Introduction Deutaleglitazar (AP303) is a novel dual peroxisome proliferator-activated receptor (PPAR) α and γ agonist, which has the potential to offer the combined clinical benefit on diabetic kidney disease (DKD) management by normalizing the elevated glomerular capillary pressure, ameliorating podocyte depletion, as well as correcting diabetic dyslipidemia and hyperglycemia Methods Three single-center, randomized, placebo-controlled single-ascending-dose and/or multiple-ascending-dose studies investigated its pharmacokinetics (PK), pharmacodynamic, safety and tolerability in healthy participants with different ethnicities and in patients with diabetic kidney disease (DKD) and reduced kidney function. Results A total of 80 healthy participants, and 18 patients with DKD and estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73m2 from Australia and China received either placebo, a single oral dose or multi-dose of deutaleglitazar for 14 days. Deutaleglitazar exposure increased in a dose-dependent manner both after a single dose and at steady state, with no accumulation. Minor differences of PK profiles in Caucasian vs. Asian participants, and in those with normal vs reduced kidney function are considered unlikely to be clinically significant. Reduction in eGFR with reversibility after drug discontinuation was evident. Improvement in diabetic dyslipidemia and hyperglycemia were observed. Few adverse events were reported, only neutropenia was dose related. Conclusion The PPARα and PPARγ related effects occurred over similar dose ranges, indicating that deutaleglitazar is a balanced agonist of the two receptor subtypes targeting on the root cause and multi-pathway of DKD progression.

Purpose:This study is the first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of single ascending doses (SAD) and multiple ascending doses (MAD) of JMKX003142 injection in healthy Chinese subjects. Patients and Methods:In this Phase I, randomized, double-blind, placebo-controlled study, 48 subjects in the SAD (0.1-6 mg) study received intravenous injection of JMKX003142 or placebo in ascending dose. Thirty subjects in the MAD (1-4 mg) study received an intravenous injection of JMKX003142 or placebo once a day for five consecutive days. The primary endpoint was the safety and tolerability of JMKX003142 injection, with the secondary and exploratory endpoints focusing on its PK and PD profiles, respectively. Results:The JMKX003142 injection exhibited favourable safety and tolerability, with all treatment-emergent adverse events (TEAEs) being mild. No serious adverse events, deaths or discontinuations due to TEAEs were observed. Following single and multiple intravenous injections of JMKX003142, the maximum concentration (Cmax) and area under plasma concentration-time curve (AUC) of JMKX003142 and its metabolites increased with dose level, with increases in Cmax being dose-proportional. In 1 mg or higher dose group of SAD study, the mean terminal half-life (t1/2) of JMKX003142 was between 5.2 and 12.7 h. Following multiple intravenous injections of JMKX003142, the t1/2 of JMKX003142 was determined to range from 11.1 and 11.8 h. Moreover, JMKX003142 demonstrated favourable PD profiles following both single and multiple intravenous injections. The evaluation of the daily cumulative urine volume indicated that the diuretic effect of the JMKX003142 injection was evident at doses of 1 mg and above, with effects intensifying at higher doses. Conclusion:Overall, both single and multiple intravenous injections of JMKX003142 have been demonstrated to be safe, well tolerated, and to possess excellent PK characteristics as well as significant diuretic activity. Trial Registration:This study was registered with ClinicalTrials.gov (NCT06344533).

AIM:Cetirizine is widely used to treat children with allergic rhinitis and urticaria, yet optimal doses are undefined. Limited pharmacokinetic (PK) data and undefined renal P-glycoprotein (P-gp) ontogeny hinder the direct extrapolation of dosing from adults to children. This study aims to develop a paediatric cetirizine physiologically based pharmacokinetic (PBPK) model to explore renal P-gp ontogeny and guide optimal dosing strategies. METHODS:An adult PBPK model for cetirizine was developed to determine drug-specific parameters. Combining the age-dependent physiological parameters embedded in SimCYP® and cetirizine PK from Caucasian children of varying ages to infer renal P-gp ontogeny, the paediatric cetirizine PBPK model was constructed. The ontogeny was validated using PK data from Chinese children across various age groups. The validated model was then employed to evaluate optimal dosing regimens for children in different age groups. RESULTS:The renal P-gp ontogeny equation was successfully inferred and incorporated into the PBPK model, capturing 100% and 87.8% of the observed PK data in Caucasian and Chinese children within the 90% prediction interval, respectively. Simulation results suggest that 5 mg twice daily (BID) for children aged 6-12 years and 0.25 mg/kg BID for children under 6 years are optimal, whereas fixed doses of 5 mg once-daily (QD) for children aged 2-6 years and 2.5 mg BID for children aged 0.5-2 years are also appropriate. CONCLUSION:Utilizing PBPK modelling and simulation, this study elucidated P-gp ontogeny and recommended the optimal cetirizine dosage regimen for children across all age groups.

BackgroundDiabetes patients often exhibit suboptimal efficacy and adverse reactions, accompanied by pharmacokinetic (PK) changes, indicating drug-metabolizing enzymes and transporters (DMET) activities may change. This study aimed to determine whether type 2 diabetes affects DMET activities and quantify impact magnitude. Furthermore, gut microbiome, pharmacogenetic and demographic characteristics were assessed to elucidate the sources of inter-individual variability (IIV) in DMET activities.MethodsThe activities of CYP3A and transporters P-gp, OATP and BCRP were evaluated in type 2 diabetes patients and healthy volunteers (HVs) following a single oral dose of five probe drugs (midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin). Population pharmacokinetics (PopPK) and an exploratory machine learning (ML) analysis were employed to quantify the impact of type 2 diabetes on DMET activities.ResultsBased on observed PK parameters, compared to HVs, type 2 diabetes patients exhibited increased exposure to midazolam (1.38-fold), dabigatran (1.40-fold), and atorvastatin (1.93-fold), whereas pitavastatin (0.931-fold) and rosuvastatin (1.25-fold) showed no change. PopPK analysis revealed that the mean activities of CYP3A and P-gp were potentially decreased by 23% and 27%, respectively, in type 2 diabetes patients, while no changes for OATP and BCRP. Notably, unlike the direct patient population covariate for P-gp, reduced CYP3A activity was indirectly estimated from lower Salmonella abundance. Additionally, factors such as sex, BCRP genotype, and Clostridium_XlVb partly explained the IIV in probe drugs exposure.ConclusionThe findings regarding altered DMET activities and identified influence factors help to identify specific drug classes that may warrant closer clinical attention in type 2 diabetes patients.

Glomerular filtration rate (GFR) maturation is critical for drug dosing in neonates and children. Current equations face dual limitations: they are primarily derived from Caucasian populations and fail to account for the fundamental physiological differences between neonates and children. This study aimed to develop Chinese-specific GFR equations and to characterize how the key predictors of GFR differ between these two developmental stages. Creatinine clearance as measured GFR (mGFR) in 58 hospitalized neonates (gestational age range, 30.3-41.0 weeks, postnatal age range, 0 to 26 days, mGFR = 3.08 ± 1.86 mL/min) without renal impairment were enrolled. Moreover, a published database of Chinese children (N = 87, age range, 1 to 18 years, mGFR = 97.0 ± 31.9 mL/min/1.73 m2) was applied. Demographic and renal function markers were included to develop equations using the stepwise regression method in allometric form. The GFR prediction equation of serum cystatin C, blood urea nitrogen and postmenstrual age of Chinese neonates was established. In children, GFR is associated with cystatin C, creatinine, weight and age. In an internal comparison with 16 published equations, our newly developed models showed favorable performance within our cohorts, with correlation (R2 of 0.617 and 0.578) and accuracy (P20 of 46.6% and 70.1%, P50 of 93.1% and 100%), respectively. The equations would provide scientific basis for aiding diagnosis of renal function of Chinese neonates and children, and supporting better precision medicine of drugs mainly excreted by kidney.

Background/Objectives: Meropenem pharmacokinetic variability in sepsis often leads to suboptimal exposure and therapeutic failure. Existing covariates like creatinine clearance (CLcr) only partially explain this variability. This study evaluated pyridoxic acid (PDA), an endogenous biomarker of OAT1/3 transporters, as a novel covariate to quantify active tubular secretion and explore pharmacokinetic/pharmacodynamic (PK/PD) linkages with clinical outcomes. Methods: A population PK (PopPK) model was constructed using data from a prospective septic cohort (n = 28). Subsequent exposure-response analysis was conducted in an expanded cohort (n = 49), and Monte Carlo simulations were utilized to evaluate various dosing regimens. Results: The PopPK analysis suggested that PDA may complement CLcr in characterizing meropenem clearance variability. While CLcr explained 10.7% of inter-individual variability (IIV) in clearance, the inclusion of PDA explained an additional 13.7%, reducing total IIV from 50.8% to 26.4%. Achieving a stringent target of 100%fT > 4MIC was significantly associated with a rapid decline in procalcitonin (p = 0.027), establishing a key PD endpoint. Simulations demonstrated that standard dosing (1 g q8h, 1 h infusion) is insufficient for patients with normal or augmented renal function. Target attainment was highly dependent on PDA levels. Conclusions: PDA is a valuable translational biomarker for OAT-mediated clearance. To achieve 100%fT > 4MIC, we recommend (i) 1 g q8h with 3 h infusion for patients with low CLcr and high PDA levels (MIC = 0.5 mg/L), and (ii) an intensified regimen of 2 g q8h with 3 h infusion for patients with normal CLcr and low PDA levels or high resistance risk (MIC ≥ 2 mg/L).

ABSTRACT Molnupiravir is an orally administered prodrug of β‐D‐N4‐hydroxycytidine (NHC) that is conditionally approved in China for the treatment of mild to moderate COVID‐19 in nonhospitalized adults at high risk of disease progression. Molnupiravir is rapidly absorbed and hydrolyzed to deliver NHC into systemic circulation. An open‐label, fixed‐sequence, Phase 1 study was conducted to evaluate the tolerability, safety, and pharmacokinetics (PK) following single and multiple (every 12 h for 5.5 days) oral dosing of molnupiravir 800 mg in 16 healthy, male Chinese participants. After multiple doses of molnupiravir, the median time to maximum concentration was 2.0 h for plasma NHC. NHC concentrations generally decreased in a biphasic manner, with a terminal half‐life of 21.9 h, and NHC exposures (i.e., area under the curve and maximum plasma concentration) were similar following single and multiple doses of molnupiravir. No accumulation of NHC in plasma was observed. When compared with historical data from published clinical trials of similar study design, NHC exposure in Chinese participants was marginally higher than that in non‐Asian participants but remained within established clinical bounds. Overall, molnupiravir was generally well‐tolerated. Ten participants (63.5%) experienced at least one adverse event throughout the study, the severity of which was mild or moderate, and none led to treatment discontinuation. There were no clinically meaningful findings in other safety evaluations. These data support use of the standard 5‐day regimen of molnupiravir 800 mg every 12 h without dose adjustment for the treatment of COVID‐19 in the Chinese population.

Enarodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor. We evaluated the pharmacokinetics, pharmacodynamics, and safety profile of domestic enarodustat (SAL-0951) and analyzed the influence of ethnic factors. In this phase I study, healthy Chinese participants received single and multiple oral doses (1, 5, and 15 mg) of SAL-0951 while in a fasted state. We monitored the pharmacokinetics, pharmacodynamics, and safety characteristics and analyzed the impact of ethnicity on pharmacokinetic characteristics. In total, 33 healthy Chinese participants were enrolled; the mean age was 31.2 ± a standard deviation of 5.5 years. After single doses of 1, 5, and 15 mg were administered under fasted conditions, SAL-0951 was rapidly absorbed. Mean maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration increased dose proportionately from 0.14 to 2.54 μg/mL and from 0.63 to 9.50 h × μg/mL, respectively. The elimination half-life was 6.13, 6.32, and 6.74 h, respectively, in these three groups, and the mean value of apparent clearance ranged from 1.64 to 1.89 L/h. SAL-0951 was excreted mostly as the parent compound. It reached a stable concentration after 5 days of multiple-dose administration. We observed no drug accumulation or time-dependent pharmacokinetic characteristics and no significant difference in pharmacokinetic characteristics between Chinese and Japanese participants. SAL-0951 was safe and well tolerated in healthy Chinese participants and had a linear pharmacokinetic profile. We found no ethnic differences in the pharmacokinetic characteristics of the drug between Chinese and Japanese populations. Registered at Chinadrugtrials.org.cn, registration number CTR2020245.

Accumulating evidence highlights the critical role of circadian rhythms in regulating bone turnover. Bone turnover markers, including parathyroid hormone, C-terminal telopeptide of type I collagen, and N-terminal propeptide of type I procollagen, all exhibit distinct diurnal variations. Teriparatide, a recombinant parathyroid hormone analog, demonstrates time-dependent efficacy influenced by these endogenous rhythms. However, the impact of administration timing on bone metabolism remains underexplored. This randomized, open-label, exploratory trial investigates the impact of teriparatide administration timing by comparing subcutaneous injection at 08:00 versus 20:00 on bone turnover markers in postmenopausal women with osteoporosis. Twenty-eight participants (aged 60–70 years, lumbar spine T-score ≤ -3.0) will be randomized in a 1:1 ratio to receive 20 µg/day of teriparatide via subcutaneous injection at either 08:00 or 20:00 for 12 weeks. All participants will receive standardized calcium (1000–1500 mg/day) and cholecalciferol (800–1200 IU/day) supplementation throughout the study period. The primary outcomes are the between-group differences in serum parathyroid hormone, C-terminal telopeptide of type I collagen, and N-terminal propeptide of type I procollagen profiles, which will be assessed at baseline, 4 weeks, and 12 weeks. Secondary outcomes will evaluate the safety profile during the trial. This trial is expected to provide crucial insights into optimizing teriparatide administration timing, potentially guiding personalized dosing strategies to enhance bone formation and reduce fracture risk in osteoporosis. The findings may inform future research on circadian rhythm-aligned therapies. ClinicalTrials.gov ID NCT06951776.

Dazukibart is a humanized monoclonal antibody selectively targeting interferon-β. The pharmacokinetics (PK), safety, tolerability, and immunogenicity of dazukibart were evaluated in 2 double-blind, randomized, placebo-controlled, single-dose, Phase 1 studies in healthy adults in China (Study 1: N = 18; dazukibart 900 mg = 15; placebo = 3) and Japan (Study 2: N = 12; Cohort 1: dazukibart 300 mg = 5, placebo = 1; and Cohort 2: dazukibart 900 mg = 5, placebo = 1). PK parameters were assessed after dosing in Study 1 and Study 2, and no significant differences were observed between PK findings among participants in both studies. A biphasic decline in dazukibart serum concentrations was observed in both studies. Exposures increased dose proportionally in Study 2. Body weight, but not race, was identified as an independent covariate of exposure using population PK modeling (including data from a Phase 1 US study [NCT02766621]). No deaths/discontinuations or serious/severe adverse events were observed, mostly mild adverse events were reported. No participants in Study 1 were antidrug antibody positive; 20.0% in Study 2 were positive for treatment-induced antidrug antibodies and neutralizing antibodies. PK parameters and immunogenicity rates were consistent with the US study, and no new safety signals were identified.

Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum Cmax was 1401 µg/mL, median tmax was 0.08 days, mean AUCinf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers, thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade could be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low-density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.

Introduction and Objective: Cofrogliptin is a novel ultra-long-acting DPP-4 inhibitor indicated to improve glycemic control in type 2 diabetes (T2D) as monotherapy or in combination with metformin (MET). This single-center, single-arm, phase I study aims to evaluate the drug interactions between cofrogliptin and MET in healthy subjects. Methods: Healthy subjects received MET monotherapy (Days 1-4), cofrogliptin monotherapy (Days 6-34), and combination therapy with both drugs (Days 38-47) in this study. The primary endpoint was the Pharmacokinetics (PK) interaction between cofrogliptin and MET. Results: A total of 22 healthy subjects were enrolled. After 47 days of treatment, cofrogliptin did not statistically effect the PK or pharmacodynamics (PD) of MET, as the geometric mean ratios (GMRs, MET+cofrogliptin/MET) (90% confidence interval (CI)) for MET AUC0-8h, AUC0-12h, CSS (max), Ae0-8h and Ratio0-8h, were 0.872 (0.809, 0.941), 0.900 (0.834, 0.971), 0.840 (0.743, 0.950), 0.899 (0.782, 1.032) and 0.994 (0.871, 1.136), respectively; and the GMRs (MET+cofrogliptin/MET) (90% CI) for glucose AUEC0-4h, AUEC0-0.5h and ECmax were 0.870 (0.833, 0.908), 0.915 (0.879, 0.952) and 0.866 (0.815, 0.920), respevtively, and 90% CIs all fell within 0.80-1.25. MET did not statistically effect the PK or PD of cofrogliptin as well, as the GMRs (MET+cofrogliptin/cofrogliptin) (90% CI) for cofrogliptin AUCtau and Css(max) were 1.12 (1.072, 1.169) and 1.14 (1.057, 1.220), and the GMRs (MET+cofrogliptin/cofrogliptin) (90% CI) for DPP-4 inhibition ratio AUEC0-168h, ECmax and ECmin were 1.01 (1.003, 1.015), 1.00 (1.001, 1.009) and 1.03 (1.005, 1.040), respectively, and 90% CIs all fell within 0.80-1.25. No deaths, serious adverse events (AEs), or severe hypoglycemia were reported. Conclusion: Cofrogliptin and MET did not exhibit any significant PK or PD drug interaction in healthy Chinese subjects, supporting the combination therapy in clinical practice. C. Cui: None. N. Liu: None. H. Li: None. D. Liu: None.

Introduction: SGB-3908 (IBI 3016) is a GalNAc-conjugated siRNA targeting hepatic angiotensinogen (AGT), a critical upstream component of the RAAS, for hypertension. SGB-3908 utilizes SanegeneBio’s proprietary Ligand and Enhancer Assisted Delivery (LEAD™) Platform to enhance intrinsic potency, durability and target specificity. Methods: This is a randomized, double-blind, placebo-controlled single-dose escalation study in healthy and mildly hypertensive subjects, evaluating the safety, pharmacokinetics, and pharmacodynamics of SGB-3908 following subcutaneous administration. Results: Forty participants were enrolled into five cohorts (6:2 active: placebo). All participants were Chinese, with a median (range) age of 38 (24–54) years, 37.5% female, mean BMI of 25.2 kg/m 2 , and baseline 24-hour ambulatory blood pressure mean of 123/75 mmHg. SGB-3908 demonstrated a favorable safety and tolerability, with no dose-limiting toxicities, SAE, or discontinuations due to AEs. There were no episodes of hypotension. Most AEs were mild to moderate and reversible. Treatment-related AEs occurring in ≥5% of SGB-3908 participants included injection site reaction and mild increases in C-reactive protein. The observed plasma PK profile aligns with siRNA kinetics, with C max occurring at 6–8 hours and levels falling below the detection limit by 48 hours post-dose. After a single dose, AGT levels dropped below 80% of baseline within 2 weeks and then reached maximum mean reductions of 91.7%, 91.4%, 94.7%, 96.2%, and 97.5% for Doses 1-5 at approximately 4 weeks. At 3 months, sustained reductions were 91.2%, 90.0%, 93.8%, 96.2%, and 96.6% for Doses 1-5, respectively. For Doses 1-3, reductions of 85.9%, 84.0%, and 90.8% persisted at 6 months (study ongoing)(Figure 1). At 3 months, the 24-hour mean ambulatory daytime SBP/DBP changes from baseline were −8.8/-9.7, −2.1/0.8, −7.1/-5.5, −11.0/-12.5, and −16.7/-14.7 mmHg for Dose 1–5, respectively, compared to −3.2/-5.7 mmHg with placebo. Nighttime SBP/DBP changes were −9.4/-3.3, −7.1/-4.9, −15.1/-10.7, −11.6/-6.7, and −16.0/-12.9 mmHg for Doses 1–5, respectively, versus −5.0/-2.6 mmHg with placebo (Figure 2). Conclusion: SGB-3908 demonstrated a favorable safety profile, sustained AGT reduction, and preliminary BP reduction in healthy and mildly hypertensive subjects. These findings support further investigation for hypertension and other indications where RAAS inhibitors are effective, with potential advantages in dosing frequency and adherence.

OATP1B, P-gp, BCRP, and CYP3A are the most contributing drug-metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end-stage renal disease (ESRD) patients with large inter-individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8-, 3.1-, 1.1-, and 1.3-fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus Veillonella and Clostridium_XIVb were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P-gp activity decreased by 35-75% and 29-44%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.