The infections caused by methicillin-resistant Staphylococcus aureus (MRSA), such as bloodstream infection, endocarditis, bone and joint infection, and skin and soft tissue infection, are usually associated with high morbidity and mortality (Turner et al., 2019; Johnson et al., 2021). According to China Antimicrobial Surveillance Network (CHINET), the average prevalence of MRSA was 31% in 2020 in the hospitals across China (Fupin et al., 2021).

Vancomycin has been the first choice and sometimes the last resort for treatment of serious MRSA infections (Lakhundi and Zhang, 2018). However, nephrotoxicity and emerging resistance have limited its clinical use. Linezolid, as the first oxazolidinone antibiotic available in clinical practice, is effective for managing the infections caused by MRSA (Rodvold and McConeghy, 2014) or vancomycin-resistant S. aureus (VRSA). However, longer treatment duration (>2 weeks) is linked to increased incidence of myelosuppression and other side effects (Gerson et al., 2002).

Contezolid (formerly known as MRX-I) is another oxazolidinone antibiotic newly approved in 2021 for treatment of complicated skin and soft tissue infections (cSSTIs) in China (Hoy, 2021). It has potent activity against Gram-positive bacteria, particularly the resistant strains such as MRSA, methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus (VRE) (Wu et al., 2020). Contezolid has a more favorable safety profile than linezolid in terms of myelosuppression and monoamine oxidase inhibition (Wu et al., 2020). The results of phase I studies in China and Australia have indicated that contezolid was rapidly absorbed after oral single dose administration. Plasma concentration reached peak about 2 h post dose. The maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) increased with dose, but the increase was not linear for doses above 800 mg (Eckburg et al., 2017; Wu et al., 2018). Contezolid was metabolized mostly by the liver, involving the oxidative opening of the dihydropyridine (DHPO) ring (Meng et al., 2015). About 0.8%–2.3% of the administered dose of contezolid was excreted in unchanged form via kidneys within 48 h after single-dose or multiple-dose administration (Wu et al., 2018).

A mass balance study in humans with a single oral dose [¹⁴C]contezolid reported that 91.5% of the administered dose was recovered from urine (76.7% of the dose) and feces (14.8% of the dose) over a 168-h period after administration. The unchanged contezolid recovered from both urine and feces over 168 h accounted for less than 3% of the dose. The DHPO ring opening via Baeyer-Villiger oxidation is the main metabolic pathway of contezolid in humans, which generates metabolites M2 and MRX459. The recovery of M2 and MRX459 from urine and feces was approximately 48% and 15% of the dose, respectively (Wu et al., 2021).

Considering the fact that contezolid is mainly metabolized in the liver, it is reasonably expected that hepatic impairment might affect, to some extent, the metabolism and excretion of contezolid. Currently, it is not clear whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment. For this reason, we designed this study to compare the pharmacokinetics (PK) and safety of contezolid between patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration. Monte Carlo simulation was also performed to assess the necessity for dose adjustment in patients with moderate hepatic impairment based on the PK and pharmacodynamic (PD) data (Chua et al., 2021).

The liver plays a central role in the metabolism and elimination kinetics of most drugs and their active or non-active metabolites (Flanagan et al., 2014). The United States Food and Drug Administration guidance recommends PK studies in patients with impaired hepatic function if >20% of the absorbed dose of a drug is eliminated by the liver. Majority of the administered contezolid dose (>97%) is metabolized in the liver (Wu et al., 2018). Therefore, it is required to clarify whether the dose of contezolid should be adjusted in patients with moderate hepatic impairment because contezolid may be prescribed as an alternative antimicrobial therapy in such patients.

Our preliminary data indicated that moderate hepatic impairment did not affect the drug exposure (AUC) after a single oral administration of 800 mg contezolid under fed condition compared with normal liver function volunteers even though lower C_max in the patients with moderate hepatic impairment. The unbound drug AUC to MIC (fAUC/MIC) ratio was recognized as the best PK/PD index for predicting the clinical efficacy of contezolid. According to Monte Carlo simulation results, at the proposed AUC/MIC target value of 2.3, contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) in subjects with moderate hepatic impairment. Meanwhile, the results of PK/PD analysis for the subjects with normal liver function were consistent with the results in a previous study (Wu et al., 2019), which further supports the reliability of our simulation results for the patients with moderate hepatic impairment. Therefore, it is not required to adjust the dose of contezolid in patients with moderate hepatic impairment.

In a previous Phase I, single-center, three-part, randomized study evaluating the PK and safety of single and multiple oral doses of contezolid in healthy Chinese adults, contezolid was rapidly absorbed after oral administration. The t_1/2 was approximately 2.8–4.8 h when the drug was taken with food. About 2% of the administered dose of contezolid was excreted via kidneys in unchanged form (Wu et al., 2018). A previous clinical study in healthy Chinese subjects showed that the mean C_max and AUC_0–23.5h of contezolid was 26.5 μg/mL and 96.8 h μg/mL after a single oral dose of 800 mg contezolid under fed condition. The results of the healthy subjects with normal liver function in this study are consistent with the results of previous PK study, which reinforces the validity of this study (Wu et al., 2019).

As demonstrated by the concentration-time curves, the patients with moderate hepatic impairment showed lower C_max associated with a significantly longer T_max (3.98 vs. 2 h) compared to the healthy controls. However, the AUC_0–∞ of contezolid did not show significant difference between the two groups (107.02 vs. 97.07 h μg/mL, p = 0.63). Other PK parameters were also comparable between the two groups. Most of the PK parameters of M2 were also similar between the patients with moderate hepatic impairment and healthy controls, except AUC_0–24h of M2, which was significantly lower in the patients with moderate hepatic impairment (18.47 vs. 25.47 h μg/mL, p = 0.05). The metabolism and elimination of contezolid were compared in terms of the PK parameter ratios between the patients with moderate hepatic impairment and healthy controls based on several previous studies (Figure 4 ) (Meng et al., 2015; Wu et al., 2018; Wu et al., 2019; Wu et al., 2021), which highlights the main metabolism and elimination pathways of contezolid. In our study, the mean plasma exposure of M2 following a single oral dose of 800 mg contezolid was 17.3% in the patients with moderate hepatic impairment and 26.2% in healthy controls. The ratio of total cumulative urinary excretion (contezolid and M2 which was converted to contezolid) between the two groups was 37.3% and 43.2%, respectively, which suggests that moderate hepatic impairment does not have significant effect on the metabolism and elimination of contezolid. The change of cumulative amount excreted in urine was consistent with the differential exposure of contezolid between the two groups. Moderate hepatic impairment was associated with slightly higher AUC of contezolid, but lower exposure of M2 compared to the healthy controls, which indicates lower metabolic change of contezolid in patients with moderate hepatic dysfunction. Another oxazolidinone, tedizolid, is eliminated mainly by hepatic excretion via bile. About 80% of the administered dose is eliminated in feces. Both contezolid and tedzolid exhibit high protein binding (90% vs. 80%). Patients with moderate or severe hepatic impairment presented approximately 22% and 34% higher AUC_0–∞, respectively compared with those in the control group after a single oral dose of 200 mg tedizolid phosphate. Therefore, no dose adjustment is required for tedizolid phosphate in patients with any degree of hepatic impairment (Flanagan et al., 2014). Similarly, a lower exposure change of the contezolid was observed in patients with moderate hepatic impairment compared to healthy controls, suggesting that contezolid AUC might not increase significantly in patients with severe hepatic impairment.

Gastrointestinal dysfunction has been described in patients with liver disease, which may affect the absorption of orally administered drugs (Verbeeck, 2008). In the population PK studies conducted by Li et al. (2020) and Yuan et al. (2022) in healthy volunteers and patients, PK variability of contezolid was heavily affected by body weight, food effect, and disease status rather than liver or renal function. Disease status could significantly affect the absorption rate and peripheral volume of distribution. The lower C_max and prolonged T_max in the patients with moderate hepatic impairment may be explained by the slower absorption rate of contezolid in cirrhotic patients compared with the healthy controls with normal liver function. Yuan et al. (2022) reported that food, subject type, and body weight were significant covariates for the PK parameters of contezolid. In these two studies, body weight was a significant covariate for V2 and CL, and the effect on the apparent volume of distribution is more notable. In the present study, body weight did not show significant difference between the two groups (p > 0.05). Therefore, the change of contezolid exposure was not due to body weight.

Liver disease is usually associated with extensive genetic regulation of cytokines and drug-metabolizing enzymes (Dietrich et al., 2016; El-Khateeb et al., 2021). However, non-CYP and non-UGT enzymes did not show significant difference in their relative distribution between the healthy controls and patients with liver disease (El-Khateeb et al., 2021). Through incubation of human liver microsomes, cytosol, and S9 fractions, liver cytosol-fortified recombinant flavin-containing monooxygenases (FMOs), and human hepatocytes in the presence of contezolid, the enzymes involved in the metabolism of contezolid were identified as FMOs, aldo-keto reductase (AKR), short-chain dehydrogenase/reductase (SDR), aldehyde dehydrogenase (ALDH), and aldehyde oxidase (AO), but no CYP enzymes were involved (Meng et al., 2015). The reduction in the expression of metabolizing enzymes is typically associated with reduced drug clearance and increased AUC. The mean level of albumin was 32.0 g/L (95% CI: 27.31, 36.69) in the patients with moderate hepatic impairment and 47.7 g/L (95% CI: 45.04, 50.29) in healthy controls in the present study. Serum creatinine level did not show significant difference between the two groups. The decreased AUC and cumulative urinary excretion of M2 in patients with moderate hepatic impairment may support the hypothesis that moderate hepatic impairment has minimal effect on the metabolism of contezolid in the liver.

The single-dose study design is a limitation of this study. This was based on the following considerations. Firstly, contezolid demonstrated linear PK when the dosage was not higher than 800 mg, and no accumulation was found after multiple doses of contezolid (Wu et al., 2018; Wu et al., 2019). Secondly, the single-dose PK study for contezolid in patients with moderate hepatic impairment may be satisfactory according to the guidance for industry on the evaluation of the PK of medicinal products in the patients with impaired hepatic function issued by FDA (Guidance, 2003). The unbound concentration of contezolid was not determined. This is also a limitation of this study. However, albumin concentration was lower in moderate hepatic impairment group, which might be associated with higher unbound contezolid concentration because of high plasma protein binding of contezolid, which may represent higher fAUC_0–24h/MIC to treat the target pathogen.

In the population PK studies mentioned previously, liver function, and renal clearance did not exert significant impact on the PK behavior of contezolid, which may also support the result that moderate hepatic function impairment has minimal effect on the PK of contezolid. Viral infections may have some effect on drug metabolism. Some of the patients included in this study had viral hepatitis, but they were receiving stable treatment. Those with acute or subacute hepatic failure, or discontinuing antiviral drug within 1 year were excluded. The patients included in this study had a stable and moderate hepatic impaired liver disease. Viral infection was not considered a significant confounding factor in this study. Our study population was also consistent with the study population recommended in the Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function” from European Medicines Agency (Guideline, 2023). It is important to note that only moderate hepatic impaired patients were included in this study, caution should be exercised when prescribing contezolid for the patients with severe hepatic impairment. In addition, the small sample size in this study may weaken the conclusion. The data should be interpreted cautiously and the safety of contezolid will be further evaluated in more hepatic impaired patients after treatment with the recommended dosing regimen in post-marketing safety surveillance.

Our study demonstrated that the AUC of contezolid was similar between the patients with moderate hepatic impairment and the healthy controls with normal liver function, even though significantly lower C_max in the patients with moderate hepatic impairment. Ae_0–48h and CL_R of contezolid did not show significant difference between the two groups. Monte Carlo simulation results support that at the proposed AUC/MIC target value of 2.3, the dosing regimen of contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) in patients with moderate hepatic impairment. Therefore, dose adjustment is not required for contezolid in case of moderate hepatic impairment.