Drug-Drug Interaction of Chiglitazar with Empagliflozin, Atorvastatin, and Valsartan: An Open-Label, Single-Center, Self-Control, 3-Period Study

Introduction

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by the dual pathologies of insulin resistance and dyslipidemia.^1,2 For instance, polymorphisms such as ICAM1 rs5498 have been associated with increased diabetes risk through inflammatory pathways,³ underscoring the role of inflammation in diabetes pathogenesis and complication development. Peroxisome proliferator-activated receptors (PPARs), which include the α, γ, and δ isoforms, are nuclear receptors central to the regulation of glucose and lipid metabolism,⁴ and also modulate inflammatory responses.³ While traditional PPARγ agonists like thiazolidinediones (TZDs) effectively lower blood glucose, their clinical utility is often hindered by adverse events (AEs) such as weight gain, edema, and potential cardiac complications,^5–7 prompting the development of next-generation agents like dual- or pan-PPAR agonists that offer a safer, more comprehensive metabolic regulation approach.

Chiglitazar (Bilessglu®), a non-thiazolidinedione pan-PPAR agonist, was approved in China for treating T2DM, initially as an adjunct therapy in October 2021 and later for use in combination with metformin for patients inadequately controlled by metformin alone in July 2024.^8,9 Chiglitazar exhibits a moderate and well-balanced activation profile across all three PPAR subtypes, reflected by half maximal effective concentration (EC₅₀) values of 1.1 μM for PPARα, 0.08 μM for PPARγ, and 1.7 μM for PPARδ.^10,11 Beyond improving insulin sensitivity, chiglitazar effectively optimizes lipid parameters by lowering triglycerides and free fatty acids while elevating high-density lipoprotein cholesterol (HDL-C).^12–15 This multifaceted activity is further complemented by potential anti-inflam3 cit0014 cit0015atory effects and a reduced risk of typical TZD-associated AEs.^12,16–18

The disposition of chiglitazar suggests a potential for drug-drug interactions (DDIs). In vitro data indicate that it is metabolized predominantly by cytochrome P450 (CYP) 3A4/5 and is likely a substrate for the efflux transporter P-glycoprotein (P-gp).^8,19 Notably, a previous clinical trial reported an unexpected increase in chiglitazar exposure when co-administered with rifampicin, suggesting that non-CYP pathways, such as transporter modulation, play a significant role in its disposition.²⁰ Beyond its own pharmacokinetic (PK) profile, chiglitazar exhibits inhibitory effects on the organic anion transporting polypeptides (OATP) 1B1 and 1B3 in vitro, with corresponding IC₅₀ values of 0.29 μM and 2.76 μM, respectively (data on file, Chipscreen Biosciences Co. Ltd). However, the net DDI outcome is often shaped by a complex interplay between hepatic and intestinal transporters (eg., OATP2B1), where absorption-related mechanisms can yield results that contrast with classical systemic uptake inhibition. Acknowledging this complexity is essential for a comprehensive interpretation of chiglitazar’s in vivo interactions. Because hepatic OATPs are critical determinants for the clearance of a broad spectrum of xenobiotics,²¹ their inhibition can precipitate clinically meaningful DDIs, necessitating risk assessment with specific probe substrates. Several widely used agents, including the HMG-CoA reductase inhibitor atorvastatin and the angiotensin II receptor blocker valsartan, are well-established OATP1B1 substrates and are thus susceptible to such interactions.^22,23 In addition to established statins, newer lipid-lowering strategies such as PCSK9 inhibitors (eg., the novel small-molecule E28362) are emerging for managing hyperlipidemia in diabetic patients,²⁴ further highlighting the necessity of evaluating DDIs in evolving polypharmacy regimens. Empagliflozin, the sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been identified as a substrate of the OATP1B1 and OATP1B3 transporters in a clinical DDI study, though this interaction was not considered clinically significant.²⁵ While hepatic OATP inhibition typically increases substrate exposure, the interplay between transporters is complex; for instance, intestinal transporters like OATP2B1 also contribute to drug absorption. Inhibition of these intestinal uptake transporters could theoretically reduce bioavailability, leading to decreased systemic exposure—an effect opposite to that of hepatic uptake inhibition.

Given that T2DM management frequently involves polypharmacy to address comorbidities like hypertension and dyslipidemia, evaluating chiglitazar’s interactions with commonly co-administered medications is paramount for ensuring patient safety and therapeutic efficacy. The exploration of multi-target therapeutic strategies, including those investigated for conditions such as cardiomyopathy, underscores the importance of understanding drug interactions in complex regimens.²⁶ To our knowledge, while the DDI profiles of other PPAR agonists have been investigated, the potential for OATP-mediated interactions has not been clinically characterized for an approved pan-PPAR agonist. Therefore, the objective of this study aimed to investigate the potential for DDIs between chiglitazar and three widely prescribed OATP1B1 and OATP1B3 substrates: empagliflozin, atorvastatin, and valsartan.

Methods

Ethics

The study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) guidelines and the Declaration of Helsinki, and was performed at Zhongshan Hospital, Fudan University (No.180, Fenglin Road, Xuhui District, Shanghai, China). The study was approved by an Independent Ethics Committee of Zhongshan Hospital, Fudan University on 25 Nov 2022 (Approval number: 2022–184).

Study Design

This was an open-label, single-center, self-controlled, three-period study designed to evaluate the pharmacokinetic DDIs between chiglitazar (Chipscreen Biosciences, China) and empagliflozin (Boehringer Ingelheim Pharma GmbH & Co.KG, Germany), atorvastatin (Pfizer Inc., USA), and valsartan (Beijing Novartis Pharma Co., Ltd, China) in healthy Chinese participants (clinical trial registration: NCT05681273). The study consisted of three dosing periods, spanning from Day 1 to Day 4 (probe substrates), Day 5 to Day 9 (chiglitazar), and Day 10 to Day 12 (co-administration), respectively (Table 1). Eligible participants were allocated into one of three dose groups (Group A, Group B, and Group C) according to the sequence of screening number, with all doses administered 30 minutes subsequent to a standard meal. In each group, participants received a single oral dose of 10 mg empagliflozin, 20 mg atorvastatin, or 160 mg valsartan on Day 1, followed by an oral dose of 48 mg chiglitazar once daily from Day 5 to Day 9 to achieve steady-state plasma levels. On Day 10, participants received a last single dose of 48 mg chiglitazar, concurrently with a single dose of either 10 mg empagliflozin, 20 mg atorvastatin, or 160 mg valsartan. The continuous 5-day pretreatment dosing regimen for chiglitazar was established based on its elimination half-life of 9.0–11.9 hours to ensure that steady-state plasma concentrations were achieved prior to co-administration. Participants or the public were not involved in the design, conduct, or reporting of this study.

Table 1 Study Schematic and Treatment Schedule

Study Participants

Eligible participants were healthy Chinese volunteers aged between 18 and 45 years, with a minimum weight of 50 kg for males and 45 kg for females, and a body mass index (BMI) ranging from 19.0 to 26.0 kg/m². The primary exclusion criteria included: a history of drug abuse; a history of clinically significant drug allergies or atopic allergic conditions; a history of tuberculosis, hypoglycemia, or syncope; a history of recurrent infections (≥ 3 episodes) within the past year, or a history of severe infections leading to hospitalization in the 3 months prior to dosing; consumption of grapefruit juice or grapefruit-containing products within 14 days prior to dosing; use of any prescription or over-the-counter medications, vitamin supplements, or herbal products within 1 month prior to dosing; a glomerular filtration rate (GFR) of < 80 mL/min (calculated using the Cockcroft-Gault equation); and a fasting blood glucose level of < 3.9 mmol/L at screening. During the screening period (Day −28 to Day −2), participants underwent comprehensive screening including physical exams, medical history, 12-lead ECG, chest X-ray, laboratory tests, and screenings for infectious diseases, drugs of abuse, and pregnancy. Participants avoided all medications for 30 days and abstained from alcohol, caffeine, and grapefruit products for 14 days prior to dosing on Day 1.

Analytical Methods

Concentrations of chiglitazar, empagliflozin, atorvastatin and its metabolite, 2-hydroxy atorvastatin, and valsartan in plasma were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The method was validated for plasma samples of chiglitazar within the range of 4.00 to 2000 ng/mL, with a lower limit of quantification (LLOQ) of 4.00 ng/mL. It was also validated for plasma samples of empagliflozin, spanning from 1.00 to 400 ng/mL, with an LLOQ of 1.00 ng/mL. For atorvastatin, the method was validated in plasma samples from 0.05 to 50.0 ng/mL, with an LLOQ of 0.05 ng/mL. Similarly, plasma samples of 2-hydroxy atorvastatin were validated within a range of 0.05 to 50.0 ng/mL, with an LLOQ of 0.05 ng/mL. Ultimately, valsartan was validated in plasma samples with concentrations ranging from 20.0 to 5000 ng/mL, exhibiting an LLOQ of 20.0 ng/mL. Overall, twelve analytical runs were processed for chiglitazar with assay precision and accuracy of quality control (QC) samples ranging from 2.90 to 3.68% coefficient of variation (CV) and −3.13% to 4.17% relative error (RE). For empagliflozin, five runs showed assay precision and accuracy ranging from 3.20% to 5.77% CV and −2.25% to 2.67% RE. Four runs for atorvastatin yielded a CV range of 2.52% to 8.09% and RE between −1.66% and 1.33%, while for the metabolite 2-hydroxy atorvastatin, CV ranged from 2.98% to 9.87% and RE from 0.53% to 1.50%. Finally, five runs for valsartan showed assay precision and accuracy of QC samples with CV between 3.03% and 4.03% and RE from −1.00% to 1.17%. Plasma samples with concentrations exceeding an upper limit of quantification (ULOQ) were re-analyzed after appropriate dilution with blank matrix, following a pre-validated dilution integrity protocol to ensure accuracy and precision.

Pharmacokinetic Analysis

Serial blood samples for measurement of plasma concentrations of chiglitazar, empagliflozin, atorvastatin and its metabolite, 2-hydroxy atorvastatin, and valsartan were collected on Day 1 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 h), Day 9 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24h), and Day 10 (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 h). A total of 41 blood PK samples (123 mL in total) were collected from each participant over the three study periods (15 samples on Days 1–4, 12 samples on Day 9, 15 samples on Days 10–13) to ensure a comprehensive PK assessment. To ensure sampling efficiency, the 24 h PK sample following the final dose of chiglitazar on Day 9 coincided with the predose (0h) sample after the co-administration dose on Day 10.

The PK parameters for chiglitazar, empagliflozin, atorvastatin and its metabolite, 2-hydroxy atorvastatin, and valsartan were calculated using non-compartmental methods in Phoenix WinNonlin software (version 8.3.5; Certara, Princeton, NJ, USA). The main parameters calculated included maximum observed plasma concentration (C_max), time to reach maximum concentration (T_max), terminal elimination half-life (t_1/2), apparent oral clearance (CL/F), apparent volume of distribution during the terminal elimination phase following extravascular administration (V_d/F), area under the concentration-time curve (AUC) from time 0 to 24 hours (AUC_0–24h), from time 0 to the last quantifiable concentration (AUC_0–t), from time 0 to infinity (AUC_0–inf).

Safety Assessments

Safety assessments during the study included physical examinations, vital signs, 12-lead electrocardiograms (ECGs), laboratory tests (hematology, chemistry, and urinalysis), and the monitoring of AEs. Vital signs (blood pressure, heart rate, respiratory rate, and ear temperature) were measured at screening, baseline, and at 2, 24, 48, and 72 h following the first dose in each period (with an additional 96 h measurement for Period 2). Twelve-lead ECGs were recorded at screening, baseline, and at the completion of each period (the morning of Day 4, Day 9, and Day 13). Laboratory assessments were measured sequentially at the completion of each period (Day 4, Day 9, and Day 13). AEs were categorized utilizing the Medical Dictionary for Regulatory Activities (MedDRA, version 25.1) and evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

Statistical Methods

The PK parameters were summarized as geometric mean with standard deviation (SD), except for T_max, which was reported as a median value with range. The PK parameters (C_max, AUC) were analyzed using a linear mixed-effects model after natural logarithmic transformation, with different treatments (monotherapy and combination therapy) as fixed effects, and subjects as random effects. The statistical model is as follows:

In the model, Yij represents the dependent variable, ie., PK parameter (AUC or C_max) for the i-th subject at the j-th dosing stage; µ is the overall mean effect; S_i is the random effect for the i-th subject; β is the coefficient for the fixed effect for the j-th dosing stage (P_j); and ε_ij is the random error.

The adjusted mean difference (monotherapy and combination therapy) and its 90% confidence interval (CI) were used to estimate the corresponding geometric least-squares mean (GLSM) ratio (combination therapy vs. monotherapy) of the PK parameters, along with the 90% CI. If the 90% CI falls entirely within the 80–125% range for bioequivalence, it is concluded that there is no clinically significant DDI. Assuming a geometric mean ratio (GMR) of 1.05 and an intra-subject coefficient of variation (CV) of 10–40% for AUC and C_max, a sample size of 16 participants per group would provide greater than 80% power to ensure the 90% CI falls within the specific corresponding limits (eg., 65.0%–153.7% at 40% CV). All statistical analyses were performed using the Statistical Analysis System (SAS) (version 9.4, SAS Institute Inc, Cary, North Carolina, USA).

Results

Participant Disposition and Demographics

From Feb 2023 to Mar 2023, a total of 48 healthy Chinese participants were enrolled and assigned to one of three treatment groups (N=16 for each group). The demographic and baseline characteristics were comparable across the three groups (Table 2). All 48 participants completed the initial dosing periods; however, one participant in Group C discontinued the study due to moderate AEs (alanine aminotransferase increased, aspartate aminotransferase increased, and blood creatine phosphokinase increased), resulting in 47 participants completing the final co-administration phase.

Table 2 Demographics and Baseline Characteristics

Pharmacokinetics

Effect of Co-Administered Drugs on the PKs of Chiglitazar

The mean plasma concentration-time profiles (semi-log scale) for chiglitazar following multiple doses of chiglitazar alone and with a single dose of empagliflozin, atorvastatin, and valsartan are shown in Figure 1. Corresponding chiglitazar PK parameters and the GLSM ratios (90% CIs) are shown in Table 3.

Table 3 Pharmacokinetic Parameters of Chiglitazar with and without Co-Administration of Empagliflozin, Atorvastatin, or Valsartan

Figure 1 Mean (± SD) plasma concentration-time profiles of chiglitazar on a semi-logarithmic scale. The profiles show chiglitazar concentrations following multiple doses of chiglitazar 48 mg alone (steady state, Day 9) and co-administered with a single dose of (a) empagliflozin 10 mg, (b) valsartan 160 mg, or (c) atorvastatin 20 mg (Day 10). The blue circles represent chiglitazar administered alone, while the squares (red, purple, or Orange) represent chiglitazar co-administered with the respective probe drugs. Abbreviation: SD, standard deviation.

The systemic exposure of chiglitazar remained stable and was not significantly affected by the co-administration of empagliflozin, atorvastatin, or valsartan. In the assessment of DDI effects on chiglitazar, the GLSM ratios for its C_max and AUC_0-24h were within the conventional bioequivalence range of 80% to 125%.

Effect of Chiglitazar on the PKs of Co-Administered Drugs

The mean plasma concentration-time profiles (semi-log scale) for the probe substrates (empagliflozin, valsartan, atorvastatin and its metabolite, 2-hydroxy atorvastatin) when administered alone or co-administered with chiglitazar are shown in Figure 2. Corresponding PK parameters of the probe substrates and the GLSM ratios (90% CIs) are presented in Figure 3 and Tables 4 and 5.

Table 4 Pharmacokinetic Parameters of Empagliflozin and Valsartan with and without Co-Administration of Chiglitazar

Table 5 Pharmacokinetic Parameters of Atorvastatin and Its Metabolite, 2-Hydroxy Atorvastatin, with and without Co-Administration of Chiglitazar

Figure 2 Mean (± SD) plasma concentration-time profiles of probe substrates on a semi-logarithmic scale. The profiles show concentrations of probe substrates following a single oral dose administered alone (Day 1) or co-administered with chiglitazar 48 mg at steady state (Day 10). Panels depict concentrations for (a) empagliflozin, (b) valsartan, (c) atorvastatin, and (d) 2-hydroxy atorvastatin. The blue squares represent the probe substrate co-administered with chiglitazar, while the circles (red, purple, Orange, or yellow) represent the probe substrate administered alone.

Figure 3 The effect of steady-state chiglitazar on the pharmacokinetics of co-administered probe substrates. The forest plot presents the geometric least squares mean (GLSM) ratios and their corresponding 90% confidence intervals (CIs) for the peak plasma concentration (Cmax) and the area under the plasma concentration–time curve from time zero to infinity (AUC0–inf) of empagliflozin, atorvastatin, and valsartan. Results are shown for probe substrates co-administered with chiglitazar (test) relative to the probe substrate administered alone (reference). The blue shaded area represents the bioequivalence limit of 0.80–1.25.

The systemic exposure of the three co-administered drugs (empagliflozin, atorvastatin, and valsartan) was differentially altered when co-administered with chiglitazar. For instance, co-administration with chiglitazar resulted in a minor increase in empagliflozin exposure, with empagliflozin AUC_0-inf and C_max increasing approximately 1.9% and 13.1%, respectively, which largely remained in the 80%–125% bioequivalence range (Table 4 and Figure 3). Conversely, when co-administered with chiglitazar, valsartan AUC_0-inf and C_max were 14.3% and 24.7% lower, respectively (Table 4). A similar reduction was observed for atorvastatin. When co-administered with chiglitazar, atorvastatin AUC_0-inf and C_max decreased by 26.6% and 26.9%, respectively (Table 5). In contrast, the exposure of its primary metabolite, 2-hydroxy atorvastatin, was not significantly changed, with its AUC_0-inf and C_max decreasing by only 7.7% and 1.2%, respectively. For valsartan and atorvastatin, the 90% CIs for AUC_0-inf and C_max extended below the 80% lower bioequivalence limit (Tables 4, 5 and Figure 3). Conversely, the exposures of 2-hydroxy atorvastatin and empagliflozin were well within these limits (Tables 5 and Figure 3), with only empagliflozin C_max slightly exceeding the upper boundary.

Safety and Tolerability

Chiglitazar was generally safe and well-tolerated, when administered alone or co-administered with empagliflozin, valsartan, and atorvastatin. A total of 8/48 (16.7%) participants experienced at least one AE, and 7/48 (14.6%) participants experienced AEs that were considered by the investigator to be treatment-related (Table 6). All AEs were mild (Grade 1) except the three AEs reported by a participant in Group C, who had increased alanine aminotransferase (Grade 2), increased aspartate aminotransferase (Grade 2), and increased blood creatine phosphokinase (Grade 2). This participant discontinued the study drug due to these AEs. No serious AEs or deaths occurred during the study.

Table 6 Treatment-Emergent Adverse Events (TEAEs) per Treatment Group

Discussion

This study provided the first clinical evidence on the OATP-mediated DDI profile of the pan-PPAR agonist chiglitazar with three OATP1B1/1B3 substrates (empagliflozin, atorvastatin, and valsartan) in healthy Chinese participants. Our principal findings revealed the PK profiles of chiglitazar were not affected by co-administration of these agents. Chiglitazar had a negligible effect on empagliflozin exposure and slightly reduced atorvastatin and valsartan exposure; however, the reduction was not expected to have a clinical significance, and chiglitazar can be co-administered with these agents without dose adjustments. These results highlight the potential for chiglitazar to be safely integrated into multi-drug regimens for diabetes management, which may also include adjuvant therapies targeting diabetic complications.²⁷

The most intriguing finding of this study was the moderate reduction in atorvastatin and valsartan exposure, which contradicts the initial hypothesis based on in vitro OATP1B1/B3 inhibition data. In vitro studies have shown that chiglitazar inhibits OATP1B1 and OATP1B3 (data on file, Chipscreen Biosciences Co. Ltd)., for which valsartan and atorvastatin are known substrates.^22,23 An increase in their systemic exposure of these two drugs would therefore be anticipated when co-administered with chiglitazar. In contrast to our initial expectation, a slight reduction was found in the systemic exposure of both atorvastatin and valsartan. This observed disparity indicates that a different mechanism of action, which may surpass the effect of hepatic OATP1B inhibition, could potentially prevail in vivo. We hypothesize that the observed reduction in exposure stems from the inhibition of intestinal uptake transporters by chiglitazar. Transporters such as OATP2B1 may play a role in the absorption of atorvastatin and valsartan from the gut lumen. If chiglitazar inhibits the absorption by OATP2B1, it could reduce the oral bioavailability of the co-administered drugs, leading to lower systemic exposure. This proposed mechanism is further supported by the PK profiles, where the reduction in C_max (26.9% for atorvastatin and 24.7% for valsartan) was comparable to or greater than the reduction in AUC_0-inf (26.6% and 14.3%, respectively). Such a pattern is characteristic of an impaired absorption process rather than an alteration in systemic clearance. This dominant intestinal inhibition carries significant implications, suggesting that chiglitazar’s effect on uptake transporters could be more decisive than its effect on hepatic clearance for drugs with narrow absorption windows. Future research, perhaps employing microdosing of specific OATP2B1 probes or clinical trials in patients with varying transporter polymorphisms, is required to confirm whether this intestinal effect extends to other class of medications. Apart from OATP2B1 inhibition, other potential mechanisms should be fully considered. For instance, chiglitazar might influence gastric emptying or gastrointestinal motility, which could delay or reduce the absorption of probe drugs. Additionally, chiglitazar could act as an activator or inducer of intestinal efflux transporters (eg., P-gp or BCRP), thereby limiting the net uptake of atorvastatin and valsartan. Interactions involving bile transporters or altered enterohepatic circulation could also contribute to the disposition of these agents, as observed in previous chiglitazar studies involving biliary pathways. However, current evidence remains speculative to confirm which specific pathway predominates.

Despite the 90% CIs for atorvastatin and valsartan ratios extending below the 80% bioequivalence boundary, these PK interactions are not considered clinically significant. For atorvastatin, the observed 26.6% decrease in AUC_0-inf is minor within the range of its wide therapeutic window. The approved 10–80 mg dose range corresponds to an approximately 17-fold variation in the AUC of total active atorvastatin equivalents, all within the established therapeutic range.²⁸ Crucially, this slight reduction is comparable to or less than that caused by interactions for which dose adjustments are not recommended, such as with colestipol (26% reduction in C_max) or maalox (33% reduction in C_max and 34% reduction in AUC).²⁹ These precedents establish that changes of this magnitude are clinically acceptable. Similarly, the reduction (AUC_0-inf by 14.3% and C_max by 24.7%) for valsartan is well within its accepted exposure variability. The prescribing information for valsartan acknowledges that co-administration with food can reduce its exposure (AUC by ~40% and C_max by ~50%) without compromising its clinical efficacy, as evidenced by the instruction that it can be taken with or without food.³⁰ The PK effect of chiglitazar is therefore substantially less than that of a food effect, which already requires no dose modification. These PK interactions are smaller than or comparable to other documented precedents that have been established as clinically insignificant for both atorvastatin and valsartan. Since both atorvastatin and valsartan demonstrate relatively flat dose-response curves at standard clinical doses, a reduction of this extent is unlikely to translate into a measurable loss of pharmacodynamic efficacy, such as LDL-C reduction or blood pressure control. Therefore, no dose adjustments are warranted when chiglitazar is co-administered with atorvastatin or valsartan.

When co-administered with empagliflozin, atorvastatin, and valsartan, the PK stability of chiglitazar is consistent with its established profile and further strengthens its potential clinical utility in polypharmacy settings. Previous studies have shown that the PKs of chiglitazar were not significantly affected by the strong CYP3A4 inhibitor itraconazole and the widely used antihyperglycemic agent metformin, demonstrating its resilience to common metabolic interaction pathways.^20,31 Regarding P-gp, chiglitazar is a substrate, while atorvastatin acts as both a substrate and a weak inhibitor. However, atorvastatin’s clinical C_max (~ 0.02 µM) is significantly below its reported IC₅₀ (>100 µM) for P-gp,^28,32 resulting in a negligible I/K_i ratio that precludes significant systemic inhibition.³³ Furthermore, since chiglitazar is primarily cleared by CYP3A4-mediated metabolism,⁸ P-gp-mediated transport is unlikely the rate-limiting step in its elimination. Paradoxically, co-administration with the strong CYP3A4 inducer rifampicin was found to substantially increase chiglitazar exposure (C_max by nearly 100% and AUC_0-t by over 50%), a finding hypothesized to result from competitive inhibition of biliary transporters like the bile salt export pump (BSEP) rather than classic enzyme induction.²⁰ Chiglitazar demonstrated a negligible effect on empagliflozin exposure, with PK parameters remaining largely within bioequivalence limits, indicating this combination can be used without dose adjustment.

Moreover, a limitation of this study is the absence of a definitive mechanistic explanation for the reduction in atorvastatin and valsartan exposure. Although we hypothesized that chiglitazar might inhibit intestinal uptake transporters (eg., OATP2B1), this remains a mechanistic hypothesis that lacks direct validation. Future studies using specific endogenous biomarkers or physiologically based pharmacokinetic (PBPK) modeling are essential to confirm these pathways. Furthermore, future studies incorporating advanced diagnostic and monitoring tools, such as serum Raman spectroscopy combined with machine learning models (eg., DBAN) for the early detection of diabetic kidney disease, could further elucidate the clinical impact of these PK interactions and enhance patient-specific therapeutic strategies.³⁴ Additionally, the small sample size (N=16) and use of single-dose probe substrates may not fully capture rare individual variations or long-term cumulative effects observed in chronic clinical dosing. Constraints also arise from the open-label design and the recruitment of healthy Chinese participants, which potentially restricts the generalizability of these findings to broader ethnic populations or to patients with T2DM.

Conclusion

In this study, the PKs of chiglitazar were not affected by co-administration with empagliflozin, atorvastatin, or valsartan. Although chiglitazar slightly reduced the systemic exposure of atorvastatin and valsartan that fell outside the standard bioequivalence limits, these reductions were not considered clinically significant based on the wide therapeutic windows and known exposure variability of the co-administered agents. Throughout the study, all tested combinations were well-tolerated. Therefore, chiglitazar can be co-administered with these agents without dose adjustments.