Pharmacokinetics of Nirmatrelvir/Ritonavir after Multiple Administration in a Phase 1, Open-Label Study in Healthy Chinese Adults and Compared with Non-Chinese Participants

Abstract

Background and Objectives

Nirmatrelvir (PF-07321332) has demonstrated antiviral activity and an acceptable safety profile in clinical studies. This study aimed to demonstrate the pharmacokinetic (PK) profiles of Chinese participants after administration of nirmatrelvir/ritonavir, and to further evaluate the ethnic differences between different races.

Methods

This Phase 1, open-label, single-site study assessed the PK, safety, and tolerability of nirmatrelvir 300 mg plus ritonavir 100 mg administered twice daily for 10 days in healthy Chinese adults. In total, 14 Chinese participants were enrolled with an age range of 24 to 43 years. Samples were collected after first-dose administration on day 1 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 h after drug administration) and last-dose administration on day 10 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after drug administration) to assess PK parameters after a single dose and multiple doses; pre-dose samples were collected on days 5, 8, and 10 to confirm that steady-state was achieved. All PK samples were assayed with a liquid chromatography-tandem mass spectrometry method to quantify plasma concentration of nirmatrelvir and ritonavir. Study participants were monitored for safety for 28–35 days after the last-dose administration. Adverse events (AEs), clinical safety laboratory tests, vital signs, and 12-lead electrocardiograms were all monitored during study. Results for Chinese participants were compared with results in healthy non-Chinese adult participants who received the same nirmatrelvir/ritonavir dose in other Phase 1 studies.

Results

All 14 healthy Chinese adults completed the study. Nirmatrelvir was rapidly absorbed, with a median t_max of approximately 2 h. Geometric mean nirmatrelvir C_max and AUC were 3.08 μg/mL and 19.66 μg·h/mL after the first dose and increased to 4.50 μg/mL and 32.01 μg·h/mL at steady state, with less than 2-fold accumulation and a mean terminal half-life of 6.84 h. Steady-state concentrations were achieved before day 5. Nirmatrelvir/ritonavir was well tolerated; 6 participants (42.9%) reported AEs, 4 of which (28.6%) were treatment-related mild dysgeusia. No serious AEs or discontinuations were reported. The results showed that the PK characteristics of nirmatrelvir/ritonavir in healthy Chinese adults were comparable with results from previous studies in non-Chinese healthy adults, with no apparent clinically significant differences observed between Chinese and non-Chinese participants.

Conclusions

In healthy Chinese participants, the PK profile of nirmatrelvir 300 mg plus ritonavir 100 mg twice daily was comparable with that observed in non-Chinese participants, with an overall favorable safety profile, supporting the use of this dosing regimen for the Chinese population.

ClinicalTrials.gov ID

NCT05339334.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40261-026-01554-y.

Key Points

This Phase 1, open-label study evaluated the pharmacokinetics, safety, and tolerability of nirmatrelvir 300 mg plus ritonavir 100 mg administered twice daily in healthy Chinese adults.

Nirmatrelvir and ritonavir exhibited predictable pharmacokinetic profiles in this Chinese population, with steady-state exposures achieved and key pharmacokinetic parameters generally comparable with those reported in non-Chinese adult participants.

In this Phase 1 study, the pharmacokinetic characteristics of nirmatrelvir/ritonavir in healthy Chinese adults appeared comparable with those observed in non-Chinese adults, and the regimen was generally well tolerated.

Introduction

In late 2019, a previously unknown coronavirus—later designated SARS‑CoV‑2—was recognized as the source of a newly emerging respiratory disease with the potential for severe outcomes. The World Health Organization first classified the outbreak as a Public Health Emergency of International Concern on 20 January 2020, and subsequently, on 11 March 2020, announced that the rapid global spread of the disease had escalated into a pandemic [1].

Nirmatrelvir is a potent and selective inhibitor of SARS-CoV-2 3CL protease developed as an oral treatment for COVID-19 [2, 3]. To maintain unbound systemic trough concentrations above the in vitro antiviral 90% effective concentration (EC₉₀), 300 mg nirmatrelvir is co-administered with 100 mg of ritonavir, a pharmacokinetic (PK) enhancer [3, 4]. Ritonavir is a strong cytochrome P450 (CYP) 3A4 inhibitor being used to inhibit the metabolism and increase the plasma concentrations of nirmatrelvir to values that are anticipated to be effective [3, 4].

The objective of this Phase 1 study in China was to evaluate the PK, safety, and tolerability of nirmatrelvir/ritonavir (Paxlovid™; Pfizer Inc, New York, NY, USA) at the recommended label dosage (300 mg/100 mg nirmatrelvir/ritonavir twice daily [BID]) in healthy Chinese adults. Additionally, the results of this study were compared with the results of two previous Phase 1 studies in non-Chinese participants given nirmatrelvir/ritonavir at the same dosing regimen, thereby providing a comprehensive ethnic sensitivity analysis to facilitate the administration of nirmatrelvir/ritonavir by Chinese and Western physicians [5].

In addition to the global integrated population PK analysis, which did not identify race as a significant covariate, a dedicated Phase 1 study in healthy Chinese adults was conducted to meet the regulatory requirement of the China National Medical Products Administration (NMPA). Although the Population PK (popPK) dataset included individuals from multiple regions, the proportion of East Asian participants was relatively limited; therefore, supplementing the model-based findings with prospectively collected PK data from Chinese subjects provides more robust evidence regarding the absence of clinically meaningful ethnic differences.

Evaluation of ethnic differences in PK is important because demographic and physiologic factors may influence drug exposure across populations. Consistent with regulatory expectations, this Phase 1 study was conducted to assess the PK, safety, and tolerability of nirmatrelvir/ritonavir in healthy Chinese adults.

Methods

Study Design

This Phase 1, open-label study aimed to evaluate the PK, safety, and tolerability of nirmatrelvir when co-administered with ritonavir in healthy Chinese participants (ClinicalTrials.gov identifier: NCT05339334). The study involved a single treatment regimen: 10 days of oral administration of nirmatrelvir 300 mg combined with ritonavir 100 mg. The study enrolled 14 healthy male and female adults and was conducted at a single site in China from 10 March to 21 April 2022. The study design was reviewed and accepted by the Chinese Center for Drug Evaluation and an independent ethics committee before study initiation.

The study consisted of a screening phase, a treatment phase, and a follow-up phase. All participants provided informed consent and underwent screening evaluations to determine their eligibility. All screening evaluations occurred up to 28 days before administration of the study treatment.

Eligible participants reported to the clinical research unit on day 1 and received nirmatrelvir/ritonavir 300 mg/100 mg BID, the dose amount and frequency consistent with the product labeling [2, 6, 7], for 10 days. In total, 19 doses were administered during the treatment period. The first dose was given on the morning of day 1 and the final dose on the morning of day 10; no evening dose was administered on day 10 to facilitate the intensive PK sampling that occurred after the first and last doses. Each dose was administered with ambient temperature water to a total volume of approximately 240 mL. At least a 2-h fast was required before and after drug administration for all doses. Participants refrained from consuming red wine, grapefruit, or related citrus fruits from 7 days prior to the first dose of study intervention until collection of the final PK blood sample to avoid effect on CYP3A4. Only standard meals provided by the clinical research unit were permitted throughout the hospitalization.

Participants were monitored for safety during the screening and treatment phases and for 28 to 35 calendar days after the last-dose administration. The final study protocol is available online at https://clinicaltrials.gov/study/NCT05339334 [8].

Participants

Eligible participants were healthy Chinese men or women, aged 18–60 years. Key exclusion criteria included any evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease or a clinically significant illness, medical/surgical procedure, or trauma within 4 weeks before the first administration of study treatment. Estimated glomerular filtration rate < 90 mL/min/1.73 m² (with 10% variation) based on the Chronic Kidney Disease Epidemiology Collaboration equation [9] and systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg were also exclusion criteria. Any coadministration of potentially interacting drugs, for example strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin) and sensitive CYP3A4 substrate (midazolam, lovastatin, sildenafil), was prohibited, and all participants received nirmatrelvir/ritonavir after fasting for ≥ 2 h.

Written informed consent was obtained from all participants prior to the conduct of any study-specific procedures. Participants were recruited through a professional recruitment agency using approved recruitment advertisements. All recruitment activities were conducted in accordance with applicable ethical and regulatory requirements. Participants received appropriate compensation for their time and study participation.

PK Analyses

Intensive PK samples were collected after first-dose administration on day 1 (0, 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after drug administration) and last-dose administration on day 10 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after drug administration) to obtain PK parameters after a single dose and multiple doses; trough PK samples were collected on days 5, 8, and 10 to confirm that steady state was achieved. Whole blood samples (4 mL) to provide a minimum of 1.5 mL plasma for PK analysis were collected in tubes containing ethylenediaminetetraacetic acid (EDTA) at the following times (± 10%): 0, 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the first-dose administration on day 1 (morning) and after the final dose administration on day 10 (morning); 24 and 48 h after the last dose on day 10; and a trough plasma sample (i.e., 12 h after the dose) on day 5 and day 8.

Pharmacokinetic parameters calculated using non-compartmental analysis (NCA) included maximum observed plasma concentration (C_max), time to maximum concentration (t_max), area under the plasma concentration–time curve over the dosing interval (AUC_tau) or over 12 h (AUC₁₂), terminal elimination half-life (t½), apparent oral clearance (CL/F), apparent volume of distribution during the terminal phase (Vz/F), trough concentration (C_trough), and renal clearance (CLr) as applicable. Urinary PK parameters for nirmatrelvir were also calculated, including the amount of unchanged drug excreted in urine over the dosing interval (Aeτ), the percentage of dose excreted in urine (Aeτ%), and CLr, as applicable.

PK Sample Assay Method

Specific and sensitive bioanalytical methods using liquid chromatography with tandem mass spectrometry (LC–MS/MS) bioanalytical methods were developed and validated at Labcorp Bioanalytical Services (Shanghai, China) for the simultaneous quantification of nirmatrelvir and ritonavir in human plasma and for the quantification of nirmatrelvir in human urine. Calibration curves for the plasma assay ranged from 10.0 to 10,000 ng/mL for nirmatrelvir and from 5.00 to 5000 ng/mL for ritonavir. The urine assay calibration range for nirmatrelvir was 100–200,000 ng/mL. All method validations and study sample analyses were conducted in accordance with US Food and Drug Administration (FDA) and European Medicines Agency (EMA) bioanalytical method validation guidelines [10, 11]. Validation results included determination of whether accuracy, precision, linearity, selectivity, specificity, carryover, matrix effects, sensitivity, recovery, and dilution integrity met the acceptance criteria.

Plasma Assay Methodology and Assay Performance

Briefly, nirmatrelvir and ritonavir, together with their respective stable isotope-labeled internal standards (IS), were extracted from 50.0 μL of human plasma using a protein precipitation procedure with acetonitrile. The resulting supernatant was diluted and analyzed by LC–MS/MS in positive ionization mode. Overall inter-run assay accuracy (percent relative error) ranged from − 3.7 to − 1.7% for nirmatrelvir and from − 5.3 to 0.4% for ritonavir. Assay precision (percentage coefficient of variation) was ≤ 5.4% for nirmatrelvir and ≤ 9.4% for ritonavir across all quality control levels during accuracy and precision runs. Matrix effects evaluated at all tested concentrations met predefined acceptance criteria. All plasma clinical samples were stored at − 70°C until analysis, and analyses were conducted within the established analyte stability periods.

Urine Assay Methodology and Run Performance

Briefly, nirmatrelvir and its stable isotope-labeled IS were extracted from 50.0 μL of human urine using a protein precipitation procedure with 950 μL of acetonitrile:water:formic acid (40:60:0.1, v/v/v). The resulting supernatant was diluted and analyzed by LC–MS/MS with electrospray ionization operated in positive ionization mode. Overall, inter-run accuracy (percentage relative error) ranging from − 4.3 to 0.6%, while assay precision (percentage coefficient of variation) was ≤ 5.4% during validation runs. All urine clinical samples were stored at − 70 °C until analysis and analyzed within the stability limits.

Safety Assessments

Safety was assessed by the incidence of adverse events (AEs) and serious AEs (SAEs) throughout the study. MedDRA v25.0 coding dictionary was applied for AE/SAE coding. Adverse events and SAEs were monitored for each participant throughout the study, which included a minimum of 28 calendar days, and were assessed by investigators. Vital signs, 12-lead electrocardiograms (ECGs), and safety lab testing were also monitored throughout the study.

Statistical Methods

This Phase 1 study was descriptive and did not include an inferential statistical hypothesis; therefore, no formal sample size calculation or statistical power analysis was performed. The sample size of 14 participants was determined based on regulatory expectations for PK studies by China NMPA, with the aim to ensure that at least 12 evaluable participants would complete all scheduled PK sampling. This number is adequate to characterize the PK profile using NCA and is consistent with commonly accepted sample sizes for early-phase PK studies in healthy volunteers.

Plasma (both nirmatrelvir and ritonavir) and urine (only nirmatrelvir) PK parameters were calculated with noncompartmental analysis (NCA) methods using an internally validated software system (openNCA, version 2.6.21) for the PK parameters analysis set (i.e., all participants who were assigned to investigational product and treated who had ≥ 1 of the PK parameters). Graphical analyses were conducted using R (4.1.3 or updated version), and popPK modeling and simulations were performed using NONMEM (7.5.0 or updated version). All software used in the analyses were validated or qualified according to internal quality standards.

Comparison with Non-Chinese Ethnicities

To further evaluate potential differences between ethnicities in the PK properties of nirmatrelvir/ritonavir, individual and median plasma concentration-time profiles of nirmatrelvir/ritonavir after single- and multiple-dose administration from the current study in Chinese participants were compared with results in healthy non-Chinese participants who received the same nirmatrelvir/ritonavir dose in other Phase 1 studies completed by Cox et al [5]. Steady-state PK parameters of nirmatrelvir/ritonavir in non-Chinese participants were obtained from Table 2 (cohort without itraconazole) of Cox et al. [5] and were used to compare with the steady-state PK parameters observed in Chinese participants in the present study; while, single-dose PK parameters from Table 3 (cohort without carbamazepine) of Cox et al. [5] were used as the reference for comparing with the PK parameters during the first dosing interval following the initial dose in our study. Although AUC₁₂ was not reported in the published Table 3 of Cox et al. [5], this parameter was retrieved from the original clinical data system of the corresponding Pfizer study (ClinicalTrials.gov ID: NCT04962230) to allow a consistent comparison across studies.

Table 2.

Descriptive summary of nirmatrelvir and ritonavir PK parameters following nirmatrelvir/ritonavir oral administration (300/100 mg, BID): Chinese and non-Chinese participants

Parameter	Nirmatrelvir		Ritonavir
	Chinese participantsa	Non-Chinese participantsb	Chinese participantsa	Non-Chinese participantsb
After first dose on day 1
N, n	14, 14	12, 12	14, 14	12, 12
Median (range)
Weight, kg	62.0 (54.3–79.0)	78.1 (60.6–99.9)	62.0 (54.3–79.0)	78.1 (60.6–99.9)
tmax , h	1.76 (1.00–4.00)	3.00 (1.02–6.00)	2.00 (1.00–4.00)	3.98 (1.48–4.20)
Geometric mean (geometric %CV)
AUC12, µg·h/mL	19.66 (26)	17.26 (26)	3.136 (49)	2.632 (40)
Cmax , µg/mL	3.082 (29)	2.210 (33)	0.5458 (50)	0.3593 (46)
Aetau (mg)	86.43 (19)	N/A	N/A	N/A
Aetau%	28.81 (19)	N/A	N/A	N/A
CLr (L/h)	4.397 (13)	N/A	N/A	N/A
Steady state ( day 10 for Chinese participants and day 3 for non-Chinese participants)
N, n	14, 14	12, 11c	14, 14	12, 11c
Median (range)
Weight, kg	62.0 (54.3–79.0)	80.2 (60.7–101.0)	62.0 (54.3–79.0)	80.2 (60.7–101.0)
tmax, h	2.00 (1.00–4.02)	1.02 (0.500–2.08)	2.00 (1.50–4.00)	1.57 (1.47–3.98)
Arithmetic mean ± SD
t½, h	6.842 ± 1.2336	8.255 ± 1.9465	5.471±1.7871	5.720 ± 1.2484
Geometric mean (geometric %CV)
AUCtau, µg·h/mL	32.01 (21)	33.35 (20)	6.152 (29)	7.185 (30)
Cmax, µg/mL	4.500 (14)	4.678 (17)	1.109 (33)	1.44 (23)
CL/F, L/h	9.379 (21)	8.990 (20)	16.25 (29)	13.92 (30)
Vz/F, L	91.01 (29)	104.70 (33)	123.0 (23)	112.4 (30)
Aetau (mg)	134.5 (19)	N/A	N/A	N/A
Aetau%	44.82 (19)	N/A	N/A	N/A
CLr (L/h)	4.201 (12)	N/A	N/A	N/A

Ae_tau amount excreted in urine as unchanged drug over the dosing interval tau of 12 h, Ae_tau% percent of dose excreted in urine as unchanged drug over the dosing interval tau of 12 h, AUC₁₂ area under the concentration-time curve over 12 h, AUC_tau area under the concentration-time curve over the dosing interval, CL/F apparent oral clearance, CL_r renal clearance, CV coefficient of variation, N number of participants in the treatment group contributing to the weight’s summary statistics, n number of participants contributing to the PK parameters’ summary statistics, PK pharmacokinetics, t_½ half-life, t_max maximum concentration, V_z/F apparent oral volume of distribution during the terminal phase

^aDay 1: single dose; day 10: steady state

^bData are from Cox et al [5]. Day 1: single dose (Table 3—cohort without carbamazepine administration); day 3: steady state (Table 2—cohort without itraconazole administration). AUC₁₂ after single-dose administration in non-Chinese participants was not reported in the published manuscript (Cox et al) but was extracted from the original clinical data system of the corresponding Pfizer study (ClinicalTrials.gov ID: NCT04962230)

^cOne non-Chinese participant discontinued early and did not provide sufficient samples for steady-state PK assessment; therefore, n = 11 for the non-Chinese steady-state PK summary

Table 3.

Treatment-emergent adverse events (AEs)

Number (%) of participants	Adverse events
	All causalities, n (%) N = 14	Treatment related, n (%) N = 14
Total AEs	10	4
Participants with AEs	6 (42.9)	4 (28.6)
Dysgeusia	4 (28.6)	4 (28.6)
Diarrhea	4 (28.6)	0
Blood creatinine increased	1 (7.1)	0
Rash	1 (7.1)	0
Participants with serious AEs	0	0
Participants with severe AEs	0	0
Participants discontinued from study due to AEs	0	0
Participants discontinued study drug due to AE but continue study	0	0
Participants with dose reduction or temporary discontinuation due to AEs	0	0

In addition, using a previously reported popPK model that incorporated all available nirmatrelvir/ritonavir PK data to date, ethnic sensitivity and nirmatrelvir exposure simulations analysis were evaluated [12]. This popPK model was developed using nonlinear mixed‑effects modeling based on pooled plasma concentration data from multiple Phase 1 studies and the Phase 2/3 study, including 13.1% Asian participants. Potential covariate effects, including body weight, age, sex, renal function, and race/ethnicity (Asian vs non‑Asian), were evaluated on key PK parameters such as CL/F and apparent volume of distribution. Furthermore, the predicted day 5 nirmatrelvir exposure parameters and percentages of simulated participants achieving C_min ≥ EC₉₀ on day 1 and day 5 were also conducted.

Results

Participants

The study enrolled 8 male and 6 female Chinese participants at a single site in China between March and April 2022. The mean age, height, weight, and body mass index were 33.1 years, 165.0 cm, 63.4 kg, and 23.3 kg/m², respectively. Demographics and baseline characteristics are summarized in Table 1. All 14 participants were assigned to treatment with nirmatrelvir/ritonavir, completed all treatment and follow-up phases, and were included in the PK analysis set and the safety analysis set.

Table 1.

Summary of participant demographic and baseline characteristics; safety analysis set

Characteristics	Nirmatrelvir 300 mg + ritonavir 100 mg (N = 14)
Age, n (%), years
18–25	2 (14.3)
26–35	7 (50.0)
36–45	5 (35.7)
Mean (SD)	33.1 (6.78)
Median (range)	33.5 (24–43)
Sex, n (%)
Male	8 (57.1)
Female	6 (42.9)
Race, n (%)
Asian	14 (100.0)
Ethnicity, n (%)
Not Hispanic or Latino	14 (100.0)
Height, cm
Mean (SD)	165.0 (9.07)
Median (range)	167.3 (150.1–178.9)
Weight, kg
Mean (SD)	63.4 (7.39)
Median (range)	62.0 (54.3–79.0)
Body mass index,a kg/m2
Mean (SD)	23.3 (2.08)
Median (range)	22.3 (20.2–26.5)

^aBody mass index (kg/m²) = weight (kg)/[height (cm) × 0.01]²

PK Results in Chinese Participants

Plasma concentrations-time profiles for nirmatrelvir/ritonavir at steady state are shown in Figs. 1 and 2. Plasma (nirmatrelvir/ritonavir) and urine (nirmatrelvir) PK parameters are summarized descriptively by dosing day in Table 2.

Fig. 1.

Individual and median plasma concentration-time profiles of nirmatrelvir on a linear scale after a first-dose and b multiple-dose administration of nirmatrelvir/ritonavir 300 mg/100 mg in healthy Chinese and non-Chinese participants and on a semi-logarithmic scale after c first-dose and d multiple-dose administration. EC₉₀ 90% effective concentration

Fig. 2.

Individual and median plasma concentration-time profiles of ritonavir after a first-dose and b multiple-dose administration of nirmatrelvir/ritonavir 300 mg/100 mg in healthy Chinese and non-Chinese participants

Nirmatrelvir PK

After single doses and at steady-state, median time to nirmatrelvir maximum concentration (t_max) was observed to be 1.76 h after the first dose on day 1 and 2.00 h after the last dose on day 10 (Table 2). Nirmatrelvir mean half-life (t½) was 6.842 h following multiple dosing on day 10. After multiple-dose administration, the steady-state concentrations were likely achieved before day 5, based on similar median nirmatrelvir trough (pre-dose) plasma concentrations on day 5 to day 10 (data not shown), with drug accumulation for nirmatrelvir following multiple BID dosing less than 2-fold on day 10. Peak exposure based on geometric mean nirmatrelvir maximum concentration (C_max) was 3.082 µg/mL on day 1 and 4.500 µg/mL on day 10, and overall systemic exposure of nirmatrelvir based on geometric mean area under the concentration-time curve (AUC) over 12 h (AUC₁₂; day 1) and AUC over the dosing interval (AUC_tau; day 10) was 19.66 µg·h/mL and 32.01 µg·h/mL, respectively.

Urinary recovery of unchanged nirmatrelvir based on the percentage of the dose excreted over a 12-hour interval was 28.81% following a single dose on day 1 and 44.82% following multiple dosing on day 10, with geometric mean renal nirmatrelvir clearance values of 4.397 L/h and 4.201 L/h on days 1 and 10, respectively (Table 2).

Ritonavir PK

Following single and multiple BID oral doses, median ritonavir t_max was observed to be 2.00 h after dosing on days 1 and 10. Steady-state plasma ritonavir concentrations were likely achieved before day 5. Ritonavir plasma concentrations were higher after multiple dosing than after a single dose. Peak exposure based on geometric mean ritonavir C_max was 0.546 µg/mL on day 1 and 1.109 µg/mL on day 10, and overall systemic exposure based on geometric mean ritonavir AUC₁₂ (day 1) and ritonavir AUC_tau (day 10) was 3.136 µg·h/mL and 6.152 µg·h/mL, respectively. Ritonavir mean t½ was 5.471 h following multiple dosing on day 10.

Safety and Tolerability

A total of 10 all-causality AEs were reported for 6 (42.9%) participants (Table 3). Four of the AEs reported by 4 participants (28.6%) were treatment related, all of which were reports of dysgeusia. In all cases, dysgeusia was reported with day 2 onset and was mild in severity. No actions were taken, and all AEs of dysgeusia were resolved. No participants experienced any SAEs, severe AEs, AEs leading to discontinuation from study or study intervention, or AEs leading to dose reduction or temporary discontinuation.

One participant experienced increased blood creatinine on days 2 through 12, which was reported as an AE of increased blood creatinine and was mild in severity. Individual PK exposure (C_max, AUC, and C_trough) for this participant was within the range observed across the study population, with no evidence of increased exposure to nirmatrelvir or ritonavir. No actions were taken during the study, and the AE resolved on day 12. This AE was not considered treatment related by the investigator. No other laboratory abnormalities in this study were considered to be clinically significant by the investigator. There were no clinically significant changes in vital signs or ECGs.

Comparison of Ethnicities

As shown in Figs. 1 and 2, exposures of nirmatrelvir/ritonavir in the healthy Chinese participants in this study are generally comparable with the healthy non-Chinese participants in other Phase 1 studies [5], according to comparisons based on NCA results. The popPK model was evaluated and updated to fully characterize the PK of nirmatrelvir in the presence of ritonavir, and to evaluate potential covariates that may be important predictors of variability in co-administered nirmatrelvir/ritonavir PK using available data from completed Phase 1 and Phase 2/3 studies. The dataset contained 1237 participants, including 150 participants from Phase 1 studies and 1087 participants from a Phase 2/3 study; 162 (13.1%) participants were Asian. In this analysis, race was not retained in the final model as a significant covariate affecting clearance or volume of distribution, which means there is no evidence that Asian participants have a different rate of clearance or volume of distribution than other racial groups [12].

According to nirmatrelvir exposure simulations analysis, the change from baseline in viral load at day 5 did not show any general trend with nirmatrelvir exposure across the range observed in the analyzed population, suggesting that, even if there are differences between ethnicities in nirmatrelvir exposure, its impact on antiviral efficacy should be limited [4].

Discussion

This was the first study to assess the PK, safety, and tolerability of nirmatrelvir/ritonavir in Chinese adults. The dosage used (nirmatrelvir 300 mg and ritonavir 100 mg, BID) was the same as that used in the Phase 3 pivotal study Evaluation of Protease Inhibition for COVID-19 in High Risk Patients (EPIC-HR) [13]. The treatment duration was 10 days, which is the longest treatment duration in the completed Phase 1 and EPIC-HR. Although this dose was approved in China and other countries, five days of treatment for patients with COVID-19 who were at increased risk of progressing to severe illness proved to be sufficient. Thus, this Phase 1 study with 10-day dosing in a Chinese patient population provided a more robust safety profile over longer-term administration.

When given alone, nirmatrelvir is eliminated primarily through CYP450-mediated oxidation, with CYP3A4 as the major contributor (fraction metabolized, 0.99) and minimal renal excretion as unchanged nirmatrelvir [14]. To maintain unbound systemic trough concentrations above the in vitro antiviral EC₉₀, nirmatrelvir is co-administered with ritonavir, a PK enhancer [4]. Ritonavir inhibits the CYP3A4-mediated metabolism of nirmatrelvir, resulting in renal excretion being the primary route of elimination of nirmatrelvir. Based on these clearance pathways, marked differences in the exposure of nirmatrelvir are not anticipated between the Chinese/Asian and non-Chinese participants because the clearance of nirmatrelvir is correlated to renal function [15].

As shown in Fig. 1 and Table 2, the nirmatrelvir exposure in Chinese participants following a single dose (day 1) was slightly higher than in non-Chinese participants, with approximately 13.9% higher geometric mean AUC_tau and 39.5% higher geometric mean C_max. Importantly, both cohorts received the tablet formulation for their respective single-dose assessments; therefore, the day  1 differences reflect a tablet-versus-tablet comparison rather than a formulation effect. Additionally, according to a popPK analysis, body weight is a significant covariate on clearance and volume of distribution [16]. As shown in Table 2, median body weight in the Chinese group was lower than in the non-Chinese group, so the slight difference in exposure may also be attributed to this weight difference.

In contrast, nirmatrelvir PK parameters at steady state (day 10) in Chinese participants were slightly lower than non-Chinese participants, with approximately 4.0% lower geometric mean AUC_tau and 3.8% lower geometric mean C_max. This may be due to the respective formulations of tablets (used in Chinese participants) versus suspension (used in non-Chinese participants). Results from a previous relative bioavailability study show that nirmatrelvir plasma exposure was lower when formulated as a tablet versus suspension, with approximately 19% and 44% lower geometric mean AUC to time of last measurable concentration and C_max values, respectively [17]. Thus, the direction of the steady-state difference aligns with the established formulation effect—the tablet used in the Chinese participants tends to decrease exposure. At the same time, demographic differences—such as the lower body weight of Chinese participants—tend to increase exposure. Thus, the steady-state comparison represents the combined effect of formulation differences and population characteristics.

However, together with the popPK analysis, as well as both day 1 and steady-state NCA comparison results, the difference in PK is not considered clinically significant. The unbound trough concentrations were calculated using reported plasma fraction unbound for nirmatrelvir (f_u≈0.69) [18]. Mean total C_trough values after the first dose (mean [SD], 670.9 ng/mL [177.6]) and steady state (mean [SD], 1071 ng/mL) were converted to unbound concentrations of approximately 463 ng/mL and 739 ng/mL, respectively. Both values exceed the in vitro unbound EC₉₀ (292 ng/mL) in both groups (Fig. 1). Treatment was generally well tolerated in both the Chinese and non-Chinese groups.

Ritonavir was administered as a 100-mg dose in this study, which is the standard clinical dose for ritonavir as a PK enhancer. Lopinavir/ritonavir 400 mg/100 mg, BID (Ke Li Zhi, AbbVie Inc, China) and/or 800 mg/200 mg daily (KALETRA; AbbVie Inc., North Chicago, IL, USA) has been approved by the NMPA and the FDA, respectively [19, 20]. Population PK modelling of ritonavir has been conducted with results showing that no covariates, such as race or other genetic polymorphism, were retained in the final model [21]. As shown in Fig. 2 and Table 2, the PK profiles of ritonavir in Chinese and non-Chinese participants are generally comparable.

To further confirm the ethnic sensitivity analysis, a popPK model was used. As previously described, this popPK model was developed with available data from seven completed Phase 1 studies as well as EPIC-HR to fully characterize the PK of nirmatrelvir in the presence of ritonavir and to evaluate potential covariates that may be important predictors of variability in nirmatrelvir PK co-administered with ritonavir [12]. The dataset contained 1237 participants, including 150 from Phase 1 studies and 1087 from EPIC-HR, 162 of whom (13.1%) were Asian [12]. Race was not retained in the final model as a significant covariate on clearance or volume of distribution, indicating a lack of evidence that Asian participants have a clearance or volume of distribution that is different from other racial groups. Therefore, based on popPK analysis, there is no expectation of clinically significant difference between ethnicities in nirmatrelvir PK.

According to nirmatrelvir exposure simulations analysis, the change from baseline in viral load at day 5 did not show any general trend with nirmatrelvir exposure across the range observed in the analyzed population, suggesting that, even if there are differences between ethnicities in nirmatrelvir exposure, its impact on antiviral efficacy should be limited [4].

From a clinical efficacy perspective, treatment effects through day 28 demonstrated by the comparison of nirmatrelvir/ritonavir to placebo were consistent between the Asian and overall study populations in EPIC-HR [13]. From a safety perspective, treatment with nirmatrelvir/ritonavir was generally well tolerated in the healthy Chinese participants and Asian patients as observed, with no new safety signals seen compared with the global population [13].

Several limitations of these ethnic analyses should be acknowledged. First, the relatively small sample size of Chinese/Asian participants in clinical studies may limit detection of subtle ethnic differences. Second, although the dose amount and dose frequency were consistent between Chinese and non-Chinese participants in Phase 1 studies, differences in treatment duration complicate the direct comparisons across ethnic groups, especially safety profiles (PK profiles are generally comparable if taking drug exposure at steady state on day 2 into consideration). Furthermore, in the steady-state comparison, the use of distinct drug formulations (suspensions vs tablets) in Chinese and non-Chinese Phase 1 studies introduces potential variability in bioavailability that could not be fully accounted for in the PK bridging analysis. Finally, the extrapolation of efficacy findings to Chinese/Asian populations carries inherent uncertainty due to the limited clinical efficacy data from these groups in EPIC-HR [13]. These analyses relied on the assumption that achieving similar exposures would translate to comparable clinical efficacy outcomes—a hypothesis that requires further validation in ethnically diverse populations with robust clinical endpoints.

Even so, based on existing nirmatrelvir/ritonavir clinical development programs and the comprehensive analyses, no notable differences between ethnicities in PK and safety were seen. The indicated dose regimen of nirmatrelvir/ritonavir 300 mg/100 mg (BID) for the treatment of patients with COVID-19, which has been proven suitable in non-Chinese participants [13], is also suitable for the Chinese population.

Conclusions

In healthy Chinese participants, the PK profile of nirmatrelvir 300 mg plus ritonavir 100 mg twice daily was comparable with that observed in non-Chinese participants, with an overall favorable safety profile.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This study was funded by Pfizer. Pfizer was responsible for the study design and contributed to the conduct of the study, data collection, data analysis, data interpretation and writing of this manuscript.

Declarations

Conflicts of interest

Nanyang Li, Jicheng Yu, Jufang Wu, and Jing Zhang have no competing interests to declare. All other authors are employees of Pfizer and may hold stock or stock options.

Availability of data and material

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 deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Ethics approval

The study design was reviewed and accepted by the Chinese Center for Drug Evaluation and an independent ethics committee before study initiation. This study was conducted in accordance with the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, guidelines for Good Clinical Practice, and applicable laws and regulations. Ethics committee meeting number is 2021M-023, and approval letter ID is (2021) Lin Shen No. (1013).

Consent to participate

All participants provided written informed consent.

Consent for publication

Not applicable.

Code availability

Not applicable.

Author contributions

Nanyang Li: data curation, investigation, project administration, writing—original draft, writing—review and editing; Jicheng Yu: Data curation, investigation, project administration, writing—original draft, writing—review and editing; Jufang Wu: data curation, investigation, project administration, resources, supervision, writing—original draft, writing—review and editing; Jing Zhang: data curation, investigation, project administration, resources, supervision, writing—original draft, writing—review and editing; Ying Ma: conceptualization, data curation, formal analysis, methodology, validation, writing—original draft, writing—review and editing; Chunye Zhang: data curation, methodology, validation, writing—original draft, writing—review and editing; Xiaoran Han: conceptualization, data curation, formal analysis, methodology, validation, writing—original draft, writing—review and editing; Jackie Gerhart: conceptualization, data curation, methodology, resources, supervision, validation, writing—original draft, writing—review and editing; Shuangchen Cong: conceptualization, data curation, formal analysis, methodology, resources, supervision, validation, writing—original draft, writing—review and editing. Approval: all authors have read and approved the final version of the manuscript.