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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.

•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.

Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers. Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate). Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC ) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs. The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window. This trial (NCT03723395) was registered on October 29, 2018.

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.

A physiologically based pharmacokinetic (PBPK) model was developed and verified for dordaviprone, a small molecule with antitumor effects in glioma patients. The model was applied to assess the drug–drug interaction (DDI) potential of dordaviprone as a victim of CYP3A4 inhibitors and inducers, and as a perpetrator of CYP3A4, CYP2C8, CYP2D6 inhibition. A combination of in vitro and clinical data was used to develop a minimal distribution PBPK model with a single adjusting compartment and mechanistic absorption using the Simcyp Population‐Based Simulator (V21). Simulated maximum concentration (Cmax) and area under the concentration time curve (AUC) of the 3 clinical studies used to verify the PBPK model were within 1.4‐fold of observed exposures. The simulated increase in dordaviprone AUC and Cmax (4.6‐ and 1.7‐fold) following administration of multiple doses of itraconazole was consistent with the observed values (4.4‐ and 1.9‐fold). All PBPK‐simulated changes in dordaviprone plasma exposure when administered with CYP3A4 moderate (erythromycin, fluconazole) and weak (cimetidine) inhibitors, and moderate (efavirenz) and strong (rifampicin) inducers were consistent with their CYP3A4 potency classification (AUC ratio = 2.68, 2.48, 1.42, 0.35, and 0.17, respectively). The simulated AUC and Cmax of probe substrates for CYP3A4 (midazolam), CYP2C8 (repaglinide) and CYP2D6 (desipramine) after coadministration with 625 mg dordaviprone were the same as those in the absence of dordaviprone (ratio = 1.0) and remained unchanged after a sensitivity analysis using 10‐fold more potent inhibition constants. Due to changes in dordaviprone plasma exposure when co‐administered with CYP3A4 inhibitors, dordaviprone dose adjustments may be necessary; CYP3A4 inducers should be avoided.

PurposeCytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme.MethodsThis study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin.ResultsThe geometric mean baseline midazolam area under the plasma concentration curve (AUC0–6) in Caucasians (1057 μg/L/min) was 27% greater than South Asians (768 μg/L/min). Similarly, the post-induction midazolam AUC0–6 in Caucasians (308 μg/L/min) was 50% greater than South Asians (154 μg/L/min), while the post-inhibition midazolam AUC0–6 in Caucasians (1834 μg/L/min) was 41% greater than South Asians (1079 μg/L/min). The difference in baseline AUC0–6 between Caucasians and South Asians was statistically significant (p ≤ 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC0–6 ratio, in both unadjusted and genotype adjusted analyses.ConclusionsSignificantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.

Pirtobrutinib is a reversible Bruton tyrosine kinase (BTK) inhibitor. In vitro, pirtobrutinib is metabolized by cytochrome P450 (CYP) 3A4 and uridine 5′‐diphosphoglucuronosyl transferases (UGTs) and causes reversible and time‐dependent inhibition and induction of CYP3A4. Coadministration of itraconazole, a strong CYP3A4 inhibitor, with pirtobrutinib in healthy human subjects, resulted in a pirtobrutinib area under the plasma concentration‐time curve (AUC) ratio of 1.49, while rifampin, a strong CYP3A4 inducer, decreased pirtobrutinib AUC by 71%. Oral administration of pirtobrutinib 200 mg once daily (QD) increased the AUC of oral and intravenous midazolam by 1.70‐ and 1.12‐fold, respectively. A physiologically based pharmacokinetic (PBPK) model was developed for pirtobrutinib using physicochemical properties, in vitro data, and clinical pharmacology study results. The PBPK model captured the clinically observed interactions for itraconazole, rifampin, and midazolam, with predicted pirtobrutinib and midazolam AUC ratios within 0.91‐ to 1.16‐fold of observed. The model predicted 1.20‐ to 1.73‐fold increases in the pirtobrutinib AUC with strong and moderate CYP3A4 inhibitors. Furthermore, the predicted pirtobrutinib AUC ratios were within 0.51–0.86 with moderate and weak CYP3A4 inducers. The predicted effects of CYP3A4 modulators on pirtobrutinib pharmacokinetics, together with the known exposure‐response relationships for safety and efficacy in patients with hematological malignancies, were used for recommending appropriate dosing regimens during coadministration.

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.

Tepotinib is a highly selective, potent, mesenchymal‐epithelial transition factor (MET) inhibitor, approved for the treatment of non‐small cell lung cancer harboring MET exon 14 skipping alterations. This work aimed to investigate the potential for drug–drug interactions with strong inhibitors and inducers of both cytochrome P450 (CYP) 3A4/5 and P‐glycoprotein (P‐gp) with tepotinib. Two clinical studies were conducted to investigate the effect of the strong CYP3A4/P‐gp inhibitor itraconazole (200 mg once daily) (NCT05203822) and the strong CYP3A4/P‐gp inducer carbamazepine (titrated to 300 mg twice daily) (NCT05213481) on the pharmacokinetics of single dose tepotinib 500 mg (450 mg active moiety) in healthy participants. An investigational physiologically‐based pharmacokinetic model, developed leveraging mass balance data, was used to evaluate the mechanisms underlying these interactions. Itraconazole increased tepotinib area under the curve extrapolated to infinity (AUC0‐∞) by 22% (geometric mean ratio [GMR] 122.35%; 90% confidence intervals [CIs] 111.48%, 134.29%), but had no effect on tepotinib Cmax (GMR 101.53%, 90% CI: 94.00%, 109.67%). Carbamazepine decreased tepotinib AUC0‐∞ by 35% (GMR 65.15%, 90% CI: 59.80%, 70.88%) and Cmax by 11% (GMR 89.31%, 90% CI: 83.43%, 95.60%). None of these changes were considered to be clinically relevant. Single doses of tepotinib were considered safe and well tolerated in both studies. The observed pharmacokinetic interactions were consistent with a low ( 17%) contribution of CYP3A4 to tepotinib metabolism without a relevant role for P‐gp mediated biliary secretion. The potential of tepotinib to be a victim of modulators of both CYP3A4 and P‐gp at the intended posology is considered low.

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71–1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.