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SKLB1028 is a novel multi‐target protein kinase inhibitor under investigation for the treatment of FLT3‐ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug–drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co‐administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co‐administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

Background Non-small cell carcinoma is the main pathologic type of lung cancer, and a large number of clinical trials have shown that epidermal growth factor receptor tyrosinase inhibitors exhibit superior clinical efficacy and lower toxicity compared with chemotherapy. FHND9041 is a new irreversible EGFR T790M mutation-selective small molecule kinase inhibitor, a third-generation EGFR inhibitor developed by Nanjing Chuangte Pharmaceutical Technology Co., Ltd. The aim of this study was to evaluate the effects of oral Itraconazole capsules and oral Rifampicin capsules on the pharmacokinetic profile and safety and tolerability of a single oral dose of FHND9041 capsules in healthy Chinese male subjects. Patients and methods This study employed a single-center, open-label, fixed-sequence design, comprising two parallel groups: Group 1 received FHND9041 40 mg in combination with Itraconazole, while Group 2 received Rifampicin in combination with FHND9041 80 mg. Each group enrolled 16 subjects for a two-period study, with the first period involving monotherapy and the second period involving co-administration. All subjects participating in this clinical trial were healthy adult Chinese males. Results In healthy subjects, after a single oral administration of 40 mg FHND9041 capsules, the corrected geometric mean ratios (90% confidence intervals) of FHND9041 C max , AUC 0 − last , and AUC 0 − inf when co-administered with itraconazole capsules compared to the monotherapy phase were 111.46% (103.26 − 120.30%), 169.53% (156.21 − 183.99%), and 168.25% (156.26 − 181.15%), respectively. The 90% confidence interval for C max fell within the 80-125% range, while the 90% confidence intervals for both AUC 0 − last and AUC 0 − inf exceeded the 80-125% range. Following a single oral dose of 80 mg FHND9041 capsules, the adjusted geometric mean ratios (90% confidence intervals) of C max , AUC 0 − last , and AUC 0 − inf for FHND9041 during co-administration with Rifampicin compared to monotherapy were 52.12% (41.95 − 64.74%), 16.47% (13.34 − 20.31%), and 16.51% (13.56 − 20.09%), respectively. The 90% confidence intervals for C max , AUC 0 − last , and AUC 0 − inf all fell outside the 80 − 125% range. No serious adverse events occurred during the trial. Conclusions Co-administration with Rifampicin significantly reduced the exposure of FHND9041. Therefore, it is recommended to avoid co-administration of FHND9041 with Rifampicin and other potent CYP3A4 inducers. Conversely, co-administration with Itraconazole significantly increased the total exposure of FHND9041. Caution is advised when FHND9041 is co-administered with Itraconazole or other strong CYP3A4 inhibitors. Close monitoring of tolerability during co-administration is essential, and dose reduction may be necessary if required. FHND9041 capsules demonstrated good safety and tolerability when used alone or in combination with strong CYP3A4 inhibitors or inducers. Trial registration Registered 03/27/2023 ( http://www.chinadrugtrials.org.cn/index.html , CTR202300931).

Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed or refractory peripheral T‐cell lymphoma, including adult T‐cell leukemia/lymphoma, and globally under investigation for the treatment of non‐Hodgkin lymphomas and solid tumors. Valemetostat is a substrate of cytochrome P450 3A (CYP3A) and P‐glycoprotein (P‐gp) in vitro. This phase 1, open‐label, single‐sequence crossover study assessed the effect of repeated oral doses of rifampicin, a strong CYP3A and P‐gp inducer, on the pharmacokinetics (PK) of valemetostat in healthy Japanese participants. In this trial, 20 participants received two doses of valemetostat 200 mg, once alone and once after repeated daily doses of rifampicin 600 mg. Coadministration with rifampicin decreased the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve extrapolated to infinity (AUCinf) of total valemetostat. The geometric least‐squares mean ratios (GMR, test/reference) for Cmax and AUCinf were 0.417 [90% confidence interval (CI), 0.319–0.545] and 0.286 [90% CI, 0.225–0.364], respectively. Cmax of CALZ‐1809a (a major valemetostat oxidative metabolite) increased (GMR, 1.287 [90% CI, 1.036–1.600]), while the AUCinf decreased (GMR, 0.713 [90% CI, 0.573–0.886]). No treatment‐related or Grade ≥ 2 adverse events were reported. These results showed that valemetostat exposure was reduced upon coadministration of rifampicin, suggesting that concomitant use of valemetostat with strong CYP3A and P‐gp inducers should be avoided. Trial Registration: Japan Registry: jRCT2080225242

This parallel‐arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI‐1065845 (TAK‐653), an investigational α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with midazolam, then NBI‐1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol–levonorgestrel on Day 1, then NBI‐1065845 alone on Days 5–13; on Day 14, NBI‐1065845 was administered with ethinyl estradiol–levonorgestrel, then NBI‐1065845 alone on Days 15–17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI‐1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79–1.13); ethinyl estradiol, 1.00 (0.87–1.15); and levonorgestrel, 0.99 (0.87–1.13). For area under the plasma concentration–time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78–0.98); and ethinyl estradiol, 1.01 (0.88–1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78–0.96). These findings indicate that NBI‐1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI‐1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

SHR6390 is an oral, potent and selective small-molecule CDK4/6 inhibitor for the treatment of human breast, ovarian and colon cancer. Previous studies have shown that SHR6390 in combination with rifampicin, a potent inducer of CYP3A4, significantly reduces exposure levels. Therefore, we further investigated the effect of efavirenz, a moderate CYP3A4 inducer, on a single oral dose of SHR6390 in healthy volunteers. Twenty healthy subjects were enrolled in this single-center, open, single-dose, self-controlled DDI study. On Day 1, subjects received a single oral dose of 150mg SHR6390; on Day 8-26, subjects received 600 mg efavirenz orally at night, with a single dose of 150 mg SHR6390 on Day 22. Blood samples for pharmacokinetic analyses were collected. The geometric mean ratios of the maximum concentration(C ) and the area under the concentration curve from zero to infinity (AUC ) between combination therapy and SHR6390 monotherapy (combination therapy/SHR6390 monotherapy) and their 90% confidence intervals were 0.562 (0.482, 0.654) and 0.328 (0.278, 0.386), respectively. This indicates that the Cmax and AUC0 inf of SHR6390 decreased by approximately 43.8% and 67.2%, respectively. Oral administration of 150 mg SHR6390 alone or together with efavirenz was safe and tolerable in healthy subjects. It is suggested that under the action of the moderate CPY3A4 inducer efavirenz, the exposure AUC of SHR6390 exhibits a moderate level of induction. It is recommended to avoid concomitant administration of moderate inducers of CYP3A4 during treatment with SHR6390. http://www.chinadrugtrials.org.cn/index.html, CTR20211571/ https://classic.clinicaltrials.gov, NCT04973020.

Acebilustat is a new once‐daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases. It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment. Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers. No significant differences between study populations were observed for peak plasma level (Cmax) or exposure (AUC). In healthy volunteers, a shift in time to Cmax (Tmax) was observed after a high‐fat meal, but there was no change in AUC. LTB4 production was reduced in the blood of both populations and in sputum from CF patients. Acebilustat did not induce CYP3A4. These results support continued clinical study of once‐daily oral acebilustat in CF at doses of 50 and 100 mg.

Background and Objectives Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. Methods Randomised, open-label studies were conducted in healthy volunteers ( n  = 34 ketoconazole, n  = 34 carbamazepine, n  = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. Results Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration ( C max ) by 39 % [90 % confidence interval (CI) 31–47 %] and area under the concentration–time curve (AUC) by 57 % (90 % CI 47–67 %), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26 % (90 % CI 22–30 %) and 29 % (90 % CI 26–32 %), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. Conclusions Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

•TPN171 is a self-developed PDE5 inhibitor used to treat Pulmonary arterial hypertension and erectile dysfunction with the advantages of high activity, good selectivity, low toxicity, rapid oral absorption, and long half-life in vivo.•The Cmax and AUC0-∞ for TPN171 were increased by 76.00% and 185.67% when combined with itraconazole versus TPN171 alone, and reduced by 74.53% and 90.14% when combined with rifampin versus TPN171 alone.•Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects.•TPN171 demonstrated a favorable safety profile and was well-tolerated in healthy subjects, whether administered as monotherapy or co-administered with the CYP3A4 inhibitor itraconazole or inducer rifampicin.•TPN171 exhibits a significant interaction with CYP3A4 inhibitors/inducers. TPN171, a novel, highly selective, and potent phosphodiesterase type 5 (PDE5) inhibitor, is currently under clinical development for the treatment of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED). The drug is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4. We evaluated the pharmacokinetic (PK) profile and safety of TPN171, both alone and in combination with itraconazole (a CYP3A4 potent inhibitor) or rifampin (a CYP3A4 potent inducer), in healthy Chinese volunteers. In this open-label, fixed-sequence study, TPN171 (10 mg) was administered orally once daily on Days 1 and 6 in Cohort 1, followed by oral itraconazole (200 mg) once daily from Days 3 to 6. Cohort 2 received oral TPN171 (20 mg) once daily on Days 1 and 10, with concurrent oral rifampin (600 mg) once daily administered from Days 3 to 10. Twenty-four healthy subjects were enrolled (12 per cohort). The PK parameters of TPN171 were estimated through noncompartmental analysis with its plasma concentration detection. Comparisons of the maximum plasma concentration (Cmax) and the area under the concentration–time curve extrapolated to infinity (AUC0-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. The Cmax and AUC0-∞ for TPN171 were increased by 76.00% (least squares geometric mean ratios (LSGMR), 176.00% [90% CI, 160.37%–193.15%]) and 185.67% (LSGMR, 285.67% [90% CI, 261.87%–311.64%]) when combined with itraconazole versus TPN171 alone. The Cmax and AUC0-∞ of TPN171 were reduced by 74.53% (LSGMR, 25.47% [90% CI, 21.98%–29.50%]) and 90.14% when combined with rifampin versus TPN171 alone (LSGMR, 9.86% [90% CI, 9.08%–10.71%]). Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects. CYP3A4 potent inhibitors and inducers can significantly affect the exposure level of TPN171, especially the inducers. Therefore, when taking TPN171, it is recommended to avoid concomitant administration with CYP3A4 potent inhibitors or potent/moderate inducers, or adjust the dosage of TPN171.

TPN171 is a potent phosphodiesterase type 5 inhibitor used to treat pulmonary arterial hypertension and erectile dysfunction, primarily metabolized by CYP3A4. This study aimed to evaluate its drug-drug interaction (DDI) potential and determine the optimal dosing when co-administered with CYP3A4 modulators. A physiologically based pharmacokinetic (PBPK) model was developed and validated using clinical DDI data for itraconazole (strong CYP3A4 inhibitor) and rifampin (strong CYP3A4 inducer). The model was then applied to predict DDIs with moderate (diltiazem, fluconazole) and mild (fluvoxamine) inhibitors, as well as moderate (efavirenz) and mild (zanubrutinib) inducers. Predicted AUC ratios aligned with observed data: itraconazole (2.42-fold predicted vs. 2.67- fold observed) and rifampicin (0.14-fold predicted vs. 0.096-fold observed). For other modulators, geometric mean AUC ratios were 2.40 with diltiazem, 3.27 with fluconazole (400 mg), 2.07 with fluconazole (100 mg), 1.16 with fluvoxamine, 0.53 with efavirenz, and 0.70 with zanubrutinib. These simulations indicate that strong and moderate CYP3A4 inhibitors and inducers significantly alter TPN171 exposure, whereas weak modulators have no clinically meaningful impact. These findings provide a scientific basis for dose recommendations when TPN171 is used with CYP3A4 modulators.

Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug‐resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open‐label, 2‐part, fixed‐sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time‐concentration curve (AUC)0‐last, and AUC0‐inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.