Strong Cytochrome P450 3A Inhibitor Research Articles

Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n=748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

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.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study

Background: Revumenib (SNDX-5613), a potent, selective small-molecule inhibitor of the menin-histone-lysine N-methyltransferase 2A (KMT2A) interaction, is being investigated in patients (pts) with relapsed/refractory (R/R) KMT2A-rearranged ( KMT2Ar) and nucleophosmin 1-mutated ( NPM1m) acute leukemias. An initial analysis of the phase 1 of AUGMENT-101 (NCT04065399) has been reported ( Nature. 2023;615:920-924). Here we report an update of >1 year additional experience in the phase 1 portion of the study, which has completed enrollment, with safety data from 131 treated pts and efficacy data in 80 pts with R/R KMT2Ar leukemia. Demographic data from pivotal phase 2 cohorts are included; safety and efficacy data of a preplannedanalysis will be reported at the meeting. Methods: In phase 1, pts aged ≥30 days with R/R acute leukemias were assigned to 1 of 6 dose-escalation arms designed to identify a recommended phase 2 dose (RP2D) for concomitant administration of weak, moderate, or strong cytochrome P450 3A4 inhibitor (CYP3A4i) azole antifungal or no CYP3A4i. Pts received revumenib every 12 hours (q12h) or 3 times a day at a flat dose (≥40 kg) or a body surface area-based dose (<40 kg). Safety was assessed in all pts who received ≥1 dose of revumenib; responses are reported for all treated pts with KMT2Ar. In pts who underwent hematopoietic stem cell transplant (HSCT), responses reported are those achieved before HSCT. The Phase 2 study was initiated following identification of an RP2D of 163 mg (95 mg/m 2 if <40 kg) q12h with a strong CYP3A4i in 28-day cycles until unacceptable toxicity, lack of at least morphological leukemia-free state (MLFS) by end of cycle 4, or progressive disease without clinical benefit as defined by the investigator. The phase 2 primary objectives are evaluation of safety and tolerability of revumenib and assessment of the complete remission (CR) + CR with partial hematologic recovery (CRh) rate. The safety and efficacy of revumenib at an RP2D is being explored in 3 expansion cohorts: Cohort 2A, KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia; Cohort 2B, KMT2Ar acute myeloid leukemia (AML); and Cohort 2C, NPM1m AML. A preplanned pooled analysis of adult and pediatric pts with KMT2Ar acute leukemia will be conducted when a subset of Cohorts 2A+2B pts have completed a minimum of 4 cycles or have discontinued therapy. Results: Phase 1: As of June 19, 2023, 80 pts with R/R KMT2Ar acute leukemia were treated with revumenib in the 6 dose-escalation arms (Table 1). In adults with AML (n=51), the largest KMT2Ar subgroup, CR+CRh was 28% and overall response rate (ORR) was 59%. Responses were consistent in ALL/other leukemia subtype (n=15), with 27% CR+CRh and 53% ORR. ORR (61%) was similar in pediatric pts (<18 years, n=18), with 22% proceeding to HSCT. Although similar percentages of adult and children proceeded to transplant, consistent with common clinical practice in pediatrics, 75% of children transplanted went on to HSCT prior to achieving a CR/CRh (2 MLFS, 1 CRp) versus 17% of adults. In the safety population (n=131), 24% of pts had a ≥Grade 3 treatment-related adverse event (TRAE), with Grade 3 QTc prolongation in 8% and differentiation syndrome in 2% (Table 1). QTc prolongation remained as the only dose-limiting toxicity; no patients experienced ventricular arrhythmias. In addition, based on updated phase 1 pharmacokinetics, clinical activity, and safety data, an RP2D of 276 mg q12h without a strong CYP3A4i was established. Phase 2: In a preliminary analysis of Cohorts 2A and 2B (June 19, 2023), 88 pts with KMT2Ar acute leukemia were enrolled and treated with revumenib at an RP2D (Table 2). Ages ranged from 1.3 to 75 years (22 aged <18 y; Table 2). Leukemia subtypes included ALL (15%), AML (81%), and other (3%). Pts were heavily pretreated, having received a median of 3 prior lines of therapy (range 1-12); 38% received ≥4 prior lines and 48% had prior HSCT. Conclusions: These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing. Pivotal Phase 2 safety and efficacy data for the KMT2Ar population will be reported at the meeting.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study

Background: Most patients (pts) with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia, relapse after conventional chemotherapy and hematopoietic stem cell transplant (HSCT). Remission rates after relapse (complete remission [CR], 5%) and median overall survival (2.4 mo) in ≥2nd salvage therapies in adults remain low (Blood Cancer J. 2021;11[9]:162). In KMT2Ar leukemia, interaction of menin with KMT2A fusion proteins is a key driver of leukemogenesis. However, no therapies targeting the menin-KMT2A interaction have been approved. Revumenib (SNDX-5613; rev), a small-molecule inhibitor of menin-KMT2A interactions, demonstrated preliminary efficacy and safety in a phase 1 study of R/R KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. We report topline efficacy and safety for pts with R/R KMT2Ar acute leukemia treated with rev in a pivotal phase 2 study (AUGMENT-101; NCT04065399). Methods: Pts aged ≥30 days with R/R KMT2Ar acute leukemia were enrolled in cohort A (acute lymphoblastic leukemia [ALL]/mixed phenotype acute leukemia [MPAL]) and B (acute myeloid leukemia [AML]); cohort C continues to enroll pts with NPM1m and is not included in this analysis. Pts received rev (163 mg or 95 mg/m2 if body weight <40 kg) q12h with a strong cytochrome P450 3A4 inhibitor orally in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state (MLFS) after 4 cycles of treatment. Phase 2 primary objectives were safety and tolerability of rev and CR+CR with partial hematologic recovery (CRh) rate. Key secondary endpoints included composite CR rate (CRc, CR+CRh+CR with incomplete platelet recovery [CRp]+CR with incomplete count recovery [CRi]) and overall response rate (ORR, CRc+MLFS+partial remission). A planned interim analysis (IA) of pooled adult and pediatric pts with KMT2Ar acute leukemia was conducted. Results:As of July 24, 2023, 94 pts with R/R KMT2Ar acute leukemia received ≥1 dose of study drug and were included in the safety analysis (Table 1). Median age was 37.0 y (range, 1.3-75.0). Of the 94 pts, 23 (24.5%) were aged <18 y and 13 (13.8%) were aged ≥65 y. Seventy-eight (83%) had AML and 16 (17.0%) had ALL or MPAL. Over half of pts were female; 17.5% of pts were non-White. Pts were heavily pretreated (median 2 [range, 1-11] prior lines of therapy), with 41 pts (43.6%) having received ≥3 prior lines. Fifty-four pts (57.4%) had refractory relapse disease (unresponsive to most recent salvage treatment), and 47 pts (50%) had prior HSCT. Treatment-related adverse events (TRAEs) were reported in 81.9% of the safety population. Most common TRAEs (≥20%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Grade ≥3 TRAEs were observed in 51 pts (54.3%), the most common being differentiation syndrome (16.0%), febrile neutropenia (13.8%), and QTc prolongation (13.8%) (Table 2). Overall, 6.4% of pts discontinued therapy due to TRAEs; none discontinued rev due to differentiation syndrome or QTc prolongation. The pooled efficacy population for the IA (n=57) included all phase 2 pts with centrally confirmed KMT2Ar and ≥5% blasts in bone marrow at baseline who had received ≥1 dose of study drug and started treatment on or before the 38th adult AML efficacy evaluable patient. The IA was specified to occur when the 57 patients have had the opportunity to be followed for 6 months. After median follow-up of 6.1 mo, 13 pts (22.8% [95% confidence interval (CI), 12.7-35.8]) achieved CR+CRh, surpassing the predefined IA efficacy boundary for the pooled KMT2Ar population; CR+CRh rate was similar in adult and pediatric pts. Median duration of CR+CRh was 6.4 mo (95% CI, 3.4-not reached). CRc was 43.9% (95% CI, 30.7-57.6); ORR was 63.2% (95% CI, 49.3-75.6). Most pts with a CR or CRh response, and for whom measurable residual disease (MRD) status was reported, achieved MRD negativity (7/10, 70.0%); most pts with CRc and MRD reported also achieved MRD negativity (15/22, 68.2%). Fourteen of 36 responders (38.9%) proceeded to HSCT, with half resuming rev post HSCT. Conclusions: Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.

A case of extrapyramidal side effects due to possible paliperidone: voriconazole interaction

AbstractBackgroundIt is thought that paliperidone, an active metabolite of risperidone, has limited potential for pharmacokinetic drug–drug interactions (DDIs) due to minimal metabolism by cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). However, DDIs have been reported and include a theoretical interaction between paliperidone and voriconazole based on interactions between risperidone and strong CYP3A4 inhibitor azoles.AimTo describe the first recorded DDI between paliperidone and voriconazole leading to extrapyramidal side effects (EPSEs).Clinical detailsA 34‐year‐old male presented with febrile neutropenia presumed due to clozapine. Clozapine was ceased and paliperidone commenced with voriconazole added to the patient's empiric piperacillin/tazobactam therapy due to a suspected fungal infection. Two days after starting voriconazole, the patient developed hypertonia and hyperreflexia in all limbs, thought most likely to be antipsychotic induced EPSEs. Paliperidone was withheld and EPSEs resolved.OutcomesThe patient had previously tolerated long‐term paliperidone at higher doses, prior to transitioning to clozapine. The development of EPSEs occurred two days post azole initiation, indicating a probable paliperidone adverse drug reaction (ADR) due to strong CYP3A4 inhibition by voriconazole. This case appears to be the first documented report of this previous theoretical DDI in practice. Further studies, including therapeutic drug monitoring, are required to confirm findings.ConclusionPaliperidone may be affected by pharmacokinetic drug–drug interactions and patients should be monitored for ADRs when CYP3A4 inhibitors are concomitantly administered.

Physiologically Based Pharmacokinetic Modeling of the Drug-Drug Interaction Between CYP3A4 Substrate Glasdegib and Moderate CYP3A4 Inducers in Lieu of a Clinical Study.

Glasdegib (DAURISMO) is a hedgehog pathway inhibitor approved for the treatment of acute myeloid leukemia (AML). Cytochrome P450 3A4 (CYP3A4) has been identified as a major metabolism and clearance pathway for glasdegib. The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug-drug interaction (DDI) studies following the coadministration of glasdegib with the strong CYP3A4 inhibitor ketoconazole and the strong inducer rifampin. To evaluate potential drug interactions with CYP3A4 modulators, the coadministration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator. The glasdegib compound file was developed using measured physicochemical properties, data from human intravenous and oral pharmacokinetics, absorption, distribution, metabolism, and excretion studies, and invitro reaction phenotyping results. The modeling assumptions, model parameters, and assignments of fractional CYP3A4 metabolism were verified using results from clinical pharmacokinetics (PK) and DDI studies with ketoconazole and rifampin. The verified glasdegib and efavirenz compound files, the latter of which was available in the Simcyp simulator, were used to estimate the potential impact of efavirenz on the PK of glasdegib. PBPK modeling predicted a glasdegib area under the concentration-time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following coadministration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label, with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by a resumption of the original dose 7days post-discontinuation.

Adverse events with quetiapine and clarithromycin coprescription: A population-based retrospective cohort study.

Quetiapine is an atypical antipsychotic predominantly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. We studied the risk of adverse events following coprescription of clarithromycin (a strong CYP3A4 inhibitor) versus azithromycin (not a CYP3A4 inhibitor) in quetiapine users. This was a population-based retrospective cohort study from 2004 to 2020 in Ontario, Canada in adult quetiapine users newly co-prescribed clarithromycin (n = 16,909) or azithromycin (n = 25,267). The primary outcome was the composite of hospital encounters with encephalopathy (defined as a diagnosis of delirium, disorientation, transient alteration of awareness, transient ischemic attack, or unspecified dementia), a fall, or a fracture within 30 days of new coprescription. Secondary outcomes were individual components of the composite outcome, hospital encounter with computed tomography(CT) head scan, and all-cause mortality. Coprescription of clarithromycin versus azithromycin with quetiapine was associated with a higher risk of the primary composite outcome (365 of 16,909 clarithromycin users [2.2%] vs. 309 of 16,929 azithromycin users [1.8%]; absolute risk increase, 0.34% [95% confidence interval,CI, 0.04-0.63]; relative risk [RR], 1.19 [95% CI,1.02-1.38]). This was primarily driven by an increase in fragility fractures (78 of 16,909 clarithromycin users [0.5%] vs. 45 of 16,923 azithromycin users [0.3%]; absolute risk increase, 0.20% [95% CI, 0.07-0.32]; RR, 1.74 [95% CI, 1.21-2.52]). Hospital encounters with a CT head scan were higher in clarithromycin users (220 of 16,909 [1.3%] vs. 175 of 16,923 azithromycin users [1.0%]; absolute risk increase, 0.27% [95% CI, 0.04-0.50]; RR, 1.26 [95% CI, 1.04-1.54]), but there was no difference in hospital encounters with encephalopathy, falls, or all-cause mortality between macrolide groups. Among adults taking quetiapine, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically greater 30-day risk of a hospital encounter for encephalopathy, falls, or fracture, which was predominantly related to a higher rate of fragility fractures.

Dietary phytochemicals against COVID‐19: A focus on thymoquinone

Dietary phytochemicals against COVID‐19: A focus on thymoquinone

Understanding the Risk of Drug Interactions Between Ritonavir-Containing COVID-19 Therapies and Small-Molecule Kinase Inhibitors in Patients With Cancer.

The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer. Physiologically based pharmacokinetic modeling was used to conduct virtual clinical trials with a parallel group study design in the presence and absence of ritonavir (100 mg twice daily for 5 days). The magnitude and time course of changes in KI exposure when coadministered with ritonavir was evaluated as the primary outcome. Dosing of ritonavir resulted in a > 2-fold increase in steady-state area under the plasma concentration-time curve and maximal concentration for six of the 10 KIs. When the KI was coadministered with ritonavir, dose reductions to between 10% and 75% of the original dose were required to achieve an area under the plasma concentration-time curve within 1.25-fold of the value in the absence of ritonavir. To our knowledge, this study provides the first data to assist clinicians' understanding of the drug interaction risk associated with administering ritonavir-containing COVID-19 therapies to patients with cancer who are currently being treated with KIs. These data may support clinicians to make more informed dosing decisions for patients with cancer undergoing treatment with KIs who require treatment with ritonavir-containing COVID-19 antiviral therapies.

Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

IntroductionOral administration of ritonavir-boosted nirmatrelvir (Paxlovid) was found to be promising in the treatment of coronavirus disease 2019. The active antiviral component nirmatrelvir in Paxlovid is co-formulated with ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Many oral targeted therapies indicated for lung cancer are known substrates of CYP 3A4, and concurrent use with Paxlovid may lead to potential drug-drug interaction (DDI). The purpose of this review is to evaluate the potential DDI between targeted therapies and supportive care for lung cancer and ritonavir-boosted nirmatrelvir. MethodsDrug database search in PubMed and the Food and Drug Administration was conducted to identify pharmacokinetic data on oral tyrosine kinase inhibitors (TKIs) used in NSCLC, both Food and Drug Administration approved and those in development. Metabolism pathways for various TKIs are extracted, and the impact of TKI area under the curves and maximum concentration by strong CYP 3A4 inducers and inhibitors is summarized. The most common toxicities and supportive care medications for the TKI were identified. ResultsAmong EGFR and exon 20 insertion inhibitors, afatinib is least likely to be affected by CYP 3A4, followed by dacomitinib and osimertinib. Among ALK inhibitors, alectinib is the least susceptible to CYP 3A4. ROS1 inhibitors are affected by CYP 3A4 inhibition with the exception of crizotinib. Among MET inhibitors, capmatinib is substantially affected by CYP 3A4 inhibition. Drug exposure of RET inhibitors is expected to increase with CYP 3A4 inhibition, with selpercatinib being the least affected. Certain supportive care medications for lung cancer TKI may have relevant DDIs. ConclusionsThe clinical impact of the DDI between lung cancer TKI and ritonavir-boosted nirmatrelvir varies largely on the basis of the susceptibility of CYP 3A4 inhibition caused by the antiviral. Close monitoring and medication adjustments (i.e., dose changes or alternative coronavirus disease 2019 therapy) can be used to overcome DDI to ensure patient safety.

1131. Evaluation of drug-drug interaction potential of ensitrelvir for CYP3A by clinical studies and physiologically-based pharmacokinetic model

Abstract Background Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days. Disclosures Ryosuke Shimizu, Shionogi & Co., Ltd.: employee Kana Horiuchi, Shionogi & Co., Ltd.: employee Hiroki Koshimichi, n/a, Shionogi & Co., Ltd.: employee Takanobu Matsuzaki, Ph.D., Shionogi & Co., Ltd.: Employee Shinpei Yoshida, Ph.D., Shionogi & Co., Ltd.: employee Shingo Sakamoto, n/a, Shionogi & Co., Ltd.: employee Ryuji Kubota, Ph.D., Shionogi & Co., Ltd.: employee|Shionogi & Co., Ltd.: employee.

Impact of Multiple Concomitant CYP3A Inhibitors on Venetoclax Pharmacokinetics: A PBPK and Population PK-Informed Analysis.

Venetoclax is an approved, orally bioavailable, B-cell lymphoma type2 (BCL-2) inhibitor that is primarily metabolized by cytochromeP4503A (CYP3A). Polypharmacy is common in patients undergoing treatment for hematological malignancies such as acute myeloid leukemia or chronic lymphocytic leukemia, and although venetoclax exposure has been well characterized with 1 concomitant CYP3A inhibitor, complex drug-drug interactions (DDIs) involving more than 1 inhibitor have not been systematically evaluated. Here, we aimed to describe the potential impact of multiple concomitant CYP3A inhibitors on venetoclax pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) and population PK modeling. The modeling approaches were informed by clinical data in the presence of single or multiple CYP3A inhibitors, and the effects of 1 or more inhibitors were systematically considered within these modeling frameworks. The PBPK modeling approach was independently validated against clinical data involving more than 1 CYP3A inhibitor along with CYP3A substrates other than venetoclax. Both approaches indicated that combining a strong CYP3A inhibitor with another competitive CYP3A inhibitor does not seem to result in any additional increase in venetoclax exposure, beyond what would be expected with a strong inhibitor alone. This suggests that the current dose reductions recommended for venetoclax would be appropriate even when 2 or more CYP3A inhibitors are taken concomitantly. However, the results indicate that the involvement of time-dependent inhibition might lead to additional inhibitory effects over and above the effect of a single strong CYP3A inhibitor. Thus, the clinical management of such interactions must consider the underlying mechanism of the interactions.

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

IntroductionExposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. MethodsThis was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22–26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2–4 months) of the boosting effect. ResultsThe mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%–192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. ConclusionPharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.

Evaluation of drug–drug interactions between midostaurin and strong CYP3A4 inhibitors in patients with FLT-3-mutated acute myeloid leukemia (AML)

Midostaurin, approved for the treatment of newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), is metabolized by cytochrome P450 3A4 (CYP3A4). Midostaurin with concomitant strong CYP3A4 inhibitors use (e.g., antifungal azoles) may result in drug-drug interactions. This post hoc analysis of RATIFY phase 3 study data evaluated effects of strong CYP3A4 inhibitor use on the exposure and safety of midostaurin. Trough concentrations were used to assess midostaurin and metabolite exposure in the presence and absence of strong CYP3A4 inhibitors. Adverse event (AE) frequency was assessed in patients who received concomitant strong CYP3A4 inhibitors vs those who did not. Time to first clinically notable AE (CNAE) was also assessed in patients with high midostaurin plasma exposure vs those of matched placebo controls. Use of concomitant strong CYP3A4 inhibitors was most frequent during the induction phase (60.8%). A 1.44-fold increase in midostaurin plasma exposure was observed in patients with concomitant strong CYP3A4 inhibitor use vs those without. Midostaurin-treated patients who received concomitant strong CYP3A4 inhibitors experienced grade 3/4 infection-related AEs more frequently vs those who did not. Patients with high levels of midostaurin exposure had a shorter median time to first grade 3/4 CNAE vs placebo controls (36 vs 41days, respectively; P = .012). Although concomitantly administered strong CYP3A4 inhibitors increased midostaurin exposure 1.44-fold, no clinically relevant differences in safety were noted. Midostaurin dose adjustment is not necessary with concomitant strong CYP3A4 inhibitors in patients with FLT3-mutated AML; however, caution is advised, and patients should be closely monitored.

Abstract CT125: Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs)

Abstract Background Futibatinib is an oral, irreversible FGFR1-4 inhibitor with clinical activity in cholangiocarcinoma and other FGFR-aberrant tumors. The recommended futibatinib dosage is 20 mg once daily (QD). In vitro studies have shown that futibatinib is predominantly metabolized by and inhibits cytochrome p450 3A (CYP3A); futibatinib is also a P-glycoprotein substrate. Two phase 1 studies were performed in healthy volunteers to evaluate potential DDIs between futibatinib and CYP3A substrates (midazolam; study 1) or CYP3A inhibitors/inducers (itraconazole/rifampin; study 2). As the solubility of futibatinib is pH dependent, study 3 assessed the effect of PPI (lansoprazole) coadministration on futibatinib pharmacokinetics (PK). Methods All 3 studies, conducted in adult nonsmokers, were open-label, fixed-sequence, 2-period cross-over studies with a 1- or 2-d washout between each period. In study 1, midazolam 2 mg was given on d1 of period 1 (-futibatinib) and on d7 of period 2 (+futibatinib 20 mg QD d1-7). In study 2, futibatinib 20 mg was given on d1 of period 1 (alone) and on d5 (+itraconazole 200 mg QD d1-6) or d8 (+rifampin 600 mg QD d1-9) of period 2. In study 3, futibatinib 20 mg was given on d1 of period 1 (-lansoprazole) and d5 of period 2 (+lansoprazole 60 mg QD d1-5). Plasma samples for PK assessment were collected predose through 24 h post-midazolam dosing (study 1) and predose through 48 h post-futibatinib dosing (studies 2 and 3). Results In study 1 (N=24), coadministration of futibatinib did not result in clinically significant changes in midazolam PK, based on the area under the concentration curve extrapolated to the last measurable time (AUC0-t; -9%) or infinity (AUC0-inf; -9%) or maximum plasma concentration (Cmax; -5%), compared with midazolam alone. In study 2 (N=40), relative to futibatinib administered alone, coadministration with itraconazole increased futibatinib Cmax (+51%) and plasma exposure (AUC0-t and AUC0-inf +41% each), whereas coadministration with rifampin decreased futibatinib Cmax (-53%) and plasma exposure (AUC0-t and AUC0-inf -64% each). In study 3 (N=20), coadministration of lansoprazole did not result in clinically significant changes in futibatinib PK parameters vs futibatinib alone (AUC0-t +5%; AUC0-inf +5%; Cmax +8%). Agents were well tolerated, and all 3 studies were completed with no clinically relevant safety signals. Conclusions Futibatinib is not expected to affect the exposure of concomitant medications metabolized via CYP3A, the most common drug metabolism pathway. Caution should be exercised when coadministering strong CYP3A inducers or inhibitors with futibatinib, as significant DDIs were observed with itraconazole and rifampin. Futibatinib can be concomitantly administered with PPIs with no clinically relevant impact on futibatinib exposure. Citation Format: Ikuo Yamamiya, John Laabs, Allen Hunt, Toru Takenaka, Daryl Sonnichsen, Mark Mina, Yaohua He, Karim Benhadji. Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT125.

Concomitant Use of Midostaurin with Strong CYP3A4 Inhibitors: An Analysis from the Ratify Trial

Introduction: Midostaurin is an oral multikinase inhibitor with activity in FMS-like tyrosine kinase 3 (FLT3 )-mutated acute myeloid leukemia (AML), including internal tandem duplications and tyrosine kinase domain mutations. The phase 3, double-blind, placebo-controlled, randomized RATIFY/CALGB (Alliance) 10603 trial investigated the effect of midostaurin in combination with standard chemotherapy and as single-agent maintenance therapy on outcomes in patients with newly diagnosed FLT3 -mutated AML. When added to standard chemotherapy, midostaurin improved both event-free survival (EFS) and overall survival (OS) (Stone et al, N Engl J Med. 2017 Jun 23. [Epub ahead of print]). Midostaurin is metabolized into 2 metabolites (CGP62221 and CGP52421) by cytochrome P450 3A4 (CYP3A4). We evaluated the effects of strong CYP3A4 inhibitors on midostaurin exposure, activity, and safety based on clinical data from the RATIFY trial.Methods: Patients received placebo or midostaurin 50 mg twice daily on days 8 to 21 of each 28-day induction or consolidation cycle, followed by 50 mg twice daily as a single agent on days 1 to 28 during the 12-cycle maintenance phase. Concomitant medication use was recorded for patients throughout all 3 treatment phases (induction, consolidation, and maintenance). Plasma levels of midostaurin and its metabolites were measured in a subset of 188 patients. Data on grade ≥3 adverse events (AEs) were collected at all sites; all grade 1/2 AE data were collected by sites outside the United States while only 13 prespecified grade 1/2 AEs were recorded at North American sites. The effect of CYP3A4 on efficacy was assessed using multiple endpoints including complete response, EFS, and OS.Results: Concomitant medication use was balanced between the midostaurin and placebo groups. Strong CYP3A4 inhibitors concurrently administered most frequently were the antifungal medications posaconazole and voriconazole. Strong CYP3A4 inhibitors were used in 60.8%, 45.6%, and 10.8% of patients during induction, consolidation, and maintenance, respectively.A 1.44-fold increase in midostaurin exposure (Cmin) was observed in patients receiving coadministration of strong CYP3A4 inhibitors compared with patients not receiving strong CYP3A4 inhibitors (number of patients: n=55 vs n=112, respectively). No relevant effect was observed with CGP62221 and CGP52421. Because the protocol did not include any recommendations for dose modifications when strong CYP3A4 inhibitors were administered, the median relative dose intensity of midostaurin was >94% of the intended dose in both treatment arms. There was no notable increase in midostaurin-related AEs in patients receiving strong CYP3A4 inhibitors. Exposure-safety analyses showed a slightly shorter time to occurrence of grade 3 or 4 clinically notable AEs with increasing exposure, with an overall acceptable safety profile for midostaurin. Exposure-response analyses indicated that a higher dose intensity was associated with a larger benefit to patients, namely through complete response, EFS and OS. This observation was generally not affected by demographic covariates or presence/absence of CYP3A4 perpetrators during the cycle where the PK sample was used for the analysis.Conclusions: Overall, co-administration of midostaurin with strong CYP3A4 inhibitors, without midostaurin dose adjustment, led to a balanced safety and efficacy profile. Because strong CYP3A4 inhibitors can increase the plasma concentration of midostaurin, caution is required when concomitantly prescribing these with midostaurin. Alternative medicinal products that do not strongly inhibit CYP3A4 activity should be considered. In situations in which satisfactory therapeutic alternatives do not exist, patients should be closely monitored for midostaurin-related toxicity.Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov identifier, NCT00651261. DisclosuresOuatas:Novartis: Employment. Duval:Novartis: Employment. Sinclair:Novartis: Employment. Berkowitz:Novartis: Employment.

CYP3A inhibitors and impact of these agents on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine on the VIALE-A study

CYP3A inhibitors and impact of these agents on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine on the VIALE-A study

Open-Label Assessment of the Effects of Itraconazole and Rifampicin on Balovaptan Pharmacokinetics in Healthy Volunteers.

Balovaptan, an investigational vasopressin 1a receptor antagonist that has been evaluated for improvement of social communication and interaction, is primarily metabolized by cytochrome P450 3A4 (CYP3A4). Two single-center, non-randomized, two-period, phase 1 studies assessed the effect of the strong CYP3A4 inhibitor itraconazole (study NCT03579719) or the strong CYP3A4 inducer rifampicin (study NCT03586726) at steady state on the pharmacokinetics (PK) of steady-state balovaptan in healthy volunteers. Participants received balovaptan (5 or 10mg/day) alone for 10days, or in combination with itraconazole (200mg/day) for 15days, or rifampicin (600mg/day) for 10days, following balovaptan washout and itraconazole/rifampicin pre-dosing. Geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the area under the concentration-time curve over the dosing interval (AUC) and maximum plasma concentration (Cmax) of balovaptan dosed with vs. without itraconazole/rifampicin were estimated from a mixed effects model. Both studies comprised 15-16 healthy male and female volunteers. Itraconazole 200mg/day elevated steady-state exposure to 5mg/day balovaptan approximately 4.5-5.5-fold (Day 15 GMR [90% CI], 4.46 [4.06-4.90] for Cmax and 5.57 [5.00-6.21] for AUC) and extended the time to steady state from ~ 5days to ~ 13-14days. Rifampicin 600mg/day resulted in ~ 90% reductions in both the Cmax (Day 10 GMR [90% CI], 0.14 [0.12-0.15]) and AUC (0.07 [0.06-0.07]) of balovaptan 10mg/day. Time to balovaptan steady state could not be determined with rifampicin. There were no clinically significant safety findings in either study. Strong modulators of CYP3A4 activity will significantly alter the PK of balovaptan, with the effect of CYP3A4 induction greater than that of inhibition. Caution should be taken when concomitantly dosing balovaptan with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors. NCT03579719; NCT03586726.

Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors.

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed‐effects modeling was conducted using NONMEM (v.7.3) and Perl‐speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful.

Exposure-Response of Quizartinib Efficacy in Patients with Relapsed/Refractory AML

Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that has shown clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3 internal tandem duplications in the phase 3 QuANTUM-R trial (Cortes et al, Lancet Oncol 2019; NCT02039726). In this analysis, exposure-response relationships of select efficacy endpoints of quizartinib were evaluated. Methods: Analysis was conducted for the following 2 studies separately: phase 2 study APS2689-CL-2004 and phase 3 QuANTUM-R study. Phase 2 study APS2689-CL-2004 enrolled 76 patients who were randomized to receive quizartinib 30 or 60 mg once daily (26.5 and 53.0 mg free base, respectively). Dose escalation was allowed and no dose reduction for strong cytochrome P450 3A (CYP3A) inhibitors was made in this study. In QuANTUM-R, 245 patients were randomized to receive quizartinib. The quizartinib dosing regimen was 30 mg/day and then escalated to 60 mg/day after 2 weeks if QTcF was ≤ 450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day, because concomitant use of a strong CYP3A inhibitor approximately doubles quizartinib exposure. Efficacy endpoints included in the analysis were rate of composite complete remission (CRc; complete remission (CR) + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery), duration of CRc, and overall survival (OS). Exposure measures in individual patients, such as average daily area under the curve (AUC), maximum concentration, and trough concentration, were obtained from a population pharmacokinetic analysis of quizartinib plasma concentration data (Kang et al, EHA 2019) and then used for correlating with the efficacy endpoints. Logistic regression analysis was used for CRc rate, and time-to-event analysis was performed for the duration of CRc and OS. The effect of quizartinib exposure on the percentage of subjects achieving bone marrow (aspirate) blasts of < 5% in QuANTUM-R was also assessed. Results: Patients were divided into 4 quartile groups according to average daily quizartinib AUC for the investigation of exposure-response relationships for OS and the duration of CRc. The lowest exposure quartile group showed shorter OS than the higher 3 quartile groups. The overall median OS from the intent-to-treat (ITT) population was 6.2 months in the phase 3 study; the median OS in the lowest exposure quartile group (Q1) was 4.5 months, whereas the median OS in the highest exposure quartile group (Q4) was 9.6 months (Fig. 1). Analysis of OS for the phase 2b study APS2689-CL-2004 demonstrated a similar trend, in which the lower AUC quartile demonstrated decreased OS. The overall OS from the ITT population was 5.2 months in the phase 2 study, and the median OS in Q1 and Q4 was 4.6 and 6.9 months, respectively (Fig. 2). Consistent with analyses for OS, the duration of CRc showed a trend of shorter duration of response in the lower AUC quartiles in both studies. Additionally, the lower AUC quartile appeared to result in a smaller proportion of subjects who achieved blast reduction of < 5% (ie, 33.3% in Q1 vs 45.6% to 52.6% in Q2 to Q4). However, no apparent trend of exposure-response relationship was shown for CRc (P > .05 from logistic regression analysis). Conclusions: Exposure-response analysis suggests a consistent trend for reduced clinical benefit at lower quizartinib AUC quartiles across various efficacy endpoints (but not CRc) in both the phase 2 and phase 3 studies. Current analysis supports the recommended dosing regimen of 30-mg starting dose with escalation to 60 mg as the target clinical dose. Figure Disclosures Kang: Daiichi Sankyo: Employment. Passarell:Cognigen Corporation: Employment. Abutarif:Daiichi Sankyo: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Yin:Daiichi Sankyo: Employment.