Yue Liu, Xin Gao, Yang Li, Xuemei He, Zhe Shi, Ling Zhang, Yaolin Wang, Aixin Shi
{"title":"食物对单次口服KRASG12C选择性抑制剂D-1553在健康人体内药代动力学特性的影响","authors":"Yue Liu, Xin Gao, Yang Li, Xuemei He, Zhe Shi, Ling Zhang, Yaolin Wang, Aixin Shi","doi":"10.1007/s40261-025-01430-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>D-1553 (garsorasib) is a novel and selective oral KRAS<sup>G12C</sup> inhibitor. This study aims to evaluate the effect of food on the single-dose pharmacokinetics (PK) of D-1553 tablet in healthy Chinese subjects. Also the safety and tolerability of single-dose D-1553 in subjects are also evaluated.</p><p><strong>Methods: </strong>A randomized, open-label, single-dose, two-intervention (fed vs fasting), two-period, two-sequence crossover study was performed on 14 healthy Chinese subjects. Plasma concentrations of D-1553 were determined by the liquid chromatography-tandem mass spectrometry method. Safety evaluations were carried out during the study period. The main PK parameters of the two formulations of D-1553 were calculated by non-compartmental analysis using Phoenix WinNonlin (Version 8.3) software.</p><p><strong>Results: </strong>The geometric mean ratios (90% confidence interval [CI]) of AUC<sub>0-t</sub> and AUC<sub>0-∞</sub> in the high-fat meal condition versus the fasting condition were 86.19% (78.30%, 94.87%) and 83.30% (75.77%, 91.58%), respectively. The geometric mean ratio (90% CI) of C<sub>max</sub> values in high-fat meal condition to that observed in fasting condition were 109.74% (100.22%,120.15%). The p value of T<sub>max</sub> was 0.1484 (fed vs fasting). Two subjects (14.3%) reported 4 treatment-emergent adverse events (TEAEs) in the fasting condition, and no subjects reported TEAEs in the fed condition. All adverse reactions were mild and had recovered by the end of the study.</p><p><strong>Conclusion: </strong>The study indicated that a high-calorie and high-fat meal has no clinically relevant impact on the PK and bioavailability of D-1553 in healthy Chinese subjects. D-1553 was generally safe and well-tolerated under both fasting and fed conditions. The findings suggest that D-1553 could be administered orally with or without food.</p><p><strong>Clinical trials: </strong>ClinicalTrials.gov Identifer CTR20212761; registered on 4 Nov 2021.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"201-206"},"PeriodicalIF":2.9000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effect of Food on the Pharmacokinetic Characteristics of a Single Oral Dose of D-1553, a Selective Inhibitor of KRAS<sup>G12C</sup>, in Healthy Chinese Subjects.\",\"authors\":\"Yue Liu, Xin Gao, Yang Li, Xuemei He, Zhe Shi, Ling Zhang, Yaolin Wang, Aixin Shi\",\"doi\":\"10.1007/s40261-025-01430-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>D-1553 (garsorasib) is a novel and selective oral KRAS<sup>G12C</sup> inhibitor. This study aims to evaluate the effect of food on the single-dose pharmacokinetics (PK) of D-1553 tablet in healthy Chinese subjects. Also the safety and tolerability of single-dose D-1553 in subjects are also evaluated.</p><p><strong>Methods: </strong>A randomized, open-label, single-dose, two-intervention (fed vs fasting), two-period, two-sequence crossover study was performed on 14 healthy Chinese subjects. Plasma concentrations of D-1553 were determined by the liquid chromatography-tandem mass spectrometry method. Safety evaluations were carried out during the study period. The main PK parameters of the two formulations of D-1553 were calculated by non-compartmental analysis using Phoenix WinNonlin (Version 8.3) software.</p><p><strong>Results: </strong>The geometric mean ratios (90% confidence interval [CI]) of AUC<sub>0-t</sub> and AUC<sub>0-∞</sub> in the high-fat meal condition versus the fasting condition were 86.19% (78.30%, 94.87%) and 83.30% (75.77%, 91.58%), respectively. The geometric mean ratio (90% CI) of C<sub>max</sub> values in high-fat meal condition to that observed in fasting condition were 109.74% (100.22%,120.15%). The p value of T<sub>max</sub> was 0.1484 (fed vs fasting). Two subjects (14.3%) reported 4 treatment-emergent adverse events (TEAEs) in the fasting condition, and no subjects reported TEAEs in the fed condition. All adverse reactions were mild and had recovered by the end of the study.</p><p><strong>Conclusion: </strong>The study indicated that a high-calorie and high-fat meal has no clinically relevant impact on the PK and bioavailability of D-1553 in healthy Chinese subjects. D-1553 was generally safe and well-tolerated under both fasting and fed conditions. 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Effect of Food on the Pharmacokinetic Characteristics of a Single Oral Dose of D-1553, a Selective Inhibitor of KRASG12C, in Healthy Chinese Subjects.
Background and objective: D-1553 (garsorasib) is a novel and selective oral KRASG12C inhibitor. This study aims to evaluate the effect of food on the single-dose pharmacokinetics (PK) of D-1553 tablet in healthy Chinese subjects. Also the safety and tolerability of single-dose D-1553 in subjects are also evaluated.
Methods: A randomized, open-label, single-dose, two-intervention (fed vs fasting), two-period, two-sequence crossover study was performed on 14 healthy Chinese subjects. Plasma concentrations of D-1553 were determined by the liquid chromatography-tandem mass spectrometry method. Safety evaluations were carried out during the study period. The main PK parameters of the two formulations of D-1553 were calculated by non-compartmental analysis using Phoenix WinNonlin (Version 8.3) software.
Results: The geometric mean ratios (90% confidence interval [CI]) of AUC0-t and AUC0-∞ in the high-fat meal condition versus the fasting condition were 86.19% (78.30%, 94.87%) and 83.30% (75.77%, 91.58%), respectively. The geometric mean ratio (90% CI) of Cmax values in high-fat meal condition to that observed in fasting condition were 109.74% (100.22%,120.15%). The p value of Tmax was 0.1484 (fed vs fasting). Two subjects (14.3%) reported 4 treatment-emergent adverse events (TEAEs) in the fasting condition, and no subjects reported TEAEs in the fed condition. All adverse reactions were mild and had recovered by the end of the study.
Conclusion: The study indicated that a high-calorie and high-fat meal has no clinically relevant impact on the PK and bioavailability of D-1553 in healthy Chinese subjects. D-1553 was generally safe and well-tolerated under both fasting and fed conditions. The findings suggest that D-1553 could be administered orally with or without food.
Clinical trials: ClinicalTrials.gov Identifer CTR20212761; registered on 4 Nov 2021.
期刊介绍：
Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes:
-Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs.
-Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice.
-Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed.
-Studies focusing on the application of drug delivery technology in healthcare.
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