Para-aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research.

AIMS: Tenofovir and para-aminosalicylic acid (PAS) may be coprescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the 2 drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics (PK). METHODS: Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (OAT1 and OAT3). Later, we estimated clinical drug interactions using static and physiologically based PK modelling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate PK in healthy male Korean subjects. RESULTS: PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The physiologically based PK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when coadministered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir PK showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. CONCLUSION: Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.

Pharmacokinetic modeling analysis of cilostazol and its active metabolites (OPC-13015 and OPC-13213) after multiple oral doses of cilostazol in healthy Korean volunteers.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes.

AIM: The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. METHODS: In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. RESULTS: The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. CONCLUSIONS: The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects.

Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

OBJECTIVE: The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. METHODS: Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. RESULTS: CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. CONCLUSION: The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin.

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.

Pharmacokinetic comparison of amlodipine adipate/valsartan fixed-dose combination with amlodipine besylate/valsartan fixed-dose combination in healthy volunteers.

The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0-t were 93.5 - 100.4% and 93.2 - 98.3% for amlodipine, and 92.1 - 121.3% and 94.1 - 115.2% for valsartan, respectively. 17 adverse events occurred in 15 subjects during the study; 5 and 7 adverse drug reactions from the 5 and 6 subjects were considered to probably be related to the test and reference treatments respectively. All adverse drug reactions were in line with those known for the reference drug. All subjects recovered fully with no sequelae. A FDC of amlodipine adipate/valsartan and amlodipine besylate/valsartan combination tablets met the regulatory criteria for bioequivalence. In addition, no significant difference was observed in the safety assessments between two treatments. Thus, the newly developed FDC of amlodipine adipate/valsartan seems to be interchangeable with amlodipine besylate valsartan combination.

Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation.

The compound 20-HETE is involved in numerous physiological functions, including blood pressure and platelet aggregation. Glucuronidation of 20-HETE by UDP-glucuronosyltransferases (UGTs) is thought to be a primary pathway of 20-HETE elimination in humans. The present study identified major UGT enzymes responsible for 20-HETE glucuronidation and investigated their genetic influence on the glucuronidation reaction using human livers (n = 44). Twelve recombinant UGTs were screened to identify major contributors to 20-HETE glucuronidation. Based on these results, UGT2B7, UGT1A9, and UGT1A3 exhibited as major contributors to 20-HETE glucuronidation. The Km values of 20-HETE glucuronidation by UGT1A3, UGT1A9, and UGT2B7 were 78.4, 22.2, and 14.8 µM, respectively, while Vmax values were 1.33, 1.78, and 1.62 nmol/min/mg protein, respectively. Protein expression levels and genetic variants of UGT1A3, UGT1A9, and UGT2B7 were analyzed in human livers using Western blotting and genotyping, respectively. Glucuronidation of 20-HETE was significantly correlated with the protein levels of UGT2B7 (r(2) = 0.33, P < 0.001) and UGT1A9 (r(2) = 0.31, P < 0.001), but not UGT1A3 (r(2) = 0.02, P > 0.05). A correlation between genotype and 20-HETE glucuronidation revealed that UGT2B7 802C>T, UGT1A9 -118T9>T10, and UGT1A9 1399T>C significantly altered 20-HETE glucuronide formation (P < 0.05-0.001). Increased levels of 20-HETE comprise a risk factor for cardiovascular diseases, and the present data may increase our understanding of 20-HETE metabolism and cardiovascular complications.

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects.

AIMS: The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol. METHODS: A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol) were measured using liquid chromatography-tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment. RESULTS: The geometric mean ratios of area under the concentration-time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89-1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90-1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93-1.03; P = 0.47) for 4'-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments. CONCLUSIONS: Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.

Population pharmacokinetic analysis of simvastatin and its active metabolite with the characterization of atypical complex absorption kinetics.

PURPOSE: The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics. METHODS: Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM. RESULTS: The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model's fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid. CONCLUSION: A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.

Effect of voglibose on the pharmacokinetics of metformin in healthy Korean subjects.

OBJECTIVE: The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. METHODS: A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. RESULTS: 22 subjects completed the study. The geometric mean ratios for C(ss,max) of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-τ, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). CONCLUSIONS: Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.

Enhancing drug administration flexibility: evaluation of pharmacokinetic properties of tegoprazan orally disintegrating tablet (ODT) administered via nasogastric tube or oral dosing.

Tegoprazan orally disintegrating tablet (ODT) formulation is a novel formulation to improve a convenience in comparison to taking the conventional tablet of tegoprazan, a potassium-competitive acid blocker. The purpose of this study was to evaluate the pharmacokinetic and safety profiles of tegoprazan ODT when administered via two routes: nasogastric tube or oral dosing. This study is expected to expand the administration route of tegoprazan ODT. The study was conducted in an open-label, randomized, single-dose, two-way crossover design with a 1-week washout period. Healthy subjects aged 19 to 45 years were administered 50 mg of tegoprazan ODT orally or dissolved in water via nasogastric tube. Tegoprazan, the active ingredient, was quantified using a ultra-high performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and pharmacokinetic parameters were determined through non-compartmental analysis. Safety was monitored throughout the study. A total of 48 subjects, successfully completed the trial. The geometric mean ratios for log-transformed Cmax and AUCt, representing the ratio of nasogastric tube group to oral dosing group, along with 90% confidence intervals, were 1.1087 (1.0243-1.2000) and 1.0023 (0.9620-1.0442), respectively. All adverse events were unrelated to tegoprazan and mild in intensity. The pharmacokinetic profiles of tegoprazan ODT were equivalent between the nasogastric tube and oral administration. Considering the demonstrated linear pharmacokinetics and concentration-dependent pharmacodynamics of tegoprazan, the administration via nasogastric tube is expected to yield effects equivalent to those of oral administration. This approach offers a viable alternative, especially beneficial for patients with oral intake difficulties.

Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals.

Hepatocyte nuclear receptor 4α (HNF4α) plays a central role in regulating human drug-metabolizing enzymes. Our previous study suggested that the newly identified polymorphism G60D in the HNF4α gene may decrease its downstream CYP2D6 activity in Asians. To confirm this effect in a clinical setting, we carried out a full pharmacokinetic study of a single oral dose of CYP2D6 substrate tolterodine in 30 healthy Korean individuals (HNF4α wild type: n = 24; HNF4α G60D heterozygotes: n = 6) who were pregenotyped for CYP2D6. Our study showed HNF4α G60D to be an independent predictor for increased AUC0-∞, C max of tolterodine and increased AUC0-∞ of the active moiety (tolterodine+5-hydroxymethyl-tolterodine) (P<0.05). A significant proportion of the variance in these parameters (R = 0.81, 0.59, and 0.63, respectively; P<0.01) was explained together by CYP2D6 and HNF4α genotypes. Further investigation of HNF4α genetic polymorphisms may improve the predictability of CYP2D6 activity in different populations.

Transforming clinical trials: the emerging roles of large language models.

Clinical trials are essential for medical research, but they often face challenges in matching patients to trials and planning. Large language models (LLMs) offer a promising solution, signaling a transformative shift in the field of clinical trials. This review explores the multifaceted applications of LLMs within clinical trials, focusing on five main areas expected to be implemented in the near future: enhancing patient-trial matching, streamlining clinical trial planning, analyzing free text narratives for coding and classification, assisting in technical writing tasks, and providing cognizant consent via LLM-powered chatbots. While the application of LLMs is promising, it poses challenges such as accuracy validation and legal concerns. The convergence of LLMs with clinical trials has the potential to revolutionize the efficiency of clinical trials, paving the way for innovative methodologies and enhancing patient engagement. However, this development requires careful consideration and investment to overcome potential hurdles.

Evaluation of pharmacokinetic drug-drug interaction between tegoprazan and clarithromycin in healthy subjects.

Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating Helicobacter pylori. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (Css,max) and area under the plasma concentration-time curve in dosing interval at steady-state (AUCss,tau) of tegoprazan (1.6-fold in Css,max and 2.5-fold in AUCss,tau) and M1 (2.0-fold in Css,max, 2.5-fold in AUCss,tau) than tegoprazan alone. The Css,max and AUCss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUCss.tau of clarithromycin was slightly increased in co-administration, but Css,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentration-response relationship is necessary to determine whether these concentration changes warrant clinical action. Trial Registration: ClinicalTrials.gov Identifier: NCT02052336.

Multimodal plasma metabolomics and lipidomics in elucidating metabolic perturbations in tuberculosis patients with concurrent type 2 diabetes.

Type 2 diabetes mellitus (DM) poses a major burden for the treatment and control of tuberculosis (TB). Characterization of the underlying metabolic perturbations in DM patients with TB infection would yield insights into the pathophysiology of TB-DM, thus potentially leading to improvements in TB treatment. In this study, a multimodal metabolomics and lipidomics workflow was applied to investigate plasma metabolic profiles of patients with TB and TB-DM. Significantly different biological processes and biomarkers in TB-DM vs. TB were identified using a data-driven, knowledge-based framework. Changes in metabolic and signaling pathways related to carbohydrate and amino acid metabolism were mainly captured by amide HILIC column metabolomics analysis, while perturbations in lipid metabolism were identified by the C18 metabolomics and lipidomics analysis. Compared to TB, TB-DM exhibited elevated levels of bile acids and molecules related to carbohydrate metabolism, as well as the depletion of glutamine, retinol, lysophosphatidylcholine, and phosphatidylcholine. Moreover, arachidonic acid metabolism was determined as a potentially important factor in the interaction between TB and DM pathophysiology. In a correlation network of the significantly altered molecules, among the central nodes, chenodeoxycholic acid was robustly associated with TB and DM. Fatty acid (22:4) was a component of all significant modules. In conclusion, the integration of multimodal metabolomics and lipidomics provides a thorough picture of the metabolic changes associated with TB-DM. The results obtained from this comprehensive profiling of TB patients with DM advance the current understanding of DM comorbidity in TB infection and contribute to the development of more effective treatment.

Development of a population pharmacokinetic model of pyrazinamide to guide personalized therapy: impacts of geriatric and diabetes mellitus on clearance.

Objectives: This study was performed to develop a population pharmacokinetic model of pyrazinamide for Korean tuberculosis (TB) patients and to explore and identify the influence of demographic and clinical factors, especially geriatric diabetes mellitus (DM), on the pharmacokinetics (PK) of pyrazinamide (PZA). Methods: PZA concentrations at random post-dose points, demographic characteristics, and clinical information were collected in a multicenter prospective TB cohort study from 18 hospitals in Korea. Data obtained from 610 TB patients were divided into training and test datasets at a 4:1 ratio. A population PK model was developed using a nonlinear mixed-effects method. Results: A one-compartment model with allometric scaling for body size effect adequately described the PK of PZA. Geriatric patients with DM (age >70 years) were identified as a significant covariate, increasing the apparent clearance of PZA by 30% (geriatric patients with DM: 5.73 L/h; others: 4.50 L/h), thereby decreasing the area under the concentration-time curve from 0 to 24 h by a similar degree compared with other patients (geriatric patients with DM: 99.87 µg h/mL; others: 132.3 µg h/mL). Our model was externally evaluated using the test set and provided better predictive performance compared with the previously published model. Conclusion: The established population PK model sufficiently described the PK of PZA in Korean TB patients. Our model will be useful in therapeutic drug monitoring to provide dose optimization of PZA, particularly for geriatric patients with DM and TB.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 versus reference tocilizumab: a randomized, double-blind, single-dose phase I study.

BACKGROUND: CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults. RESEARCH DESIGN AND METHODS: This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration - time curve (AUC) from time zero to last quantifiable concentration (AUC0-last), AUC from time zero to infinity (AUC0-inf), and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80-125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated. RESULTS: In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC0-last, AUC0-inf, and Cmax were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80-125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups. CONCLUSIONS: CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05188378.

Tocilizumab is a biologic medicine used to treat inflammatory diseases including rheumatoid arthritis. Biosimilars are drugs that are highly similar to an already approved, 'reference' biologic medicine. This means that they do not have any differences from the reference product in factors including structure, biologic function, efficacy, and safety, that might affect how well they work in patients. Biosimilars are often available at a lower cost than reference drugs, so their use can provide patients with better access to expensive treatments. There are no approved biosimilars of tocilizumab so far: CT-P47 is currently in development as a potential tocilizumab biosimilar.In the main part of this study, 289 healthy Asian volunteers were randomly allocated to receive a single injection of either CT-P47 or the reference drug, European Union-approved tocilizumab (EU-tocilizumab). The main aim of the study was to find out whether CT-P47 and EU-tocilizumab were equivalent in terms of pharmacokinetics (drug absorption, distribution, metabolism, and excretion by the body). This is part of a standard process required by regulatory authorities to ensure that biosimilars work as well as their reference drugs. Analysis of blood samples taken over 43 days showed that the pharmacokinetic profiles of CT-P47 and EU-tocilizumab were equivalent, after the volunteers received a single dose of either drug. Safety and immunogenicity (immune responses made to the drug) were also comparable between CT-P47 and EU-tocilizumab. While only healthy Asian adults were included, further research comparing CT-P47 with reference tocilizumab will help to ensure that the findings from the study can be applied to broader populations.

The pharmacokinetics of letrozole: association with key body mass metrics.

PURPOSE: To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK. METHODS: The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested. RESULTS: A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study. CONCLUSION: Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.

Assessment of the influence of severe renal impairment on the pharmacokinetics of mirodenafil in Korean male volunteers.

OBJECTIVE: To evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers. METHODS AND MATERIALS: This open-label, single-dose, parallel group clinical study enrolled a total 12 volunteers (6 healthy volunteers and 6 volunteer patients with severe renal impairment). Each volunteer was orally administered 50 mg mirodenafil and serial blood samples were obtained after drug administration to determine the plasma concentration of mirodenafil using LC-MS/MS. The measured individual plasma concentrations were used to calculate the pharmacokinetic parameters using noncompartmental methods. Tolerability was also assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: All of the volunteers completed the study with no serious adverse events (AEs). A total of 4 AEs were reported, but all were of mild or moderate intensity and not considered to be related to the study drug. The geometric mean (95% CI) of the terminal half-life (t1/2ß) and the apparent clearance (CL/F) values of mirodenafil were 2.2 (1.4 - 3.4) h and 127.2 (95.1 - 170.2) l/h in the volunteer patients, and 3.0 (2.1 - 4.4) h and 136.1 (74.4 - 249.2) l/h in the healthy volunteers, respectively. The geometric mean of the AUC0-t of the volunteer patients was 8% higher and the geometric mean for clearance was 7% lower compared with the healthy volunteers. However, the geometric mean of the Cmax of the volunteer patients was 38% higher than that of the healthy volunteers. CONCLUSIONS: A single oral 50-mg dose of mirodenafil was well tolerated. Exposure (AUC0-t) to mirodenafil was similar in both healthy volunteers and volunteer patients with severe renal impairment and healthy volunteers.

A physiologically based pharmacokinetic/pharmacodynamic modeling approach for drug-drug interaction evaluation of warfarin enantiomers with sorafenib.

Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.