (NMV/r; Paxlovid; Pfizer Inc., New York, NY, USA) [6, 7], remdesivir (Veklury; Gilead Sciences Inc., Foster City, CA, USA) [8], and molnupiravir (Lagevrio; Merck Sharp & Dohme LLC, Rahway, NJ, USA) [9] have been approved by the US Food and Drug Administration or Emergency Use Authorization for the treatment of mild to moderate COVID‐19 in individuals at high risk of progressing to severe disease [6, 7, 8, 9]. National Institutes of Health guidelines for the therapeutic management of nonhospitalized adults with mild to moderate COVID‐19 specify NMV/r as preferred, followed by remdesivir, listing molnupiravir as an alternative when the other treatments are not available or clinically appropriate [10]. However, there are some challenges surrounding the use of both preferred therapies. Remdesivir must be administered daily by intravenous infusion for 3 days, limiting its use to healthcare settings [8]. NMV/r is highly effective but underused, in large part because of the potential for drug–drug interactions (DDIs) between the pharmacokinetic (PK) enhancer ritonavir and other coadministered medications [7, 11, 12, 13]. Because of these challenges, there remains a need for additional COVID‐19 antiviral therapies that are safe and effective across a broad patient population.

Like nirmatrelvir, ibuzatrelvir is a potent, selective inhibitor of the SARS‐CoV‐2 main protease (M^pro) that has demonstrated favorable properties for clinical development based on pre‐clinical assessments [14]. Because M^pro is essential for SARS‐CoV‐2 replication and has no known close human analogs, M^pro inhibitors are particularly appealing as antiviral therapy candidates [15]. Ibuzatrelvir showed potent antiviral activity against SARS‐CoV‐2 across multiple cell culture types and SARS‐CoV‐2 variants, including the Omicron variant [14]. In rats and monkeys, ibuzatrelvir was rapidly absorbed after oral dosing and achieved high systemic concentrations. Metabolism of ibuzatrelvir was predominantly mediated by cytochrome P450 (CYP) 3A4 in human liver microsomes in vitro studies [14]. Ibuzatrelvir has low potential to affect the PK of coadministered drugs and is more metabolically stable than nirmatrelvir, obviating the need for PK enhancement [14, 16].

Here, we present the safety, tolerability, and PK of ibuzatrelvir after single ascending doses (SAD) and multiple ascending doses (MAD) in healthy adults, PK in Chinese and Japanese participants, as well as the relative bioavailability of crystalline tablet formulations, and dose selection for a dose‐ranging study in COVID‐19 patients.

2. Materials and Methods

2.1. Study Overview and Participants

This was a 6‐part, phase 1, first‐in‐human study (NCT05580003) conducted at 2 sites in Belgium and the United States, evaluating the safety, tolerability, and PK of ibuzatrelvir in healthy adults. Parts 1 and 2 were randomized, double‐blind, placebo‐controlled studies that evaluated the safety, tolerability, and PK of SAD (Part 1) and MAD (Part 2) of ibuzatrelvir. Part 2 also included a Chinese cohort. Part 3 was an open‐label crossover study to evaluate the relative bioavailabilities of different ibuzatrelvir formulations (spray‐dried dispersion [SDD] and crystalline tablets) vs. those of SDD suspension, which was used in all other parts of this study. The details are included in the Supporting Information.

Part 5 evaluated DDI with midazolam, which has been reported separately [16]. The DDI (Part 5) study design allowed comparative analysis of PK between Japanese and non‐Japanese participants, which is reported here. Results from Parts 4 and 6, which evaluated the mass‐balance and QT prolongation potential of ibuzatrelvir, respectively, will be reported separately.

Across study parts, healthy adults aged 18 to 60 years were eligible for inclusion. Inclusion in the optional MAD Chinese cohort required being born in mainland China to parents of Chinese descent. Inclusion in the Part 5 Japanese cohort required having 4 biological Japanese grandparents who were born in Japan. Individuals were excluded from the study if they were SARS‐CoV‐2–positive, had used any prescription or nonprescription drugs or supplements within the previous 28 days or 5 half‐lives, had received a COVID‐19 vaccination within 7 days, or planned to receive a COVID‐19 vaccination during the study period. A full list of exclusion criteria is provided in the Supporting Information.

2.2. Ethical Conduct of the Study

The study was carried out in accordance with all legal and regulatory requirements, consensus ethical principles derived from international guidelines, including the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, the Declaration of Helsinki, and applicable International Council for Harmonization guidelines for Good Clinical Practice. The protocol was approved by the Advarra Institutional Review Board (approval number Pro00066581) on September 22, 2022. All participants provided written informed consent.

2.3. Study Design, Randomization, and Treatments

The SAD part of the study (Part 1) included 2 interleaving cohorts over 3 periods (Figure 1A). Participants were randomly assigned to receive a single dose of ibuzatrelvir (6 participants) or placebo (2 participants) after ≥ 10 h of fasting in each period, except Cohort 2 in Petiod 3, with a 3‐period crossover in each cohort. Dose escalation (150, 500, 1500, 3000, and 4000 mg) was based on PK and safety data in ≥ 4 participants (3 active and 1 placebo) at previous dose levels. A washout interval of ≥ 5 days was used between doses for each participant. Blood samples for plasma PK analysis were collected at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 16 h (Day 1), 24 h (Day 2), 48 h (Day 3), and 72 h (Day 4). Period 3 (Cohort 2) included assessment of the effects of a high‐fat, high‐calorie meal (fed state) on a 500‐mg dose of ibuzatrelvir.

FIGURE 1.

Study design for Part 1 (A) and Part 2 (B).

The MAD part of the study (Part 2) included 4 parallel cohorts (Figure 1B) and commenced once the projected total 24‐h steady‐state exposure at the MAD starting dose was found to be safe and well tolerated in SAD. Participants were randomly assigned to receive 200 mg (Cohort 1), 600 mg (Cohort 2), or 1500 mg (Cohort 3) ibuzatrelvir or placebo every 12 h for 10 days; each dose escalation was based on ≥ 6 days of safety data and ≥ 6 h of Day 5 PK data in ≥ 4 participants (3 active and 1 placebo) at the previous dose level. Multidose PK of ibuzatrelvir in Chinese participants (MAD Cohort 4) and Japanese participants (Part 5) were assessed with 600 mg twice daily. For all MAD participants in Part 2 and Japanese participants in Part 5, morning doses on extensive PK days (Day 1, 5 and 10) were received after ≥ 10 h of fasting and all other doses after ≥ 2 h of fasting. Blood samples for plasma PK measurements were collected on Days 1, 2, 3, 5, 6, 8, 10, 11, and 12. An overview of the Part 3 study design is included in the Supporting Information.

2.4. Safety and Tolerability Outcomes and Assessments

Safety and tolerability for all study parts were assessed within the safety analysis set (SAS), which included all enrolled participants who took ≥ 1 dose of the study intervention. Adverse events (AEs), clinical laboratory values, physical examination, vital signs, and 12‐lead electrocardiograms were assessed in all study parts; in the SAD part of the study, continuous cardiac telemetry monitoring was also conducted on days when the participants received treatment. Serious AEs (SAEs) and nonserious AEs were monitored from screening through Day 36.

2.5. Bioanalytical Methods for PK Assessment

A validated liquid chromatography–tandem mass spectrometry assay was used to analyze the human plasma samples. The assay used protein precipitation with reversed‐phase liquid chromatography coupled to tandem quadrupole mass spectrometry. The bioanalytical method was validated over the range of 10.0 to 20,000 ng/mL. Full details of the bioanalytical methods are provided in the Supporting Information.

2.6. PK Outcomes and Assessments

Analyses of PK were evaluated in the PK concentration analysis set, which included all participants who were randomized, received at least 1 dose of study intervention, and had at least 1 measured concentration during at least 1 treatment period. The PK parameter analysis included all participants who were randomized, received at least 1 dose of study intervention, and for whom at least 1 of the PK parameters of primary interest could be calculated over at least 1 treatment period. In SAD and MAD parts of the study and in Part 3, plasma PK parameters were derived from concentration‐time data using standard noncompartmental methods; in MAD, urine PK parameters were also measured. PK parameter definitions and determination methods are described in Table S1 (SAD and MAD) and the Supporting Information (Part 3).

2.7. Dose and Duration Selection for Phase 2b

A population PK model was developed based on preliminary observed PK data available at the time of phase 2 dose selection from the ongoing phase 1 study. The model described the distribution of ibuzatrelvir with 2 compartments, a first‐order absorption model with lag, and a dose effect on F1 (a power function normalized to an estimated relative dose of 12345.6 units). Exponential interindividual variability (IIV) estimates for dose effect on F1, apparent clearance, intercompartmental clearance (Q/F), absorption rate constant (Ka), and lag time were 4.7%, 24.3%, 71.1%, 12%, and 12.1%, respectively. The IIV for volume of distribution in compartment 3 was set equal to that for Q/F, with an estimated scaling factor of 1.5. Proportional residual variability was estimated at 24.3%. The model was developed, and covariate relationships were incorporated from this phase 1 study. The resulting preliminary model included covariate effects for food on F1 and Ka. Simulations for dose selection from this model assumed a fasted state to be conservative and changed from the fitted variability on systemic clearance to a 60% coefficient of variation, based on experience with the development of nirmatrelvir, to empirically describe the potentially increased variability in the phase 2 study.

2.8. Statistical Analysis

Formal inferential statistics were not applied, with the exception of comparing formulations in Part 3 and food effect assessments in Parts 1 and 3 (Part 3 described in Supporting Information). For Part 1, natural log‐transformed area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration (AUC_last), maximum plasma concentration (C_max), and area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC_inf) for ibuzatrelvir were analyzed using a mixed‐effects model with treatment as a fixed effect and participant as a random effect, using participants with data from relevant periods only.

3. Results

3.1. Participants

The study was conducted between October 17, 2022, and September 15, 2023. A total of 16 and 22 participants were enrolled in the SAD and MAD parts of the study, respectively (Figure 1, Figure S1), and 12 participants were enrolled in Part 3 (Supporting Information). Overall, 5 participants were enrolled in the Japanese PK portion of Part 5, with 4 participants meeting the definition of Japanese based on the inclusion criteria. In the SAD phase, 4 participants discontinued: 2 because of the physician's decision, 1 because of inappropriate behavior, and 1 because of a family emergency. In the MAD phase, 1 participant discontinued because of a family emergency. None of the Japanese participants in Part 5 who received ibuzatrelvir discontinued from the study; 1 non‐Japanese participant withdrew from the study (non–treatment‐related AE). Table 1 presents demographics and baseline characteristics of the study participants.

TABLE 1.

Demographic and baseline characteristics.

Characteristic	Single ascending doses (n = 16)	Multiple ascending doses (n = 22)*	Relative bioavailability (n = 12)	Japanese and non‐Japanese PK (n = 14) †
Age, years
18–44, n (%)	8 (50)	17 (77.3)	8 (66.7)	7 (50.0)
45–60, n (%)	8 (50)	5 (22.7)	4 (33.3)	7 (50.0)
Mean ± SD	43.1 ± 10.8	34.6 ± 9.4	38.8 ± 12.1	45.1 ± 9.3
Median (range)	44.5 (22–59)	31.5 (24–54)	35.0 (23–57)	44.5 (27–58)
Male, n (%)	12 (75.0)	20 (90.9)	6 (50.0)	10 (71.4)
Race, n (%)
White	8 (50.0)	6 (27.3)	6 (50.0)	5 (35.7)
Black or African American	7 (43.8)	7 (31.8)	4 (33.3)	3 (21.4)
Other ‡	1 (6.3)	2 (9.1%)	0 (0.0)	0 (0.0)
Asian		7 (31.8)	2 (16.7)	6 (42.9)
Ethnicity, n (%)
Hispanic	8 (50.0)	6 (27.3)	3 (25.0)	4 (28.6)
Weight, kg
Mean ± SD	74.1 ± 9.9	76.5 ± 12.0	74.1 ± 11.9	73.4 ± 13.3
Median (range)	74.7 (60.2–92.5)	77.5 (51.1–102.6)	73.3 (58.5–103.0)	73.1 (52.0–98.2)
Height, cm
Mean ± SD	172.8 ± 11.6	173.7 ± 8.0	169.5 ± 10.7	169.9 ± 9.5
Median (range)	174.0 (150–194)	174.0 (149–186)	168.5 (155–185)	172 (152–183)
Body mass index, kg/m2
Mean ± SD	24.9 ± 2.9	25.3 ± 3.3	25.8 ± 2.8	25.4 ± 3.7
Median (range)	25.0 (20.0–29.1)	25.0 (20.3–30.3)	25.3 (21.9–30.1)	26.1 (18.6–30.3)

Abbreviation: PK, pharmacokinetics.

^*Four participants in the multiple ascending dose portion of the study were Chinese.

^† Five participants in Part 5 enrolled as Japanese; however, only 4 of these participants met the definition of Japanese in accordance with the inclusion criteria.

^‡ Includes Black or African American/White, American Indian or Alaska Native, Black or African American/American Indian or Alaska Native.

3.2. Safety

Across all parts reported herein, all AEs were mild or moderate in severity, no participant died or experienced an SAE, and no participant who received ibuzatrelvir discontinued the study because of an AE. No clinically meaningful changes in electrocardiogram parameters were observed in the study.

During the SAD phase, 9 of 17 treatment‐emergent AEs (TEAEs) (52.9%) occurred in participants receiving ibuzatrelvir (Table S2). There was one treatment‐related AE (increased lipase) that occurred in a participant receiving a placebo.

During the MAD phase, 17 TEAEs occurred in 7 participants; 13 of 17 (76.5%) occurred in participants receiving ibuzatrelvir (Table S3). Of these, 4 AEs (across 3 participants) were considered potentially related to ibuzatrelvir treatment (defecation urgency, vomiting, alanine aminotransferase increase, and muscle spasms; n = 1 each), and all were mild in severity. In Part 5, a total of 25 TEAEs occurred in 11 of the 13 participants receiving ibuzatrelvir with midazolam; of these, 15 AEs (across 9 participants) were considered potentially related to treatment (somnolence, n = 9; dizziness and pruritus, n = 2 each; headache and paresthesia, n = 1 each). All TEAEs in these participants were mild in severity; 1 participant discontinued because of a non–treatment‐related AE of hemoptysis attributed to upper respiratory treatment infection and dry oropharynx. Adverse events reported for all participants in the SAD and MAD phases of the study are listed in the Supporting Information.

3.3. Pharmacokinetics

During the SAD part of the study and under fasted conditions, ibuzatrelvir exposure increased in a slightly less than dose‐proportional manner (Figure 2A), with dose‐normalized AUC_inf numerically decreasing with each increasing dose up to 3000 mg (Table 2) and with no further dose‐proportional increase in exposure between 3000 and 4000 mg. Under fed conditions, a 500‐mg dose of ibuzatrelvir was absorbed more slowly (median time of maximum observed concentration [T_max], 1.25 h) compared with the same dose received after fasting (T_max, 0.8 h; Table 2). Geometric mean AUC_inf was approximately 23% lower under fed compared with fasted conditions.

FIGURE 2.

Median plasma ibuzatrelvir concentration‐time profiles (semi‐log scales) for the single ascending dose (A) and multiple ascending dose (B) study parts. Ibuzatrelvir was administered as a suspension formulation. Gray horizontal line represents the in vitro EC₉₀ total of 221 ng/mL determined in differentiated normal human bronchial epithelial cells (equivalent to free in vitro EC₉₀ of 70 nM, fraction unbound, human = 0.155 at 70 nM). BID, twice daily; EC₉₀, 90% maximal effective concentration.

TABLE 2.

Single ascending dose assessment of plasma ibuzatrelvir pharmacokinetic parameters: Descriptive summary and statistical summary of food effects.

Descriptive summary	Ibuzatrelvir 150 mg fasted (n = 6 † )	Ibuzatrelvir 500 mg fasted (n = 6)	Ibuzatrelvir 500 mg fed (n = 4)	Ibuzatrelvir 1500 mg fasted (n = 6)	Ibuzatrelvir 3000 mg fasted (n = 5)	Ibuzatrelvir 4000 mg fasted (n = 5)
Parameter*
AUCinf, ng·h/mL	11,250 (53)	35,950 (25)	28,120 (28)	85,320 (34)	166,100 (34)	189,400 (19)
AUCinf (dn), ng·h/mL	75.0 (53)	71.8 (25)	56.2 (28)	56.9 (34)	55.3 (35)	47.3 (19)
Cmax, ng/mL	2,269 (51)	6,235 (20)	3,223 (13)	17,420 (36)	34,420 (12)	34,670 (36)
t½, h	4.5 ± 0.5	13.9 ± 10.8	16.0 ± 8.5	10.8 ± 6.2	18.8 ± 14.2	13.1 ± 7.4
Tmax, h	1.0 (0.5–1.5)	0.8 (0.5–1.5)	1.3 (1.0–2.0)	0.5 (0.5–1.0)	0.5 (0.5–1.1)	1.0 (0.6–1.5)

Statistical summary – food effects ‡	Ibuzatrelvir 500 mg fed (test)	Ibuzatrelvir 500 mg fasted (reference)	Ratio, % (test/reference) of adjusted geometric mean	90% CI, % for ratio
Parameter
AUCinf, ng·h/mL	27,520	35,950	76.6	62.2, 94.2
Cmax, ng/mL	3,246	6,235	52.1	40.9, 66.3

Abbreviations: AUC_inf, area under the plasma concentration‐time curve from time 0 extrapolated to infinity; C_max, maximum plasma concentration; dn, dose‐normalized (to a 1‐mg dose of ibuzatrelvir); t_½, terminal half‐life; T_max, time to maximum plasma concentration.

^*Shown as geometric mean (geometric % coefficient of variation) for all values except for T_max (shown as median [range]) and t_½ (shown as arithmetic mean ± SD).

^† Only 5 participants contributed to summary statistics for t_½, AUC_inf, and AUC_inf (dn).

^‡ A mixed‐effect model is used with treatment as a fixed effect and participant as a random effect with 4 vs. 6 participants in the fed and fasted treatment groups, respectively. Missing values were imputed based on the rest of the observed values.

During the MAD part of the study with twice‐daily administration under fasted conditions, ibuzatrelvir was rapidly absorbed, and systemic exposure increased dose‐proportionally (Figure 2B, Table 3). Across all doses on Days 1, 5, and 10, T_max ranged from 0.5 to 1.0 h. Steady‐state plasma concentrations were achieved by Day 2 across all doses, and accumulation ratios were similar between Days 5 and 10. Urinary recovery of ibuzatrelvir was dose‐dependent, with 9.3% for the 200‐mg dose, 16.0% for the 600‐mg dose, and 25.0% for the 1500‐mg dose. Among Chinese participants during the MAD part of the study, the area under the plasma concentration time profile from 0 to 12 h (AUC_tau) and urinary recovery were comparable with those of non‐Chinese participants receiving the same dose of ibuzatrelvir. The terminal half‐life (t_½) was numerically shorter among Chinese (8.6 h) vs. non‐Chinese (13.0 h) participants, but the accumulation ratio for AUC_tau (R_ac) was similar (Table 3). Similar results were observed in the analysis of Japanese and non‐Japanese participants in the DDI study (Part 5): AUC_tau and R_ac were comparable across Japanese and non‐Japanese participants, whereas terminal t_½ was shorter among Japanese (7.9 h) vs. non‐Japanese (12.8 h) participants (Table 3). In study Part 3, PK parameters between SDD tablets and crystalline tablets were comparable with SDD suspension under fed and fasted conditions (Supporting Information, Table S4).

TABLE 3.

Multiple ascending dose assessment: Descriptive summary of plasma and urine Ibuzatrelvir pharmacokinetic parameters.

Parameter*	Multiple ascending dose study (Part 2)				Drug–drug interaction study (Part 5)
	Ibuzatrelvir 200 mg (n = 4)	Ibuzatrelvir 600 mg (n = 4) †	Ibuzatrelvir 1500 mg (n = 4) †	Ibuzatrelvir 600 mg Chinese ‡ (n = 3)	Ibuzatrelvir 600 mg non‐Japanese (n = 9) §	Ibuzatrelvir 600 mg Japanese ‡ (n = 4)
Day 1
AUCtau, ng·h/mL	14,760 (26)	36,440 (27)	108,400 (15)	36,880 (22)	37,450 (31)	34,230 (15)
Cmax, ng/mL	3,582 (20)	8,470 (39)	24,100 (22)	8,381 (12)	8,972 (37)	8,237 (25)
Tmax, h	0.8 (0.5–1.0)	0.8 (0.5–1.0)	0.5 (0.5–1.5)	1.0 (1.0–1.1)	0.5 (0.5–1.0)	0.5 (0.5–1.1)
Day 5
AUCtau, ng·h/mL	18,460 (15)	36,300 (10)	114,000 (22)	37,680 (29)	42,320 (37)	32,830 (14)
Cmax, ng/mL	4,234 (7)	9,112 (14)	27,530 (22)	8,260 (18)	9,430 (36)	8,350 (33)
Rac	1.3 (28)	1.0 (18)	1.1 (9)	1.0 (7)	1.1 (12)	1.0 (4)
Tmax, h	0.9 (0.5–1.0)	0.5 (0.5–0.5)	0.5 (0.5–1.0)	0.5 (0.5–1.0)	0.5 (0.5–1.0)	0.8 (0.5–1.0)
Day 10
AUCtau, ng·h/mL	17,180 (10)	34,960 (8)	103,900 (18)	34,650 (29)	43,050 (20)	36,210 (24)
Cmax, ng/mL	3,492 (15)	7,852 (21)	23,420 (14)	7,306 (25)	7,965 (21)	7,644 (28)
Rac	1.2 (18)	0.9 (20)	1.0 (4)	0.9 (8)	1.1 (17)	1.1 (9)
t½, h	14.0 ± 9.4	13.0 ± 8.9	11.4 ± 6.8	8.6 ± 5.9	12.8 ± 4.9	7.9 ± 1.6
Tmax, h	0.5 (0.5–1.0)	0.5 (0.5–1.0)	0.5 (0.5–0.5)	0.5 (0.5–1.0)	0.5 (0.5–1.5)	0.5 (0.5–1.0)
Aetau, %	9.3 (16)	16.2 (5)	24.9 (10)	14.3 (20)	NR	NR
CLr, L/h	1.1 (20)	2.8 (5)	3.6 (26)	2.5 (51)	NR	NR

Abbreviations: Ae_tau, dose excreted in urine as unchanged drug over 12 h; AUC_tau, area under the plasma concentration time profile from 0 to 12 h; CL_r, renal clearance; C_max, maximum plasma concentration; dn, dose‐normalized (to a 1‐mg dose of ibuzatrelvir); NR, not reported; R_ac, accumulation ratio for AUC_tau; t_½, terminal half‐life; T_max, time to maximum plasma concentration.

^*Shown as geometric mean (geometric % coefficient of variation) for all values except for T_max (shown as median [range]) and t_½ (shown as arithmetic mean ± SD).

^† For Day 10, all parameters were calculated among 3 participants in the non‐Chinese 600‐mg dosing group, and t_½ was calculated among 3 participants in the non‐Chinese 1500‐mg dosing group.

^‡ Inclusion in the optional multiple ascending dose Chinese cohort required being born in mainland China to parents of Chinese descent. Inclusion in the Part 5 Japanese cohort required having 4 biological Japanese grandparents who were born in Japan.

^§ For Day 10, t_½ was calculated among 7 participants, and all other parameters were calculated among 8 participants.

3.4. Dose Selection for Phase 2b

A preliminary population PK model was developed using PK data from the SAD and MAD parts of the study. Based on simulations developed using this model, after the first dose of 100, 300, and 600 mg of ibuzatrelvir every 12 h, median total plasma concentrations before the next dose (C_trough) of ibuzatrelvir were predicted to be approximately 92, 253, and 482 ng/mL, respectively. C_trough after administration of ibuzatrelvir 300 and 600 mg every 12 h was above the in vitro concentration required for 90% effect (EC₉₀, total) of 221 ng/mL determined in differentiated normal human bronchial epithelial cells (equivalent to free in vitro EC₉₀ of 70 nM, fraction unbound, human = 0.155 at 70 nM) [17].

4. Discussion

Preclinical evaluations for ibuzatrelvir demonstrated a promising pharmacologic and safety profile, subsequently leading to further development. The in vitro potency and safety of ibuzatrelvir were comparable to nirmatrelvir; however, unlike nirmatrelvir, the projected PK profile of ibuzatrelvir suggested that PK enhancement using ritonavir would not be required [14, 16]. A multipart first‐in‐human study, similar to the nirmatrelvir studies, was conducted to assess the safety and pharmacokinetics after single and multiple ascending doses of ibuzatrelvir.

Ibuzatrelvir was safe and well‐tolerated after single or multiple doses, supporting further evaluation of efficacy and safety in patients with COVID‐19. No SAEs or severe AEs were reported, and there were no treatment‐related discontinuations of ibuzatrelvir.

In this study, oral ibuzatrelvir administration resulted in rapid absorption after all doses, and steady‐state plasma concentrations were achieved by Day 2 for all ibuzatrelvir doses. C_trough concentrations were several fold above the EC₉₀ total concentration, demonstrating that, unlike currently available M^pro inhibitors for the treatment of COVID‐19 in the United States and Europe [7, 18], ibuzatrelvir does not require PK enhancement through coadministration with ritonavir, which will greatly reduce the perpetrator DDI risk and will likely benefit patients who are unable to take the currently approved treatment because of DDIs [14, 19]. Renal clearance of ibuzatrelvir was low because ibuzatrelvir is primarily metabolized through CYP3A4/5 [14]. However, dose‐dependence in clearance was observed, which may be hypothesized to be attributed to nonlinear plasma protein binding, although this needs further exploration.

The exposures of ibuzatrelvir were similar between Chinese and non‐Chinese participants, as well as between Japanese and non‐Japanese participants. The t_½ in Chinese or Japanese participants was numerically different from that in non‐Chinese or non‐Japanese participants, respectively, but the accumulation factors were similar, indicating the effective t_½ was comparable. Also, the C_trough concentration in both populations was several‐fold higher than the EC₉₀ total concentration.

High‐fat meals decreased C_max and AUC_last in both SAD (Part 1) and relative bioavailability (Part 3) study parts, but the concentration at 12 h postdose was comparable to that of ibuzatrelvir when administered without food. Thus, in the phase 2b study, ibuzatrelvir was administered without regard to food. Based on similar PK parameters observed across SDD and crystalline formulations, the crystalline formulation was used in the phase 2b study (Figure S2, Table S4). Pharmacokinetic and safety data obtained from this study informed the selection of dosing regimens for the subsequent phase 2 trial, with observed minimum concentrations exceeding the EC₉₀ in selected dose ranges. The exposures recorded in the phase 2 study were consistent with those predicted by the preliminary population PK model based on phase 1 data. The expected total exposures were 92, 253, and 482 ng/mL, while the observed exposures in phase 2 were 104, 276, and 526 ng/mL. These exposures demonstrated multiple‐fold margins above EC₉₀ and were associated with significant reductions in viral load [17].

Strengths of this study included an innovative study design that allowed rapid assessment of PK and safety in healthy volunteers. This design, which was previously developed for evaluation of NMV/r in response to an urgent unmet need [20], accelerates dose and regimen selection for late‐phase clinical studies by achieving several objectives within a single study, such as safety and PK determination across doses, PK comparisons between races, DDI evaluation [16], mass balance, and metabolic profiling using [19] F‐NMR, and assessment of QT prolongation potential. Twice‐weekly dose escalation provided efficiency in shortening the time from trial initiation through completion. Although the small number of participants within each dose group was a study limitation, it was sufficient to generate clinically meaningful results at this stage of development.

This study supports the continued development of ibuzatrelvir, including the design and dose selection of a phase 2b study (NCT05799495) evaluating the effects of ibuzatrelvir on SARS‐CoV‐2 nasopharyngeal viral load in adults with confirmed COVID‐19 [17].

Author Contributions

All authors wrote the manuscript. R.S.P.S., S.S.T., A.B., and F.H. designed the research. M.S. and P.C. performed the research. R.S.P.S., S.S.T., J.P., and F.H. analyzed the data.

Funding

The authors have nothing to report.

Disclosure

All authors are current or former employees of Pfizer and may hold stock or stock options.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Definitions and derivation of pharmacokinetic parameters for the single ascending dose and multiple ascending dose study parts.

Table S2: Treatment‐emergent AEs in the single ascending dose group.

Table S3: Treatment‐emergent AEs in the multiple ascending dose group.

Table S4: Pharmacokinetic parameters across different ibuzatrelvir formulations dosed under fed and fasted conditions: Descriptive summary and statistical summary of formulation effect.

Table S5: Single ascending dose assessment of plasma ibuzatrelvir pharmacokinetic parameters: Descriptive summary (A) and statistical summary of food effects (B).

Table S6: The complete listing of all adverse events by participant.

Figure S1: Consort Flow Diagram.

Figure S2: Median plasma ibuzatrelvir concentration‐time profiles (semi‐log scales) following single oral doses of ibuzatrelvir in study Part 3 (relative bioavailability and food effect). Ibuzatrelvir was administered as spray‐dried dispersion (SDD) tablets, crystalline tablets, or suspension.

Data Availability Statement

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.