The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239.

Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.

Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.

Effect of drug interactions with non-vitamin-K oral anticoagulants on thromboembolic events in patients with nonvalvular atrial fibrillation.

Introduction: Few real-world studies have investigated drug-drug interactions (DDIs) involving non-vitamin-K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation (NVAF). The interactions encompass drugs inducing or inhibiting cytochrome P450 3A4 and permeability glycoprotein. These agents potentially modulate the breakdown and elimination of NOACs. This study investigated the impact of DDIs on thromboembolism in this clinical scenario. Method: Patients who had NVAF and were treated with NOACs were selected as the study cohort from the National Health Insurance Research Database of Taiwan. Cases were defined as patients hospitalised for a thromboembolic event and who underwent a relevant imaging study within 7 days before hospitalisa-tion or during hospitalisation. Each case was matched with up to 4 controls by using the incidence density sampling method. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer or inhibitor or both with NOACs was identified. The effects of these interactions on the risk of thromboembolic events were examined with univariate and multivariate conditional logistic regressions. Results: The study cohort comprised 60,726 eligible patients. Among them, 1288 patients with a thromboembolic event and 5144 matched control patients were selected for analysis. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer resulted in a higher risk of thromboembolic events (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.004-1.51). Conclusion: For patients with NVAF receiving NOACs, the concurrent use of cytochrome P450 3A4/ permeability glycoprotein inducers increases the risk of thromboembolic events.

Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study.

BACKGROUND: Intranasal esketamine is an approved drug for treatment­resistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative. METHODS: In collaboration with a 39­year­old female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we co­administered a single dose of the cytochrome P­450 (CYP) 3A4 inhibitor cobicistat (150 mg). RESULTS: For all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg). CONCLUSIONS: Our findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.

A physiologically-based pharmacokinetic precision dosing approach to manage dasatinib drug-drug interactions.

Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration-time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%-80% for strong and 0%-70% for moderate CYP3A4 inhibitors and a 2.3-3.1-fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient-related factors, such as elevated gastric pH.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Effectiveness and Safety of Different Oral Anticoagulants with P-glycoprotein/ CYP3A4 Inhibitors: A Network Meta-analysis.

BACKGROUND: Metabolism of oral anticoagulants (OAC) is affected by P-glycoprotein (P-gp)/ CYP3A4 enzyme. However, the P-gp/CYP3A4 inhibitors are unavoidably used with OACs. METHODS: Medline, Cochrane, and Embase were systematically searched for randomized controlled trials and cohort studies from inception till 23rd November, 2022 to assess the safety and effectiveness of OACs when concomitantly used with P-gp/CYP3A4 inhibitors. The primary outcomes were major bleeding and gastrointestinal (GI) bleeding. Secondary outcomes were stroke/systemic embolism (SE), all-cause mortality, any bleeding as well as intracranial hemorrhage (ICH). We estimated summary odds ratios (OR) with 95% credible intervals (CI) using pairwise and network meta-analysis with random effects. RESULTS: A total of 11 studies involving 37,973 patients were included. When concomitantly used with P-pg/ CYP3A4 inhibitors, network meta-analysis indicated that dabigatran, apixaban, and edoxaban were associated with significantly lower risk of major bleeding compared to rivaroxaban, with ORs of 0.56, 0.51 and 0.48, respectively. Rivaroxaban and dabigatran were associated with a significantly increased risk of GI bleeding than warfarin, apixaban and edoxaban. Dabigatran and apixaban were linked with significantly lower risk of any bleeding compared with warfarin (ORs were 0.75 and 0.68, respectively) or rivaroxaban (ORs were 0.67 and 0.60, respectively). Apixaban (OR 0.32) and edoxaban (OR 0.35) were associated with a lower risk of ICH compared with warfarin. There was no difference between any OACs in terms of stroke/SE or all-cause mortality. CONCLUSION: When concomitantly used with P-gp/CYP3A4 inhibitors, apixaban and edoxaban were associated with a lower risk of bleeding, though no significant difference in effectiveness was observed among all OACs.

Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions.

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.

Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Análisis de las interacciones de nirmatrelvir/ritonavir en pacientes ambulatorios en atención primaria / Nirmatrelvir/ritonavir drug-drug interactions in primary care outpatients

Fundamento. Nirmatrelvir/ritonavir es un antiviral oral con un alto potencial de producir interacciones farmacológicas. La población candidata a recibirlo es mayoritariamente vulnerable, con enfermedades crónicas y polimedicada. El objetivo es evaluar la validación farmacéutica previa a la ad-ministración del antiviral.Material y métodos. Las interacciones farmacológicas entre nirmatrelvir/ritonavir y el tratamiento habitual se consulta-ron en fichas técnicas y las herramientas de interacciones de UpToDate® y Universidad de Liverpool®. Se incluyeron las prescripciones validadas por un farmacéutico de atención primaria (abril/2022-abril/2023). Resultados. Se incluyeron 159 pacientes; en 83 se detecta-ron 168 interacciones que podían suponer un cambio en su tratamiento. Las estatinas (25,6%), anticoagulantes (10,7%) y antihipertensivos (10,7%) fueron los grupos terapéuticos más frecuentemente implicados. La suspensión (53,0%) y reducción de dosis (22,6%) fueron los cambios de trata-miento más frecuentes. Conclusiones. La revisión de potenciales interacciones far-macológicas, los ajustes posológicos y las modificaciones del tratamiento habitual del paciente han evitado potenciales to-xicidades, mejorando la seguridad de nirmatrelvir/ritonavir (AU)

Background. The oral antiviral nirmatrelvir/ritonavir inter-acts with a range of drugs. Candidate patients to receive this antiviral agent are usually vulnerable, multipathological and polymedicated. The objective is to evaluate the phar-maceutical validation prior to the administration of the an-tiviral.Material and methods. Drug-drug interactions between nirmatrelvir/ritonavir and patients’ usual treatment medi-cations were checked in product information and in the Up-ToDate® and the University of Liverpool® interaction tools. We included validated prescriptions between April/2022 and April/2023 by a Primary Care pharmacist.Results. Of the 159 study patients, 168 interactions were found in 83 individuals, which may have led to changes of their usual treatment. Statins (25.6%), anticoagulants (10.7%), and antihypertensives (10.7%) were the most fre-quently implicated therapeutic groups. Discontinuation (53.0%) and dose reduction (22.6%) were the most common treatment changes. Conclusions. Our search of potential drug interactions and subsequent dose adjustments and modifications of the pa-tient’s usual treatment has helped avoid potential toxicities ensuring a safe use of nirmatrelvir/ritonavir (AU)

Group based trajectory modeling to assess adherence to oral anticoagulants among atrial fibrillation patients with comorbidities: a retrospective study.

BACKGROUND: Poor adherence to oral anticoagulants is a significant problem in atrial fibrillation (AF) patients with comorbidities as it increases the risk for cardiac and thromboembolic events. AIM: The primary objective was to evaluate adherence to direct oral anticoagulants (DOACs) or warfarin using group-based trajectory modeling (GBTM). The secondary objective was to identify the predictors of adherence to oral anticoagulants. Finally, to report the drug interactions with DOACs/warfarin. METHOD: This retrospective study was conducted among continuously enrolled Medicare Advantage Plan members from January 2016-December 2019. AF patients with comorbid hypertension, diabetes and hyperlipidemia using warfarin/DOACs were included. Monthly adherence to DOAC/warfarin was measured using proportion of days covered (PDC) and then modeled in a logistic GBTM to identify the distinct patterns of adherence. Logistic regression model was conducted to identify the predictors of adherence to oral anticoagulants adjusting for all baseline characteristics. Concomitant use of DOACs/warfarin with CYP3A4,P-gp inhibitors were measured. RESULTS: Among 317 patients, 137 (43.2%) and 79 (24.9%) were DOAC, and warfarin users, respectively. The adherence trajectory model for DOACs included gradual decline (40.4%), adherent (38.8%), and rapid decline (20.8%). The adherence trajectories for warfarin adherence included gradual decline (8.9%), adherent (59.4%), and gaps in adherence (21.7%). Predictors of adherence included type of oral anticoagulant, stroke risk score, low-income subsidy, and baseline PDC. CYP3A4,P-gp drugs were co-administered with DOACs /warfarin resulting in adverse events. CONCLUSION: Adherence to oral anticoagulants is suboptimal. Interventions tailored according to past adherence trajectories may be effective in improving patient's adherence.

Effects of the Moderate CYP3A4 Inhibitor Erythromycin on the Pharmacokinetics of Palbociclib: A Randomized Crossover Trial in Patients With Breast Cancer.

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-24h ), maximum plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) were 1.46 × 103  ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103  ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0-24h , Cmax , and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24-1.66), 1.43 (1.20-1.69), and 1.46 (1.30-1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0-24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.

The pharmacokinetic study on the interaction between nobiletin and anemarsaponin BII in vivo and in vitro.

CONTEXT: The interaction between nobiletin and anemarsaponin BII could affect the pharmacological activity of these two drugs during their combination. OBJECTIVE: The co-administration of nobiletin and anemarsaponin BII was investigated to explore the interaction and the potential mechanism. MATERIALS AND METHODS: Male Sprague-Dawley rats were only orally administrated with 50 mg/kg nobiletin as the control and another six rats were pre-treated with 100 mg/kg anemarsaponin BII for 7 d followed by the administration of nobiletin. The transport and metabolic stability of nobiletin were evaluated in vitro, and the effect of anemarsaponin BII on the activity of CYP3A4 was also assessed to explore the potential mechanism underlying the interaction. RESULTS: The increasing Cmax (2309.67 ± 68.06 µg/L vs. 1767.67 ± 68.86 µg/L), AUC (28.84 ± 1.34 mg/L × h vs. 19.57 ± 2.76 mg/L × h), prolonged t1/2 (9.80 ± 2.33 h vs. 6.24 ± 1.53 h), and decreased clearance rate (1.46 ± 0.26 vs. 2.42 ± 0.40) of nobilein was observed in rats. Anemarsaponin BII significantly enhanced the metabolic stability of nobiletin in rat liver microsomes (half-life increased from 31.56 min to 39.44 min) and suppressed the transport of nobiletin in Caco-2 cells (efflux rate decreased from 1.57 ± 0.04 to 1.30 ± 0.03). The inhibitory effect of anemarsaponin BII on CYP3A4 was also found with an IC50 value of 10.23 µM. DISCUSSION AND CONCLUSIONS: The interaction between anemarsaponin BII and nobiletin was induced by the inhibition of CYP3A4, which should draw special attention in their clinical co-administration.

Functional evaluation of vandetanib metabolism by CYP3A4 variants and potential drug interactions in vitro.

AIM: To investigate the enzymatic properties of cytochrome P450 3A4 (CYP3A4) variants and their ability to metabolize vandetanib (VNT) in vitro, and to study potential drug interactions in combination with VNT. METHOD: Recombinant CYP3A4 cell microsomes were prepared using a Bac-to-Bac baculovirus expression system. Enzymatic reactions were carried out, and the metabolites were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The activities of 27 CYP3A4 variants were determined to assess the degree of VNT metabolism that occurred. Analysis indicated that there was enhanced intrinsic clearance (Vmax/Km, CLint) for eight variants (CYP3A4.2, 3, 9, 15, 16, 29, 32, and 33), while there was a significant decrease in CYP3A4.5, 7, 8, 10-14, 17-20, 23, 24, 28, 31, and 34. Compared with CYP3A4.1, no significant differences were found for CYP3A4.6 and 30. Furthermore, the relative clearances were compared between VNT and cabozantinib, which were all metabolized by CYP3A4 with the same indications. When combined with ketoconazole, which is a CYP inhibitor, obvious differences were observed in the potency of VNT between different variants, including CYP3A4.2, 15, and 18. CONCLUSION: This comprehensive assessment of CYP3A4 variants provides significant insights into the allele-specific metabolism of VNT and drug interactions in vitro. We hope that these comprehensive data will provide references and predictions for the clinical application of VNT.

Evidence-Based Guidelines for Drug Interaction Studies: Model-Informed Time Course of Intestinal and Hepatic CYP3A4 Inhibition by Clarithromycin.

Drug-drug interaction (DDI) studies are mandated in drug development; however, protocols for evaluating the impact of cytochrome P450 (CYP) inhibition on new molecular entities are currently inconsistent. This study utilised validated physiologically based pharmacokinetic (PBPK) software to define the optimal dose, frequency, and duration of clarithromycin to achieve optimal characterisation of CYP3A4 inhibition in a study population. The Simcyp® Simulator (Version 19.0) was used to simulate clarithromycin-mediated CYP3A4 inhibition in healthy virtual cohorts. Between trial variability in magnitude and time course of CYP3A4 activity was assessed following clarithromycin dosing strategies obtained from the University of Washington Drug Interaction Database. Heterogeneity in CYP3A4 inhibition was evaluated across sex, race, and age. Literature review identified 500 mg twice daily for 5 days as the most common clarithromycin dosing protocol for CYP3A4 inhibition studies. On simulation, clarithromycin 500 mg twice daily resulted in the largest steady-state inhibition of hepatic (percent mean inhibition [95%CI] = 80 [77-83]) and small intestine (94 [94-95]) CYP3A4 activity (as compared to 500 mg once daily, 400 mg once/twice daily, or 250 mg once/twice daily). Additionally, 500 mg twice daily was associated with the shortest time for 90% of individuals to reach 90% of their minimum hepatic (4 days) and small intestine (1 days) CYP3A4 activity. The study presented herein supports that clarithromycin dosing protocol of 500 mg twice daily for 5 days is sufficient to achieve maximal hepatic and small intestine CYP3A4 inhibition. These findings were consistent between sex, race, and age differences.

[A Survey of the Use of Direct Oral Anticoagulants in Patients' Possession at the Time of Hospitalization].

The dose of direct oral anticoagulants (DOACs) must be determined based on package insert recommendations. There are reports on the rate of inappropriate DOAC dose usage defined as a dose deviating from the approved dose in the package insert but no reports on factors that led to such deviations. Thus, patients who were admitted to the Suzuka Kaisei Hospital between 1 April 2016 and 31 March 2017 were chosen as subjects. Moreover, the factors that during hospitalization led to dose deviation from the package-insert DOAC dose were retrospectively examined. The characteristics of patients administered doses deviating from the package insert were compared with those of patients in the appropriate-dose group. The finding was that the proportion concomitantly administered antiplatelet agents was higher in the underdose group. In contrast, deviations from the recommended dose did not occur when DOACs were combined with CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors. It was suggested that increase in the risk of hemorrhage by antiplatelet agents in combination with oral anticoagulants could explain deviations from the stipulated DOAC dose. In addition, a higher proportion of patients in the overdose group showed depressed Ccr, and gastrointestinal bleeding. In future, it will be necessary to propose principle-based dose changes for patients administered doses deviating from the package insert. If an underdose is administered, it is important to make a dose change that takes the concomitant drugs into consideration.

Baicalein inhibits the pharmacokinetics of simvastatin in rats via regulating the activity of CYP3A4.

CONTEXT: Baicalein and simvastatin possess similar pharmacological activities and indications. The risk of their co-administration was unclear. OBJECTIVE: The interaction between baicalein and simvastatin was investigated to provide reference and guidance for the clinical application of the combination of these two drugs. MATERIALS AND METHODS: The pharmacokinetics of simvastatin was investigated in Sprague-Dawley rats (n = 6). The rats were pre-treated with 20 mg/kg baicalein for 10 days and then administrated with 40 mg/kg simvastatin. The single administration of simvastatin was set as the control group. The rat liver microsomes were employed to assess the metabolic stability and the effect of baicalein on the activity of CYP3A4. RESULTS: Baicalein significantly increased the AUC(0-t) (2018.58 ± 483.11 vs. 653.05 ± 160.10 µg/L × h) and Cmax (173.69 ± 35.49 vs. 85.63 ± 13.28 µg/L) of simvastatin. The t1/2 of simvastatin was prolonged by baicalein in vivo and in vitro. The metabolic stability of simvastatin was also improved by the co-administration of baicalein. Baicalein showed an inhibitory effect on the activity of CYP3A4 with the IC50 value of 12.03 µM, which is responsible for the metabolism of simvastatin. DISCUSSION AND CONCLUSION: The co-administration of baicalein and simvastatin may induce drug-drug interaction through inhibiting CYP3A4. The dose of baicalein and simvastatin should be adjusted when they are co-administrated.

Multiple Administrations of Itraconazole Increase Plasma Exposure to Pyrotinib in Chinese Healthy Adults.

PURPOSE: Pyrotinib, an irreversible human epidermal growth factor receptor 2 (HER2), is a epidermal growth factor receptor double-target tyrosine kinase inhibitor used for treating HER2-positive breast cancer. This study aimed to evaluate the impact of the strong CYP3A4 inhibitor itraconazole on the safety and pharmacokinetics of pyrotinib in Chinese healthy adults. PATIENTS AND METHODS: This was an open-label, randomized, self-control study. Eighteen healthy adults were included in this trial. They received a single 80 mg dose of pyrotinib orally on days 1 and 9, and a 200 mg once-daily dose of itraconazole on days 6 through 22. Blood samples were obtained, and the drug concentration was detected using liquid chromatography/tandem mass spectrometry. RESULTS: Compared with pyrotinib alone, the exposure to pyrotinib co-administered with itraconazole substantially increased, and the C max and AUC0-t increased by 2.78- and 10.8-fold, respectively. No serious adverse events were reported in this trial, and no participant dropped out of the trial because of adverse events. CONCLUSION: The exposure to pyrotinib was substantially affected by the action of itraconazole. The concomitant use of pyrotinib with itraconazole might require dose modification of pyrotinib. All treatments were well tolerated in healthy participants. CLINICAL TRIAL REGISTRY: http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, CTR20191866.